The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 12, 2018
REVIEW ARTICLE

Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout



Weifeng Zhu1, 2, Yan Deng2, 3, Xiaodong Zhou2, *
1 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Nanchang University, Nanchang, China
2 Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
3 Department of Ophthalmology of Children, The Second Affiliated Hospital of Nanchang University, Nanchang, China

Abstract

Gout is a common form of inflammatory arthritis caused by hyperuricemia and the deposition of Monosodium Urate (MSU) crystals. It is also considered as a complex disorder in which multiple genetic factors have been identified in association with its susceptibility and/or clinical outcomes. Major genes that were associated with gout include URAT1, GLUT9, OAT4, NPT1 (SLC17A1), NPT4 (SLC17A3), NPT5 (SLC17A4), MCT9, ABCG2, ABCC4, KCNQ1, PDZK1, NIPAL1, IL1β, IL-8, IL-12B, IL-23R, TNFA, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CD14, CARD8, P2X7R, EGF, A1CF, HNF4G and TRIM46, LRP2, GKRP, ADRB3, ADH1B, ALDH2, COMT, MAOA, PRKG2, WDR1, ALPK1, CARMIL (LRRC16A), RFX3, BCAS3, CNIH-2, FAM35A and MYL2-CUX2. The proteins encoded by these genes mainly function in urate transport, inflammation, innate immunity and metabolism. Understanding the functions of gout-associated genes will provide important insights into future studies to explore the pathogenesis of gout, as well as to develop targeted therapies for gout.

Keywords: Gout, Single nucleotide polymorphism, Genome-wide association study, Case-control study, Imume regulatory genes, MSU.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 94
Last Page: 113
Publisher Id: TORJ-12-94
DOI: 10.2174/1874312901812010094

Article History:

Received Date: 24/3/2018
Revision Received Date: 30/5/2018
Acceptance Date: 20/6/2018
Electronic publication date: 24/7/2018
Collection year: 2018

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© 2018 Zhu et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Internal Medicine/Rheumatology, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA; Tel: 713-500-6088; E-mail: xiaodong.zhou@uth.tmc.edu




1. INTRODUCTION

Gout is a chronic inflammatory arthritis resulting from high levels of serum urate (hyperuricemia) and monosodium urate crystal deposition in joints and soft tissues. The prevalence of gout is about 1-4% in the general population, and certain racial/ethnic groups may have a higher incidence such as 13.9% in Māori men in New Zealand [1Klemp P, Stansfield SA, Castle B, Robertson MC. Gout is on the increase in New Zealand. Ann Rheum Dis 1997; 56(1): 22-6.[http://dx.doi.org/10.1136/ard.56.1.22] [PMID: 9059136] ]. Urate is formed from dietary purines (about 20%) and catabolism of endogenously synthesized purines (about 80%). In humans, two thirds of urate are excreted from kidneys and the rest via intestine. The balance of the production and the secretion determines the level of serum urate. According to patient's fractional excretion of urate clearance (urate clearance/creatinine clearance ratio, FEUA) and Urinary Urate Excretion (UUE), gout is classified into two distinct types, Renal Overload (ROL) gout and Renal Underexcretion (RUE) gout [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ]. ROL gout results from urate overproduction and/or extra-renal underexcretion, both of which are characterized by increased UUE.

Genetic contribution to hyperuricemia and gout appears very complex [3Wilk JB, Djousse L, Borecki I, et al. Segregation analysis of serum uric acid in the NHLBI family heart study. Hum Genet 2000; 106(3): 355-9.[http://dx.doi.org/10.1007/s004390051050] [PMID: 10798367] , 4Reginato AM, Mount DB, Yang I, Choi HK. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 2012; 8(10): 610-21.[http://dx.doi.org/10.1038/nrrheum.2012.144] [PMID: 22945592] ]. Some rare monogenic metabolic disorders are associated with gout. For example, Hypoxanthine-Guanine Phosphoribosyltransferase (HPRT) deficiency [5Puig JG, Torres RJ, Mateos FA, et al. The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Baltimore) 2001; 80(2): 102-12.[http://dx.doi.org/10.1097/00005792-200103000-00003] [PMID: 11307586] , 6Kostalova E, Pavelka K, Vlaskova H, Musalkova D, Stiburkova B. Hyperuricemia and gout due to deficiency of hypoxanthine-guanine phosphoribosyltransferase in female carriers: New insight to differential diagnosis. Clin Chim Acta 2015; 440: 214-7.[http://dx.doi.org/10.1016/j.cca.2014.11.026] [PMID: 25476133] ] and Phosphoribosyl Pyrophosphate Synthetase 1 (PRPS1) superactivity [7Zoref E, De Vries A, Sperling O. Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts. J Clin Invest 1975; 56(5): 1093-9.[http://dx.doi.org/10.1172/JCI108183] [PMID: 171280] -9Mittal R, Patel K, Mittal J, et al. Association of PRPS1 mutations with disease phenotypes. Dis Markers 2015; 2015: 127013.[http://dx.doi.org/10.1155/2015/127013] [PMID: 26089585] ] result in uric acid overproduction, which leads to gout. HPRT1, an important enzyme in the salvage pathway of purine nucleotide synthesis, catalyzes hypoxanthine to Inosine Monophosphate (IMP) and guanine to Guanosine Monophosphate (GMP). PRPS1, a crucial enzyme in the de novo synthesis of purine nucleotide pathway, catalyzes Adenosine Triphosphate (ATP) and ribose-5- phophate to Phosphoribosylpyrophosphate (PRPP). At present, more than 600 mutations in HPRT1 gene [10Fu R, Ceballos-Picot I, Torres RJ, et al. Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 2014; 137(Pt 5): 1282-303.[http://dx.doi.org/10.1093/brain/awt202] [PMID: 23975452] ] and 9 mutations in PRPS1 gene associated with PRPS1 superactivity [9Mittal R, Patel K, Mittal J, et al. Association of PRPS1 mutations with disease phenotypes. Dis Markers 2015; 2015: 127013.[http://dx.doi.org/10.1155/2015/127013] [PMID: 26089585] , 11Porrmann J, Betcheva-Krajcir E, Di Donato N, et al. Novel PRPS1 gain-of-function mutation in a patient with congenital hyperuricemia and facial anomalies. Am J Med Genet A 2017; 173(10): 2736-42.[http://dx.doi.org/10.1002/ajmg.a.38359] [PMID: 28742244] ] have been reported.

Over the past 20 years, extensive studies have been performed in searching for genetic factors contributing to hyperuricemia and gout. In this review, we systemically reviewed original papers of genetic association studies of gout from November 2007 to March 2018 through PubMed, and summarized the genes with polymorphisms that have been reported in associations with gout. These genes are mainly involved in urate transport, inflammation, innate immunity and material metabolism. A complete list of gout-associated genes and genetic loci is summarized in Table 1.

Table 1
A complete list of gout-associated genes and genetic loci.


2. MEMBRANE TRANSPORTERS - SOLUTE CARRIER FAMILY

2.1. URAT1

Urate transporter 1 (URAT1), also known as solute carrier family 22, member 12 (SLC22A12), is a transmembrane protein on the proximal tubule apical surface. It mediates the re-absorption of uric acid from the proximal tubule [12Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417(6887): 447-52.[http://dx.doi.org/10.1038/nature742] [PMID: 12024214] ]. In the studies on gout patients from Japan [12Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417(6887): 447-52.[http://dx.doi.org/10.1038/nature742] [PMID: 12024214] -27Fujita K, Ichida K. A novel compound heterozygous mutation in the SLC22A12 (URAT1) gene in a Japanese patient associated with renal hypouricemia. Clin Chim Acta 2016; 463: 119-21.[http://dx.doi.org/10.1016/j.cca.2016.10.025] [PMID: 27780716] ], Korea [28Cheong HI, Kang JH, Lee JH, et al. Mutational analysis of idiopathic renal hypouricemia in Korea. Pediatr Nephrol 2005; 20(7): 886-90.[http://dx.doi.org/10.1007/s00467-005-1863-3] [PMID: 15912381] -30Kim HO, Ihm CG, Jeong KH, et al. A case report of familial renal hypouricemia confirmed by genotyping of SLC22A12, and a literature review. Electrolyte Blood Press 2015; 13(2): 52-7.[http://dx.doi.org/10.5049/EBP.2015.13.2.52] [PMID: 26848304] ], Iraq [31Dinour D, Bahn A, Ganon L, et al. URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant 2011; 26(7): 2175-81.[http://dx.doi.org/10.1093/ndt/gfq722] [PMID: 21148271] ], China [32Li Z, Ding H, Chen C, Chen Y, Wang DW, Lv Y. Novel URAT1 mutations caused acute renal failure after exercise in two Chinese families with renal hypouricemia. Gene 2013; 512(1): 97-101.[http://dx.doi.org/10.1016/j.gene.2012.09.115] [PMID: 23043931] ], and Czech Republic [33Stiburkova B, Sebesta I, Ichida K, et al. Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis. Eur J Hum Genet 2013; 21(10): 1067-73.[http://dx.doi.org/10.1038/ejhg.2013.3] [PMID: 23386035] , 34Mancikova A, Krylov V, Hurba O, et al. Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin Exp Nephrol 2016; 20(4): 578-84.[http://dx.doi.org/10.1007/s10157-015-1186-z] [PMID: 26500098] ], loss-of-function mutations of SLC22A12 (R90H, R92C, V138M, G164S, R203C, T217M, A226V, R228E, W258X, Q297X, E298D, Q312L, D313A, Q382L, R406C, M430T, L418R, G444R, R477H, A51fsX64, V547fsX602, L415_G417del, IVS2+1G>A, c.935_997delinsTGG) were associated with hypouricemia. Two frequent causative mutations, rs121907892 (W258X) [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 36Sakiyama M, Matsuo H, Shimizu S, et al. The effects of URAT1/SLC22A12 nonfunctional variants, R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression. Sci Rep 2016; 6: 20148.[http://dx.doi.org/10.1038/srep20148] [PMID: 26821810] ] and rs121907896 (R90H) [36Sakiyama M, Matsuo H, Shimizu S, et al. The effects of URAT1/SLC22A12 nonfunctional variants, R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression. Sci Rep 2016; 6: 20148.[http://dx.doi.org/10.1038/srep20148] [PMID: 26821810] ], appeared protective against gout, and were associated with a decreased urate-transport function [12Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417(6887): 447-52.[http://dx.doi.org/10.1038/nature742] [PMID: 12024214] , 14Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004; 15(1): 164-73.[http://dx.doi.org/10.1097/01.ASN.0000105320.04395.D0] [PMID: 14694169] ]. A study of a Spanish cohort showed that T allele of URAT1 rs11231825 (H142H) was associated with gout, in particular with patients who presented a reduced uric acid excretion [37Torres RJ, de Miguel E, Bailén R, Banegas JR, Puig JG. Tubular urate transporter gene polymorphisms differentiate patients with gout who have normal and decreased urinary uric acid excretion. J Rheumatol 2014; 41(9): 1863-70.[http://dx.doi.org/10.3899/jrheum.140126] [PMID: 25128519] ]. In addition, there are some other URAT1 SNPs examined, but achieved conflicting results from different study populations, such as rs475688 [38Tu HP, Chen CJ, Lee CH, et al. The SLC22A12 gene is associated with gout in han Chinese and Solomon Islanders. Ann Rheum Dis 2010; 69(6): 1252-4.[http://dx.doi.org/10.1136/ard.2009.114504] [PMID: 19762362] , 39Flynn TJ, Phipps-Green A, Hollis-Moffatt JE, et al. Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. Arthritis Res Ther 2013; 15(6): R220.[http://dx.doi.org/10.1186/ar4417] [PMID: 24360580] ], rs505802 [40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] , 41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] ] and rs2285340 [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ].

2.2. GLUT9

Glucose transporter type 9 (GLUT9), also known as solute carrier family 2 member 9 (SLC2A9), has two distinct isoforms based on the alternative splicing of the N-terminal, GLUT9-L and GLUT9ΔN [42Augustin R, Carayannopoulos MO, Dowd LO, Phay JE, Moley JF, Moley KH. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): Alternative splicing alters trafficking. J Biol Chem 2004; 279(16): 16229-36.[http://dx.doi.org/10.1074/jbc.M312226200] [PMID: 14739288] , 43Kimura T, Takahashi M, Yan K, Sakurai H. Expression of SLC2A9 isoforms in the kidney and their localization in polarized epithelial cells. PLoS One 2014; 9(1): e84996.[http://dx.doi.org/10.1371/journal.pone.0084996] [PMID: 24409316] ]. Loss-of-function mutations of SLC2A9 (W23X, G72D, L75R, Ile118HisfsX27, T125M, R171C, R198C, G207X, G216R, N333S, R380W,P412R, dupExon1a-11, delExon7, c.1215+1 G>A) could result in renal hypouricemia [24Kaito H, Ishimori S, Nozu K, et al. Molecular background of urate transporter genes in patients with exercise-induced acute kidney injury. Am J Nephrol 2013; 38(4): 316-20.[http://dx.doi.org/10.1159/000355430] [PMID: 24107611] , 34Mancikova A, Krylov V, Hurba O, et al. Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin Exp Nephrol 2016; 20(4): 578-84.[http://dx.doi.org/10.1007/s10157-015-1186-z] [PMID: 26500098] , 44Anzai N, Ichida K, Jutabha P, et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 2008; 283(40): 26834-8.[http://dx.doi.org/10.1074/jbc.C800156200] [PMID: 18701466] -56Windpessl M, Ritelli M, Wallner M, Colombi M. A novel homozygous SLC2A9 mutation associated with renal-induced hypouricemia. Am J Nephrol 2016; 43(4): 245-50.[http://dx.doi.org/10.1159/000445845] [PMID: 27116386] ]. Multiple genetic studies on GLUT9 gene have been conducted in gout. Rs734553 was associated with gout in German [41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] ] and Han Chinese male [40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] ] populations. Some of the reported gout-associated polymorphisms appeared inconsistent in different study populations. For instance, rs16890979 (V253I) was associated with gout in a Genome-Wide Association Study (GWAS) of US Caucasian [57Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: A genome-wide association study. Lancet 2008; 372(9654): 1953-61.[http://dx.doi.org/10.1016/S0140-6736(08)61343-4] [PMID: 18834626] ], which was replicated in the studies of New Zealand Māori, Pacific Island, Caucasian [58Hollis-Moffatt JE, Xu X, Dalbeth N, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum 2009; 60(11): 3485-92.[http://dx.doi.org/10.1002/art.24938] [PMID: 19877038] ], Spanish [37Torres RJ, de Miguel E, Bailén R, Banegas JR, Puig JG. Tubular urate transporter gene polymorphisms differentiate patients with gout who have normal and decreased urinary uric acid excretion. J Rheumatol 2014; 41(9): 1863-70.[http://dx.doi.org/10.3899/jrheum.140126] [PMID: 25128519] ] and Chinese [59Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.[http://dx.doi.org/10.1038/srep43614] [PMID: 28252667] ] cohorts, but inconsistent in some Asia cohort studies including Korean, Japanese male and Han Chinese male [60Kim YS, Kim Y, Park G, et al. Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population. Korean J Intern Med (Korean Assoc Intern Med) 2015; 30(6): 913-20.[http://dx.doi.org/10.3904/kjim.2015.30.6.913] [PMID: 26552468] -62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] ] populations and a Czech population [63Hurba O, Mancikova A, Krylov V, Pavlikova M, Pavelka K, Stibůrková B. Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout. PLoS One 2014; 9(9): e107902.[http://dx.doi.org/10.1371/journal.pone.0107902] [PMID: 25268603] ]. In addition, rs1014290 was associated with gout in British [64Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40(4): 437-42.[http://dx.doi.org/10.1038/ng.106] [PMID: 18327257] ], Japanese and Chinese populations [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] , 35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 61Urano W, Taniguchi A, Anzai N, et al. Association between GLUT9 and gout in Japanese men. Ann Rheum Dis 2010; 69(5): 932-3.[http://dx.doi.org/10.1136/ard.2009.111096] [PMID: 20413573] , 65Tu HP, Chen CJ, Tovosia S, et al. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann Rheum Dis 2010; 69(5): 887-90.[http://dx.doi.org/10.1136/ard.2009.113357] [PMID: 19723617] ], but the study in a Solomon Islanders population indicated a negative result [65Tu HP, Chen CJ, Tovosia S, et al. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann Rheum Dis 2010; 69(5): 887-90.[http://dx.doi.org/10.1136/ard.2009.113357] [PMID: 19723617] ]; rs6449213 in British [64Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40(4): 437-42.[http://dx.doi.org/10.1038/ng.106] [PMID: 18327257] ], German [66Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008; 3(4): e1948.[http://dx.doi.org/10.1371/journal.pone.0001948] [PMID: 18398472] ] and US [57Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: A genome-wide association study. Lancet 2008; 372(9654): 1953-61.[http://dx.doi.org/10.1016/S0140-6736(08)61343-4] [PMID: 18834626] ] populations, but not in Korean population [60Kim YS, Kim Y, Park G, et al. Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population. Korean J Intern Med (Korean Assoc Intern Med) 2015; 30(6): 913-20.[http://dx.doi.org/10.3904/kjim.2015.30.6.913] [PMID: 26552468] ]; rs3733591 (R265H) in Japanese male [61Urano W, Taniguchi A, Anzai N, et al. Association between GLUT9 and gout in Japanese men. Ann Rheum Dis 2010; 69(5): 932-3.[http://dx.doi.org/10.1136/ard.2009.111096] [PMID: 20413573] ] and Han Chinese [65Tu HP, Chen CJ, Tovosia S, et al. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann Rheum Dis 2010; 69(5): 887-90.[http://dx.doi.org/10.1136/ard.2009.113357] [PMID: 19723617] ] populations, but not in Solomon Islanders [65Tu HP, Chen CJ, Tovosia S, et al. Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann Rheum Dis 2010; 69(5): 887-90.[http://dx.doi.org/10.1136/ard.2009.113357] [PMID: 19723617] ], New Zealand Māori, Pacific Island, Caucasian [67Hollis-Moffatt JE, Gow PJ, Harrison AA, et al. The SLC2A9 nonsynonymous Arg265His variant and gout: Evidence for a population-specific effect on severity. Arthritis Res Ther 2011; 13(3): R85.[http://dx.doi.org/10.1186/ar3356] [PMID: 21658257] ] and inconsistent in Chinese populations [68Wan W, Xu X, Zhao DB, Pang YF, Wang YX. Polymorphisms of uric transporter proteins in the pathogenesis of gout in a Chinese Han population. Genet Mol Res 2015; 14(1): 2546-50.[http://dx.doi.org/10.4238/2015.March.30.13] [PMID: 25867401] , 69Zheng C, Yang H, Wang Q, Rao H, Diao Y. Association analysis of five SNP variants with gout in the Minnan population in China. Turk J Med Sci 2016; 46(2): 361-7.[http://dx.doi.org/10.3906/sag-1409-58] [PMID: 27511497] ]; rs6855911 in German [41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] , 66Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008; 3(4): e1948.[http://dx.doi.org/10.1371/journal.pone.0001948] [PMID: 18398472] ], not in a Chinese cohort [69Zheng C, Yang H, Wang Q, Rao H, Diao Y. Association analysis of five SNP variants with gout in the Minnan population in China. Turk J Med Sci 2016; 46(2): 361-7.[http://dx.doi.org/10.3906/sag-1409-58] [PMID: 27511497] ]; rs12510549 in German [66Stark K, Reinhard W, Neureuther K, et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study. PLoS One 2008; 3(4): e1948.[http://dx.doi.org/10.1371/journal.pone.0001948] [PMID: 18398472] ] and New Zealand Caucasian populations [58Hollis-Moffatt JE, Xu X, Dalbeth N, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum 2009; 60(11): 3485-92.[http://dx.doi.org/10.1002/art.24938] [PMID: 19877038] ], not in New Zealand Māori and Pacific Island populations [58Hollis-Moffatt JE, Xu X, Dalbeth N, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum 2009; 60(11): 3485-92.[http://dx.doi.org/10.1002/art.24938] [PMID: 19877038] ]; rs11722228 in a Han Chinese male cohort [62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] ], not in a Malaysian male cohort [70Das Gupta E, Sakthiswary R, Lee SL, Wong SF, Hussein H, Gun SC. Clinical significance of SLC2A9/GLUT9 rs11722228 polymorphisms in gout. Int J Rheum Dis 2018; 21(3): 705-9.[http://dx.doi.org/10.1111/1756-185X.12918] [PMID: 27456670] ]. The G allele of rs3775948 was reported as a risk to gout in a Japanese male [71Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.[http://dx.doi.org/10.1136/annrheumdis-2014-206191] [PMID: 25646370] ], but protective in a Han Chinese male cohort [62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] ]. A study on African American population showed that rs13129697 and rs7663032 were associated with gout [72Tin A, Woodward OM, Kao WH, et al. Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum Mol Genet 2011; 20(20): 4056-68.[http://dx.doi.org/10.1093/hmg/ddr307] [PMID: 21768215] ]. Rs5028843 and rs11942223 were associated with gout in New Zealander populations [58Hollis-Moffatt JE, Xu X, Dalbeth N, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum 2009; 60(11): 3485-92.[http://dx.doi.org/10.1002/art.24938] [PMID: 19877038] ]. Recently, a study showed that rs11942223 was not associated with tophi in people with gout in New Zealander populations [73He W, Phipps-Green A, Stamp LK, Merriman TR, Dalbeth N. Population-specific association between ABCG2 variants and tophaceous disease in people with gout. Arthritis Res Ther 2017; 19(1): 43.[http://dx.doi.org/10.1186/s13075-017-1254-8] [PMID: 28270222] ].In addition, the SNP rs13124007 at the promoter region was associated with gout in a Chinese male cohort [74Li C, Chu N, Wang B, et al. Polymorphisms in the presumptive promoter region of the SLC2A9 gene are associated with gout in a Chinese male population. PLoS One 2012; 7(2): e24561.[http://dx.doi.org/10.1371/journal.pone.0024561] [PMID: 22393348] ], and its C to G substitution led to a loss of a binding site for interferon regulatory factor 1 (IRF-1) [74Li C, Chu N, Wang B, et al. Polymorphisms in the presumptive promoter region of the SLC2A9 gene are associated with gout in a Chinese male population. PLoS One 2012; 7(2): e24561.[http://dx.doi.org/10.1371/journal.pone.0024561] [PMID: 22393348] ].

2.3. OAT4

Organic anion transporter 4 (OAT4), also named solute carrier family 22 member 11 (SLC22A11), is a low-affinity uric acid transporter [75Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol 2007; 18(2): 430-9.[http://dx.doi.org/10.1681/ASN.2006040415] [PMID: 17229912] ]. The G allele of rs17300741 was associated with RUE type gout in a Japanese cohort [76Sakiyama M, Matsuo H, Shimizu S, et al. A common variant of organic anion transporter 4 (OAT4/SLC22A11) gene is associated with renal underexcretion type gout. Drug Metab Pharmacokinet 2014; 29(2): 208-10.[http://dx.doi.org/10.2133/dmpk.DMPK-13-NT-070] [PMID: 24025986] ]. However, it was the A allele of this SNP in a Spanish cohort [37Torres RJ, de Miguel E, Bailén R, Banegas JR, Puig JG. Tubular urate transporter gene polymorphisms differentiate patients with gout who have normal and decreased urinary uric acid excretion. J Rheumatol 2014; 41(9): 1863-70.[http://dx.doi.org/10.3899/jrheum.140126] [PMID: 25128519] ], and no association was observed in Chinese [40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] , 68Wan W, Xu X, Zhao DB, Pang YF, Wang YX. Polymorphisms of uric transporter proteins in the pathogenesis of gout in a Chinese Han population. Genet Mol Res 2015; 14(1): 2546-50.[http://dx.doi.org/10.4238/2015.March.30.13] [PMID: 25867401] ], German [41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] ], New Zealander [39Flynn TJ, Phipps-Green A, Hollis-Moffatt JE, et al. Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects. Arthritis Res Ther 2013; 15(6): R220.[http://dx.doi.org/10.1186/ar4417] [PMID: 24360580] ] populations, and another Japanese male cohort [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] ].

2.4. NPT1 (SLC17A1)

Sodium-dependent phosphate cotransporter type 1 (NPT1) also named solute carrier family 17 member 1 (SLC17A1) is a member of the SLC17 phosphate transporter family [77Miyaji T, Kawasaki T, Togawa N, Omote H, Moriyama Y. Type 1 sodium-dependent phosphate transporter acts as a membrane potential-driven urate exporter. Curr Mol Pharmacol 2013; 6(2): 88-94.[http://dx.doi.org/10.2174/18744672113069990035] [PMID: 23876149] , 78Iharada M, Miyaji T, Fujimoto T, et al. Type 1 sodium-dependent phosphate transporter (SLC17A1 Protein) is a Cl(-)-dependent urate exporter. J Biol Chem 2010; 285(34): 26107-13.[http://dx.doi.org/10.1074/jbc.M110.122721] [PMID: 20566650] ]. It is located in the renal proximal tubule involved in urate excretion [79Sakiyama M, Matsuo H, Nagamori S, et al. Expression of a human NPT1/SLC17A1 missense variant which increases urate export. Nucleosides Nucleotides Nucleic Acids 2016; 35(10-12): 536-42.[http://dx.doi.org/10.1080/15257770.2016.1149192] [PMID: 27906618] ]. Genetic associations with gout were observed in several NPT1 SNPs. Rs3579352 was associated with gout in a Chinese cohort [59Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.[http://dx.doi.org/10.1038/srep43614] [PMID: 28252667] ]; rs1183201 in both cohorts of Chinese [40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] ] and New Zealander Caucasian [80Hollis-Moffatt JE, Phipps-Green AJ, Chapman B, et al. The renal urate transporter SLC17A1 locus: Confirmation of association with gout. Arthritis Res Ther 2012; 14(2): R92.[http://dx.doi.org/10.1186/ar3816] [PMID: 22541845] ], but which appeared conflicting in a German cohort [41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] ]; rs1165196 was associated with gout in Japanese male, Caucasian, Spanish cohorts [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 37Torres RJ, de Miguel E, Bailén R, Banegas JR, Puig JG. Tubular urate transporter gene polymorphisms differentiate patients with gout who have normal and decreased urinary uric acid excretion. J Rheumatol 2014; 41(9): 1863-70.[http://dx.doi.org/10.3899/jrheum.140126] [PMID: 25128519] , 80Hollis-Moffatt JE, Phipps-Green AJ, Chapman B, et al. The renal urate transporter SLC17A1 locus: Confirmation of association with gout. Arthritis Res Ther 2012; 14(2): R92.[http://dx.doi.org/10.1186/ar3816] [PMID: 22541845] , 81Urano W, Taniguchi A, Anzai N, et al. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis 2010; 69(6): 1232-4.[http://dx.doi.org/10.1136/ard.2008.106856] [PMID: 19556210] ], but not in a Chinese cohort [68Wan W, Xu X, Zhao DB, Pang YF, Wang YX. Polymorphisms of uric transporter proteins in the pathogenesis of gout in a Chinese Han population. Genet Mol Res 2015; 14(1): 2546-50.[http://dx.doi.org/10.4238/2015.March.30.13] [PMID: 25867401] ]. The SNPs rs1165196, rs1179086 and rs3757131 were associated with the development of gout in a Japanese male population [81Urano W, Taniguchi A, Anzai N, et al. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis 2010; 69(6): 1232-4.[http://dx.doi.org/10.1136/ard.2008.106856] [PMID: 19556210] ]. Among them, rs1165196 (I269T) is a missense variant, and 269T allele was correlated with an increased NPT1-mediated urate export [79Sakiyama M, Matsuo H, Nagamori S, et al. Expression of a human NPT1/SLC17A1 missense variant which increases urate export. Nucleosides Nucleotides Nucleic Acids 2016; 35(10-12): 536-42.[http://dx.doi.org/10.1080/15257770.2016.1149192] [PMID: 27906618] , 82Chiba T, Matsuo H, Kawamura Y, et al. NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout. Arthritis Rheumatol 2015; 67(1): 281-7.[http://dx.doi.org/10.1002/art.38884] [PMID: 25252215] ].

2.5. NPT4 (SLC17A3)

Sodium phosphate transporter 4 (NPT4) or solute carrier family 17 member 3 (SLC17A3) is a voltage-dependent efflux transport for urate, anionic compounds and drugs in renal proximal tubule cells [83Jutabha P, Anzai N, Kitamura K, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem 2010; 285(45): 35123-32.[http://dx.doi.org/10.1074/jbc.M110.121301] [PMID: 20810651] ]. The conflicting results were observed in studies of rs12664474 of the NPT4 gene in New Zealander, in which it was associated with gout in a Caucasian cohort, but not in three Polynesian cohorts [80Hollis-Moffatt JE, Phipps-Green AJ, Chapman B, et al. The renal urate transporter SLC17A1 locus: Confirmation of association with gout. Arthritis Res Ther 2012; 14(2): R92.[http://dx.doi.org/10.1186/ar3816] [PMID: 22541845] ]. In addition, rs1165205 was linked with gout in US Caucasians [57Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: A genome-wide association study. Lancet 2008; 372(9654): 1953-61.[http://dx.doi.org/10.1016/S0140-6736(08)61343-4] [PMID: 18834626] ], but it was not replicated in two Chinese cohorts [68Wan W, Xu X, Zhao DB, Pang YF, Wang YX. Polymorphisms of uric transporter proteins in the pathogenesis of gout in a Chinese Han population. Genet Mol Res 2015; 14(1): 2546-50.[http://dx.doi.org/10.4238/2015.March.30.13] [PMID: 25867401] , 69Zheng C, Yang H, Wang Q, Rao H, Diao Y. Association analysis of five SNP variants with gout in the Minnan population in China. Turk J Med Sci 2016; 46(2): 361-7.[http://dx.doi.org/10.3906/sag-1409-58] [PMID: 27511497] ].

2.6. NPT5 (SLC17A4)

Sodium/phosphate cotransporter homologue (NPT5) or solute carrier family 17 member 4 (SLC17A4) is an organic anion exporter located in the intestinal duct [84Togawa N, Miyaji T, Izawa S, Omote H, Moriyama Y. A Na+-phosphate cotransporter homologue (SLC17A4 protein) is an intestinal organic anion exporter. Am J Physiol Cell Physiol 2012; 302(11): C1652-60.[http://dx.doi.org/10.1152/ajpcell.00015.2012] [PMID: 22460716] ]. Similar to the studies of NPT4, conflicting results of NPT5 were observed in different populations. Rs9358890 was associated with gout in Chinese patients [59Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.[http://dx.doi.org/10.1038/srep43614] [PMID: 28252667] ], but not in New Zealander [80Hollis-Moffatt JE, Phipps-Green AJ, Chapman B, et al. The renal urate transporter SLC17A1 locus: Confirmation of association with gout. Arthritis Res Ther 2012; 14(2): R92.[http://dx.doi.org/10.1186/ar3816] [PMID: 22541845] ].

2.7. MCT9 (SLC16A9)

Monocarboxylate transporter 9 (MCT9) or solute carrier family 16 member 9 (SLC16A9) facilitates transportation of monocarboxylates such as lactate and pyruvate across plasma membrane [85Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation. Biochem J 1999; 343(Pt 2): 281-99.[http://dx.doi.org/10.1042/bj3430281] [PMID: 10510291] ]. Rs2242206 of SLC16A9 gene was associated with ROL gout but not with overall gout in a Japanese male cohort [86Nakayama A, Matsuo H, Shimizu T, et al. Common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility. Hum Cell 2013; 26(4): 133-6.[http://dx.doi.org/10.1007/s13577-013-0073-8] [PMID: 23990105] ].

3. ATP-BINDING CASSETTE TRANSPORTER FAMILY

3.1. ABCG2

The ATP-Binding Cassette subfamily G member 2 (ABCG2) protein, also known as breast cancer resistance protein (BCRP), is a member of the ATP-binding cassette family which transports a wide range of substrates [87Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport--an update. AAPS J 2015; 17(1): 65-82.[http://dx.doi.org/10.1208/s12248-014-9668-6] [PMID: 25236865] ]. It is highly expressed in the renal proximal tubular cells, the apical membrane of the intestinal epithelium and liver hepatocytes that regulate excretion of uric acid [88Woodward OM, Köttgen A, Coresh J, Boerwinkle E, Guggino WB, Köttgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA 2009; 106(25): 10338-42.[http://dx.doi.org/10.1073/pnas.0901249106] [PMID: 19506252] -90Hosomi A, Nakanishi T, Fujita T, Tamai I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PLoS One 2012; 7(2): e30456.[http://dx.doi.org/10.1371/journal.pone.0030456] [PMID: 22348008] ]. Several SNPs of the ABCG2 gene were associated with gout. Among them, rs2231137 (V12M), rs1481012 and rs3114018 were associated with gout in Chinese cohorts [59Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.[http://dx.doi.org/10.1038/srep43614] [PMID: 28252667] , 91Zhou D, Liu Y, Zhang X, et al. Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population. Int J Mol Sci 2014; 15(5): 9149-59.[http://dx.doi.org/10.3390/ijms15059149] [PMID: 24857923] -93Jiri M, Zhang L, Lan B, et al. Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population. Clin Rheumatol 2016; 35(1): 159-63.[http://dx.doi.org/10.1007/s10067-015-3105-9] [PMID: 26506822] ]; rs2728125 in a Japanese cohort [71Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.[http://dx.doi.org/10.1136/annrheumdis-2014-206191] [PMID: 25646370] ]; and rs72552713 (Q126X) in both Japanese male and Chinese male cohorts [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 91Zhou D, Liu Y, Zhang X, et al. Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population. Int J Mol Sci 2014; 15(5): 9149-59.[http://dx.doi.org/10.3390/ijms15059149] [PMID: 24857923] , 94Matsuo H, Takada T, Ichida K, et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: A function-based genetic analysis in a Japanese population. Sci Transl Med 2009; 1(5): 5ra11.[http://dx.doi.org/10.1126/scitranslmed.3000237] [PMID: 20368174] , 95Higashino T, Takada T, Nakaoka H, et al. Multiple common and rare variants of ABCG2 cause gout. RMD Open 2017; 3(2): e000464.[http://dx.doi.org/10.1136/rmdopen-2017-000464] [PMID: 29225919] ]. The conflicting results were observed in a study of rs3114020, in which the risk allele was C allele in a Japanese male cohort [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ], but T allele in a Han Chinese cohort [93Jiri M, Zhang L, Lan B, et al. Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population. Clin Rheumatol 2016; 35(1): 159-63.[http://dx.doi.org/10.1007/s10067-015-3105-9] [PMID: 26506822] ].

The SNP rs2231142 (Q141K) of the ABCG2 gene was extensively investigated. It was associated with gout in multiple studies of different ethnic populations [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 37Torres RJ, de Miguel E, Bailén R, Banegas JR, Puig JG. Tubular urate transporter gene polymorphisms differentiate patients with gout who have normal and decreased urinary uric acid excretion. J Rheumatol 2014; 41(9): 1863-70.[http://dx.doi.org/10.3899/jrheum.140126] [PMID: 25128519] , 41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] , 57Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: A genome-wide association study. Lancet 2008; 372(9654): 1953-61.[http://dx.doi.org/10.1016/S0140-6736(08)61343-4] [PMID: 18834626] , 60Kim YS, Kim Y, Park G, et al. Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population. Korean J Intern Med (Korean Assoc Intern Med) 2015; 30(6): 913-20.[http://dx.doi.org/10.3904/kjim.2015.30.6.913] [PMID: 26552468] , 68Wan W, Xu X, Zhao DB, Pang YF, Wang YX. Polymorphisms of uric transporter proteins in the pathogenesis of gout in a Chinese Han population. Genet Mol Res 2015; 14(1): 2546-50.[http://dx.doi.org/10.4238/2015.March.30.13] [PMID: 25867401] , 69Zheng C, Yang H, Wang Q, Rao H, Diao Y. Association analysis of five SNP variants with gout in the Minnan population in China. Turk J Med Sci 2016; 46(2): 361-7.[http://dx.doi.org/10.3906/sag-1409-58] [PMID: 27511497] , 71Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.[http://dx.doi.org/10.1136/annrheumdis-2014-206191] [PMID: 25646370] , 72Tin A, Woodward OM, Kao WH, et al. Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum Mol Genet 2011; 20(20): 4056-68.[http://dx.doi.org/10.1093/hmg/ddr307] [PMID: 21768215] , 88Woodward OM, Köttgen A, Coresh J, Boerwinkle E, Guggino WB, Köttgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA 2009; 106(25): 10338-42.[http://dx.doi.org/10.1073/pnas.0901249106] [PMID: 19506252] , 91Zhou D, Liu Y, Zhang X, et al. Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population. Int J Mol Sci 2014; 15(5): 9149-59.[http://dx.doi.org/10.3390/ijms15059149] [PMID: 24857923] , 92Yu KH, Chang PY, Chang SC, et al. A comprehensive analysis of the association of common variants of ABCG2 with gout. Sci Rep 2017; 7(1): 9988.[http://dx.doi.org/10.1038/s41598-017-10196-2] [PMID: 28855613] , 94Matsuo H, Takada T, Ichida K, et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: A function-based genetic analysis in a Japanese population. Sci Transl Med 2009; 1(5): 5ra11.[http://dx.doi.org/10.1126/scitranslmed.3000237] [PMID: 20368174] -98Zhang L, Spencer KL, Voruganti VS, et al. Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. Am J Epidemiol 2013; 177(9): 923-32.[http://dx.doi.org/10.1093/aje/kws330] [PMID: 23552988] ], except in a New Zealand Māori [97Phipps-Green AJ, Hollis-Moffatt JE, Dalbeth N, et al. A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Māori, case and control sample sets. Hum Mol Genet 2010; 19(24): 4813-9.[http://dx.doi.org/10.1093/hmg/ddq412] [PMID: 20858603] ] and a Han Chinese cohort [93Jiri M, Zhang L, Lan B, et al. Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population. Clin Rheumatol 2016; 35(1): 159-63.[http://dx.doi.org/10.1007/s10067-015-3105-9] [PMID: 26506822] ]. Compared to the wild-type of rs2231142 Q141, the K141 was correlated to a 54% reduction of urate transport rates [88Woodward OM, Köttgen A, Coresh J, Boerwinkle E, Guggino WB, Köttgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci USA 2009; 106(25): 10338-42.[http://dx.doi.org/10.1073/pnas.0901249106] [PMID: 19506252] ]. Furthermore, this SNP was reported as an important influence factor of drug response [99Tomlinson B, Hu M, Lee VW, et al. ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther 2010; 87(5): 558-62.[http://dx.doi.org/10.1038/clpt.2009.232] [PMID: 20130569] -102Roberts RL, Wallace MC, Phipps-Green AJ, et al. ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout. Pharmacogenomics J 2017; 17(2): 201-3.[http://dx.doi.org/10.1038/tpj.2015.101] [PMID: 26810134] ]. For example, the T allele of rs2231142 was associated with a reduced response and a poor response to allopurinol [101Wen CC, Yee SW, Liang X, et al. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther 2015; 97(5): 518-25.[http://dx.doi.org/10.1002/cpt.89] [PMID: 25676789] , 102Roberts RL, Wallace MC, Phipps-Green AJ, et al. ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout. Pharmacogenomics J 2017; 17(2): 201-3.[http://dx.doi.org/10.1038/tpj.2015.101] [PMID: 26810134] ].

3.2. ABCC4

The ATP-binding cassette subfamily C member 4 (ABCC4) or Multidrug Resistance Protein 4 (MRP4) is an ATP-dependent unidirectional efflux transport for urate [103Van Aubel RA, Smeets PH, van den Heuvel JJ, Russel FG. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol 2005; 288(2): F327-33.[http://dx.doi.org/10.1152/ajprenal.00133.2004] [PMID: 15454390] ]. A study in New Zealand Māori and Pacific populations showed that rs4148500 was significantly associated with gout, as well as with reduced fractional excretion of uric acid in men [104Tanner C, Boocock J, Stahl EA, et al. Population-specific resequencing associates the ATP-binding cassette subfamily C member 4 gene with gout in New Zealand Māori and pacific men. Arthritis Rheumatol 2017; 69(7): 1461-9.[http://dx.doi.org/10.1002/art.40110] [PMID: 28371506] ].

4. OTHER MEMBRANE TRANSPORTERS

4.1. KCNQ1

KCNQ1, a potassium voltage-gated channel protein that forms a functional potassium selective pore [105Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996; 384(6604): 80-3.[http://dx.doi.org/10.1038/384080a0] [PMID: 8900283] ] and plays crucial roles in cardiac rhythm and extra-cardiac effects such as secretion of insulin [106Yamagata K, Senokuchi T, Lu M, et al. Voltage-gated K+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line. Biochem Biophys Res Commun 2011; 407(3): 620-5.[http://dx.doi.org/10.1016/j.bbrc.2011.03.083] [PMID: 21426901] ]. Mutations in KCNQ1 gene were associated with congenital Long QT Syndrome (LQTS) and some variants were associated with diabetes. The GWAS in a Han Chinese male cohort showed that rs179785 of the KCNQ1 gene was associated with gout [107Li C, Li Z, Liu S, et al. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese. Nat Commun 2015; 6: 7041.[http://dx.doi.org/10.1038/ncomms8041] [PMID: 25967671] ].

4.2. PDZK1

PDZ Domain containing 1(PDZK1) is a scaffolding protein that interacts with many proteins at the plasma membrane, including urate transporter [108Anzai N, Jutabha P, Amonpatumrat-Takahashi S, Sakurai H. Recent advances in renal urate transport: Characterization of candidate transporters indicated by genome-wide association studies. Clin Exp Nephrol 2012; 16(1): 89-95.[http://dx.doi.org/10.1007/s10157-011-0532-z] [PMID: 22038265] ]. The SNPs rs1967017 and rs12129861 of the PDZK1 gene were associated with gout in men of Han Chinese [109Li M, Li Q, Li CG, et al. Genetic polymorphisms in the PDZK1 gene and susceptibility to gout in male Han Chinese: A case-control study. Int J Clin Exp Med 2015; 8(8): 13911-8.[PMID: 26550347] ]. The former was replicated in a New Zealand study [110Phipps-Green AJ, Merriman ME, Topless R, et al. Twenty-eight loci that influence serum urate levels: analysis of association with gout. Ann Rheum Dis 2016; 75(1): 124-30.[http://dx.doi.org/10.1136/annrheumdis-2014-205877] [PMID: 25187157] ], but was conflict in two US studies [111Reynolds RJ, Vazquez AI, Srinivasasainagendra V, et al. Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index. Rheumatol Int 2016; 36(2): 263-70.[http://dx.doi.org/10.1007/s00296-015-3364-4] [PMID: 26427508] , 112Yang Q, Köttgen A, Dehghan A, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 2010; 3(6): 523-30.[http://dx.doi.org/10.1161/CIRCGENETICS.109.934455] [PMID: 20884846] ]. The latter was concordant in one Japanese cohort [113Higashino T, Matsuo H, Sakiyama M, et al. Common variant of PDZ domain containing 1 (PDZK1) gene is associated with gout susceptibility: A replication study and meta-analysis in Japanese population. Drug Metab Pharmacokinet 2016; 31(6): 464-6.[http://dx.doi.org/10.1016/j.dmpk.2016.07.004] [PMID: 27720648] ], but discordant with other 4 studies in Japanese male, Han Chinese male, and German cohorts [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] , 41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] , 114Takada Y, Matsuo H, Nakayama A, et al. Common variant of PDZK1, adaptor protein gene of urate transporters, is not associated with gout. J Rheumatol 2014; 41(11): 2330-1.[http://dx.doi.org/10.3899/jrheum.140573] [PMID: 25362723] ].

4.3. NIPAL1

The Nipa-Like Domain containing 1 (NIPAL1), also known as NIPA3, is a magnesium transporter [115Goytain A, Hines RM, Quamme GA. Functional characterization of NIPA2, a selective Mg2+ transporter. Am J Physiol Cell Physiol 2008; 295(4): C944-53.[http://dx.doi.org/10.1152/ajpcell.00091.2008] [PMID: 18667602] ]. The GWAS in Japanese male cohort showed that rs11733284 of NIPAL1 gene was associated with renal underexcretion gout [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ]. Although NIPAL1 was not a urate transporter, it might be involved in the indirect regulation of urate transport kinetics [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ].

5. INTERLEUKIN FAMILY AND OTHER INFLAMMATORY RESPONDING GENES

5.1. IL1β and CD14

Interleukin-1β (IL1β) is an inflammatory cytokine. It plays a key role in sustaining inflammation in multiple inflammatory diseases, such as gout and atherosclerosis [116Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 receptor-interleukin-1 Liaison. Front Pharmacol 2017; 8: 123.[http://dx.doi.org/10.3389/fphar.2017.00123] [PMID: 28360855] ]. CD14 is a lipopolysaccharide-binding protein, which functions as an endotoxin receptor. It is critical for TLR2-mediated M1 macrophage activation [117da Silva TA, Zorzetto-Fernandes ALV, Cecílio NT, Sardinha-Silva A, Fernandes FF, Roque-Barreira MC. CD14 is critical for TLR2-mediated M1 macrophage activation triggered by N-glycan recognition. Sci Rep 2017; 7(1): 7083.[http://dx.doi.org/10.1038/s41598-017-07397-0] [PMID: 28765651] ]. IL1B rs1143623 and CD14 rs2569190 were associated with gout in a study of European and New Zealand Polynesian populations [118McKinney C, Stamp LK, Dalbeth N, et al. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout. Arthritis Res Ther 2015; 17: 288.[http://dx.doi.org/10.1186/s13075-015-0802-3] [PMID: 26462562] ]. It was reported that bothrs1143623 and rs2569190 can affect transcriptional activities of their own promoter [119Chen H, Wilkins LM, Aziz N, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet 2006; 15(4): 519-29.[http://dx.doi.org/10.1093/hmg/ddi469] [PMID: 16399797] , 120LeVan TD, Bloom JW, Bailey TJ, et al. A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 2001; 167(10): 5838-44.[http://dx.doi.org/10.4049/jimmunol.167.10.5838] [PMID: 11698458] ].

5.2. IL-8

Interleukin-8 (IL-8), a member of the CXC chemokine superfamily, is a macrophage-secreted chemokine that recruits neutrophils and causes angiogenesis. Rs4073 (-251T/A) was associated with gout in two Chinese cohorts [121Liu S, Yin C, Chu N, Han L, Li C. IL-8 -251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population. Scand J Rheumatol 2013; 42(2): 150-8.[http://dx.doi.org/10.3109/03009742.2012.726372] [PMID: 23441821] , 122Cui YX, Zhao H, Guo HQ. Role of IL-8 rs4073 and rs2227306 polymorphisms in the development of primary gouty arthritis in a Chinese population. Genet Mol Res 2016; 15(4)[http://dx.doi.org/10.4238/gmr15048511] [PMID: 27813564] ]. Functionally, compared with the T allele, the A allele of rs4073 was correlated with an enhanced transcriptional promoter activity in response to TNF-ɑ or IL-1β [123Ohyauchi M, Imatani A, Yonechi M, et al. The polymorphism interleukin 8 -251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut 2005; 54(3): 330-5.[http://dx.doi.org/10.1136/gut.2003.033050] [PMID: 15710978] ].

5.3. IL-12B

IL-12, a heterodimer of p35 subunit (encoded by IL-12A gene) and p40 subunit (encoded by IL-12B gene), plays an important role in antibody-induced joint inflammation [124Kim HS, Chung DH. TLR4-mediated IL-12 production enhances IFN-γ and IL-1β production, which inhibits TGF-β production and promotes antibody-induced joint inflammation. Arthritis Res Ther 2012; 14(5): R210.[http://dx.doi.org/10.1186/ar4048] [PMID: 23036692] ]. A study of a Chinese cohort showed that rs3212227 (1188A/C) of the IL-12B gene was associated with gout [121Liu S, Yin C, Chu N, Han L, Li C. IL-8 -251T/A and IL-12B 1188A/C polymorphisms are associated with gout in a Chinese male population. Scand J Rheumatol 2013; 42(2): 150-8.[http://dx.doi.org/10.3109/03009742.2012.726372] [PMID: 23441821] ]. Another study indicated that this SNP was correlated with an enhanced IL-12 production [125Seegers D, Zwiers A, Strober W, Peña AS, Bouma G. A TaqI polymorphism in the 3'UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 2002; 3(7): 419-23.[http://dx.doi.org/10.1038/sj.gene.6363919] [PMID: 12424624] ].

5.4. IL-23R

IL-23R is the receptor of IL-23. The binding of IL-23 to its receptor is believed to play an important role in driving gouty inflammation by production of inflammatory factors, such as IL-1 and TNF-ɑ [126Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: A key cytokine in inflammatory diseases. Ann Med 2011; 43(7): 503-11.[http://dx.doi.org/10.3109/07853890.2011.577093] [PMID: 21585245] ]. Rs7517847 and rs10889677 of the IL-23R gene were associated with gout in studies of Chinese Han male cohorts [127Liu S, He H, Yu R, et al. The rs7517847 polymorphism in the IL-23R gene is associated with gout in a Chinese Han male population. Mod Rheumatol 2015; 25(3): 449-52.[http://dx.doi.org/10.3109/14397595.2014.964823] [PMID: 25661540] , 128Liu S, Zhou Z, Wang C, Guo M, Chu N, Li C. Associations between interleukin and interleukin receptor gene polymorphisms and risk of gout. Sci Rep 2015; 5: 13887.[http://dx.doi.org/10.1038/srep13887] [PMID: 26399911] ].

5.5. TNF-A, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CARD8 and P2X7R

Tumor Necrosis Factor-ɑ (TNF-ɑ) is a proinflammatory cytokine mediating inflammation and apoptosis [129Yokose K, Sato S, Asano T, et al. TNF-ɑ potentiates uric acid-induced interleukin-1β (IL-1β) secretion in human neutrophils. Mod Rheumatol 2017; 1-5.[PMID: 28880687] ]. A promoter region SNP of the TNF-A gene rs1800630 (-863C/A) was associated with gout in a male Chinese cohort [130Chang SJ, Tsai PC, Chen CJ, Lai HM, Ko YC. The polymorphism -863C/A in tumour necrosis factor-alpha gene contributes an independent association to gout. Rheumatology (Oxford) 2007; 46(11): 1662-6.[http://dx.doi.org/10.1093/rheumatology/kem235] [PMID: 17938134] ].

Monocyte Chemoattractant Protein 1 (MCP-1), also known as CCL2 (CC chemokine ligand 2) is an important member of the C-C (Cysteine-Cysteine) chemokine family and plays a crucial role in the recruitment of monocytes, memory T cells, and basophils into inflamed tissues. A functional SNP in CCL2 gene promoter region, rs1024611 (-2518A/G) was associated with gout in a study of a Chinese male cohort [131Sun R, Zhang K, Zhang X, et al. The CC chemokine ligand 2 (CCL2) polymorphism -2518A/G is associated with gout in the Chinese Han male population. Rheumatol Int 2015; 35(3): 479-84.[http://dx.doi.org/10.1007/s00296-014-3102-3] [PMID: 25119828] ]. This SNP was reported to impact CCL2 expression in patients with Systemic Sclerosis (SSc) [132Karrer S, Bosserhoff AK, Weiderer P, et al. The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis. J Invest Dermatol 2005; 124(1): 92-8.[http://dx.doi.org/10.1111/j.0022-202X.2004.23512.x] [PMID: 15654958] ].

Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) is a component of NLRP3 inflammasome that mediates innate inflammatory responses, and is involved in onset and progression of various diseases, including metabolic disorders, as well as auto-immune and auto-inflammatory diseases [133Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases. Clin Exp Rheumatol 2016; 34(4)(Suppl. 98): 12-6.[PMID: 27586797] , 134So AK, Martinon F. Inflammation in gout: Mechanisms and therapeutic targets. Nat Rev Rheumatol 2017; 13(11): 639-47.[http://dx.doi.org/10.1038/nrrheum.2017.155] [PMID: 28959043] ]. The NLRP3 rs3806268 was associated with primary gout in a Chinese cohort [135Deng J, Lin W, Chen Y, et al. rs3806268 of NLRP3 gene polymorphism is associated with the development of primary gout. Int J Clin Exp Pathol 2015; 8(10): 13747-52.[PMID: 26722603] ].

Peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1β (PPARGC1B) is a transcriptional coactivator of PPARγ that inhibits proinflammatory cytokine production [136Vats D, Mukundan L, Odegaard JI, et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 2006; 4(1): 13-24.[http://dx.doi.org/10.1016/j.cmet.2006.05.011] [PMID: 16814729] ]. Rs45520937 of the PPARGC1B gene was associated with gout in a Chinese cohort [137Chang WC, Jan Wu YJ, Chung WH, et al. Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis. Rheumatology (Oxford) 2017; 56(3): 457-66.[PMID: 28394398] ], and the A allele of this SNP was found to significantly augment the expression of NLRP3 and IL-1β [137Chang WC, Jan Wu YJ, Chung WH, et al. Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis. Rheumatology (Oxford) 2017; 56(3): 457-66.[PMID: 28394398] ].

Toll-like receptor 4 (TLR4) plays a crucial role in MSU-mediated inflammatory disease [138Qing YF, Zhang QB, Zhou JG, Jiang L. Changes in toll-like receptor (TLR)4-NFκB-IL1β signaling in male gout patients might be involved in the pathogenesis of primary gouty arthritis. Rheumatol Int 2014; 34(2): 213-20.[http://dx.doi.org/10.1007/s00296-013-2856-3] [PMID: 24036988] , 139Xiao J, Zhang XL, Fu C, et al. Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. Int J Mol Med 2015; 35(5): 1347-54.[http://dx.doi.org/10.3892/ijmm.2015.2148] [PMID: 25813103] ]. A suggestive association of the TLR4 rs2149356 was first reported in a study of a Chinese cohort [140Qing YF, Zhou JG, Zhang QB, et al. Association of TLR4 Gene rs2149356 polymorphism with primary gouty arthritis in a case-control study. PLoS One 2013; 8(5): e64845.[http://dx.doi.org/10.1371/journal.pone.0064845] [PMID: 23738004] ]. It was then reexamined in European and New Zealand Polynesian cohorts. However, the former indicated a gout-risk T allele of rs2149356 that appeared protective in the latter [141Rasheed H, McKinney C, Stamp LK, et al. The Toll-Like receptor 4 (TLR4) variant rs2149356 and risk of gout in European and Polynesian sample sets. PLoS One 2016; 11(1): e0147939.[http://dx.doi.org/10.1371/journal.pone.0147939] [PMID: 26808548] ].

Caspase activation and recruitment domain 8 (CARD8) is involved in innate immunity including the suppression of IL-1β expression and NF-κB (nuclear factor κB) activation [142Fontalba A, Martinez-Taboada V, Gutierrez O, et al. Deficiency of the NF-kappaB inhibitor caspase activating and recruitment domain 8 in patients with rheumatoid arthritis is associated with disease severity. J Immunol 2007; 179(7): 4867-73.[http://dx.doi.org/10.4049/jimmunol.179.7.4867] [PMID: 17878386] , 143Paramel GV, Folkersen L, Strawbridge RJ, et al. CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation. Clin Sci (Lond) 2013; 125(8): 401-7.[http://dx.doi.org/10.1042/CS20120572] [PMID: 23611467] ]. The CARD8 rs2043211 (C10X) is a nonsense variant that causes the expression of a truncated protein CARD8-S leading to loss of inhibitory function on NF-κB transcriptional activity [142Fontalba A, Martinez-Taboada V, Gutierrez O, et al. Deficiency of the NF-kappaB inhibitor caspase activating and recruitment domain 8 in patients with rheumatoid arthritis is associated with disease severity. J Immunol 2007; 179(7): 4867-73.[http://dx.doi.org/10.4049/jimmunol.179.7.4867] [PMID: 17878386] ]. It was associated with gout in a European cohort [118McKinney C, Stamp LK, Dalbeth N, et al. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout. Arthritis Res Ther 2015; 17: 288.[http://dx.doi.org/10.1186/s13075-015-0802-3] [PMID: 26462562] ], but which was not concordant with the results from the studies in New Zealand Polynesian, Chinese male and Korean Men cohorts [118McKinney C, Stamp LK, Dalbeth N, et al. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout. Arthritis Res Ther 2015; 17: 288.[http://dx.doi.org/10.1186/s13075-015-0802-3] [PMID: 26462562] , 144Chen Y, Ren X, Li C, et al. CARD8 rs2043211 polymorphism is associated with gout in a Chinese male population. Cell Physiol Biochem 2015; 35(4): 1394-400.[http://dx.doi.org/10.1159/000373960] [PMID: 25790751] , 145Lee SW, Lee SS, Oh DH, et al. Genetic association for P2X7R rs3751142 and CARD8 rs2043211 polymorphisms for susceptibility of gout in Korean men: Multi-center study. J Korean Med Sci 2016; 31(10): 1566-70.[http://dx.doi.org/10.3346/jkms.2016.31.10.1566] [PMID: 27550484] ]. In addition, there was a significant multiplicative interaction between CARD8 rs2043211 and IL1B rs1143623 that appeared to amplify gout risk [118McKinney C, Stamp LK, Dalbeth N, et al. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout. Arthritis Res Ther 2015; 17: 288.[http://dx.doi.org/10.1186/s13075-015-0802-3] [PMID: 26462562] ]

Purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) is an ATP gated ion channel expressed in immune cells, and participates in process of activating inflammation [116Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 receptor-interleukin-1 Liaison. Front Pharmacol 2017; 8: 123.[http://dx.doi.org/10.3389/fphar.2017.00123] [PMID: 28360855] ]. It was suggested that the P2X7R/NLRP3/IL-1β pathway is involved in many inflammatory diseases including gout [116Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 receptor-interleukin-1 Liaison. Front Pharmacol 2017; 8: 123.[http://dx.doi.org/10.3389/fphar.2017.00123] [PMID: 28360855] , 146Gicquel T, Robert S, Loyer P, et al. IL-1β production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J 2015; 29(10): 4162-73.[http://dx.doi.org/10.1096/fj.14-267393] [PMID: 26116704] ]. Rs1653624, rs7958316 and rs17525809 of the P2X7R gene were associated with gout in a Chinese cohort [147Tao JH, Cheng M, Tang JP, et al. Single nucleotide polymorphisms associated with P2X7R function regulate the onset of gouty arthritis. PLoS One 2017; 12(8): e0181685.[http://dx.doi.org/10.1371/journal.pone.0181685] [PMID: 28797095] ].

6. CELL PROLIFERATION, DIFFERENTIATION AND MIGRATION

6.1. EGF, A1CF, HNF4G and TRIM46

Epidermal Growth Factor (EGF), a ligand of EGF Receptor (EGFR), plays important roles in cell proliferation, differentiation and migration [148Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol 2014; 28: 2-11.[http://dx.doi.org/10.1016/j.semcdb.2014.01.011] [PMID: 24513230] ]. Apobec-1 Complementation Factor (A1CF), a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family that function in cell migration and survival [149Yan X, Li Q, Ni D, et al. Apobec-1 complementation factor regulates cell migration and apoptosis through Dickkopf1 by acting on its 3′ untranslated region in MCF7 cells. Tumour Biol 2017; 39(6): 1010428317706218.[http://dx.doi.org/10.1177/1010428317706218] [PMID: 28639893] ]. Hepatocyte nuclear factor 4 gamma (HNF4G) is an orphan member of the nuclear receptor subfamily [150Drewes T, Senkel S, Holewa B, Ryffel GU. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol 1996; 16(3): 925-31.[http://dx.doi.org/10.1128/MCB.16.3.925] [PMID: 8622695] ]. In bladder cancer cells, miR-34a-HNF4G axis is an important pathway regulating cell viability, proliferation, and invasion [151Sun H, Tian J, Xian W, Xie T, Yang X. miR-34a inhibits proliferation and invasion of bladder cancer cells by targeting orphan nuclear receptor HNF4G. Dis Markers 2015; 2015: 879254.[http://dx.doi.org/10.1155/2015/879254] [PMID: 25878394] ]. The protein tripartite motif 46 (TRIM46) is a member of the tripartite motif-containing protein family, which involved in many biological processes, including transcriptional regulation, cell differentiation, apoptosis, and signaling pathways [152McNab FW, Rajsbaum R, Stoye JP, O’Garra A. Tripartite-motif proteins and innate immune regulation. Curr Opin Immunol 2011; 23(1): 46-56.[http://dx.doi.org/10.1016/j.coi.2010.10.021] [PMID: 21131187] ]. A study in a male Chinese population linked rs2298999 of EGF gene with gout [153Han L, Cao C, Jia Z, et al. Epidermal growth factor gene is a newly identified candidate gene for gout. Sci Rep 2016; 6: 31082.[http://dx.doi.org/10.1038/srep31082] [PMID: 27506295] ]. Another Chinese study showed that rs10821905 of A1CF gene, rs2941484 of HNF4G gene, and rs4971101 and rs2070803 of TRIM46 gene were associated with susceptibility to gout [59Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.[http://dx.doi.org/10.1038/srep43614] [PMID: 28252667] ].

7. METABOLISM AND ENZYMES

7.1. LRP2

Low-density Lipoprotein Receptor-Related Protein 2 (LRP2), also known as megalin, is a member of the Low-Density Lipoprotein Receptor (LDLR) family that functions in lipid metabolism and signal transduction [154Christensen EI, Birn H. Megalin and cubilin: Multifunctional endocytic receptors. Nat Rev Mol Cell Biol 2002; 3(4): 256-66.[http://dx.doi.org/10.1038/nrm778] [PMID: 11994745] ]. The LRP2 rs2544390 was examined for association with gout in Japanese male, Chinese, New Zealander and European cohorts. The results were conflicting, in which Chinese [155Dong Z, Zhao D, Yang C, et al. Common variants in LRP2 and COMT genes affect the susceptibility of gout in a chinese population. PLoS One 2015; 10(7): e0131302.[http://dx.doi.org/10.1371/journal.pone.0131302] [PMID: 26147675] ] and New Zealander [156Rasheed H, Phipps-Green A, Topless R, et al. Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption. Arthritis Res Ther 2013; 15(6): R177.[http://dx.doi.org/10.1186/ar4366] [PMID: 24286387] ] showed a positive association, European a negative [156Rasheed H, Phipps-Green A, Topless R, et al. Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption. Arthritis Res Ther 2013; 15(6): R177.[http://dx.doi.org/10.1186/ar4366] [PMID: 24286387] ], and Japanese a contradictory in two independent cohorts [35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 157Nakayama A, Matsuo H, Shimizu T, et al. Common variants of a urate-associated gene LRP2 are not associated with gout susceptibility. Rheumatol Int 2014; 34(4): 473-6.[http://dx.doi.org/10.1007/s00296-013-2924-8] [PMID: 24366390] ].

7.2. GKRP

Glucokinase Regulatory Protein (GKRP) or Glucokinase Regulator (GCKR) is a hepatocyte-specific inhibitor of the glucose-metabolizing enzyme glucokinase (GCK), and plays important roles in hepatic glucose and lipid metabolism [158Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: Complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol 2015; 26(2): 88-95.[http://dx.doi.org/10.1097/MOL.0000000000000155] [PMID: 25692341] , 159Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism 2016; 65(8): 1026-37.[http://dx.doi.org/10.1016/j.metabol.2015.08.018] [PMID: 26409295] ]. Studies in American, Chinese and Japanese cohorts showed that rs780093, rs1260326, rs6547692 and rs780094 of GCKR gene were associated with gout in general, or male population [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] , 35Urano W, Taniguchi A, Inoue E, et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 2013; 40(8): 1374-8.[http://dx.doi.org/10.3899/jrheum.121244] [PMID: 23729800] , 40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] , 59Dong Z, Zhou J, Jiang S, et al. Effects of multiple genetic loci on the pathogenesis from serum urate to gout. Sci Rep 2017; 7: 43614.[http://dx.doi.org/10.1038/srep43614] [PMID: 28252667] , 62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] , 71Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.[http://dx.doi.org/10.1136/annrheumdis-2014-206191] [PMID: 25646370] , 112Yang Q, Köttgen A, Dehghan A, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 2010; 3(6): 523-30.[http://dx.doi.org/10.1161/CIRCGENETICS.109.934455] [PMID: 20884846] , 160Wang J, Liu S, Wang B, et al. Association between gout and polymorphisms in GCKR in male Han Chinese. Hum Genet 2012; 131(7): 1261-5.[http://dx.doi.org/10.1007/s00439-012-1151-9] [PMID: 22395765] ]. The result of rs780094 was contrary to that in a German cohort [41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] ].

7.3. ADRB3

Beta-3-Adrenergic Receptor (ADRB3) is involved in the regulation of fat metabolism and thermogenesis [161Strosberg AD. Structure and function of the beta 3-adrenergic receptor. Annu Rev Pharmacol Toxicol 1997; 37: 421-50.[http://dx.doi.org/10.1146/annurev.pharmtox.37.1.421] [PMID: 9131260] ]. The results of association studies of ADRB3 with gout were conflicting between male Chinese and combined populations of Polynesian and European patients, the former reported Arg64 allele of rs4994 as a risk to gout [162Wang B, Meng D, Wang J, et al. Positive correlation between Beta-3-Adrenergic Receptor (ADRB3) gene and gout in a Chinese male population. J Rheumatol 2011; 38(4): 738-40.[http://dx.doi.org/10.3899/jrheum.101037] [PMID: 21285172] ], but latter no association [163Fatima T, Altaf S, Phipps-Green A, et al. Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout. Rheumatol Int 2016; 36(2): 255-61.[http://dx.doi.org/10.1007/s00296-015-3370-6] [PMID: 26410617] ].

7.4. ADH1B and ALDH2

Alcohol Dehydrogenase 1B (ADH1B) and Aldehyde Dehydrogenase 2 (ALDH2) are key enzymes in the alcohol metabolism. ADH1B catalyzes alcohol into acetaldehyde, and subsequently ALDH2 oxidizes acetaldehyde into acetate. Rs671 (E504K) of ALDH2 gene was associated with gout in Japanese male and Chinese male populations [62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] , 164Sakiyama M, Matsuo H, Nakaoka H, et al. Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus. Sci Rep 2016; 6: 25360.[http://dx.doi.org/10.1038/srep25360] [PMID: 27181629] -166Wang C, Li C, Ding C, et al. The polymorphisms of aldehyde dehydrogenase 2 gene are associated with gout disease in male Han Chinese. Gout and Hyperuricemia 2016; 3: 40-5.]. In addition, a missense SNP of ADH1B gene rs1229984 (H48R) was also associated with gout in a Japanese population [165Sakiyama M, Matsuo H, Akashi A, et al. Independent effects of ADH1B and ALDH2 common dysfunctional variants on gout risk. Sci Rep 2017; 7(1): 2500.[http://dx.doi.org/10.1038/s41598-017-02528-z] [PMID: 28566767] ].

7.5. COMT and MAOA

Catechol-O-Methyltransferase (COMT) is an important enzyme involves in the metabolism of dopamine [167Pestana M, Jardim H, Correia F, Vieira-Coelho MA, Soares-da-Silva P. Renal dopaminergic mechanisms in renal parenchymal diseases and hypertension. Nephrol Dial Transplant 2001; 16(Suppl. 1): 53-9.[http://dx.doi.org/10.1093/ndt/16.suppl_1.53] [PMID: 11369822] ]. Monoamine Oxidases A (MAOA) is involved in the deamination of dopamine, which plays a crucial role in the regulation of renal functions, including glomerular filtration, renin production, sodium transport [168Zeng C, Zhang M, Asico LD, Eisner GM, Jose PA. The dopaminergic system in hypertension. Clin Sci (Lond) 2007; 112(12): 583-97.[http://dx.doi.org/10.1042/CS20070018] [PMID: 17492945] ], and urate excretion [169Sulikowska B, Manitius J, Odrowaz-Sypniewska G, Łysiak-Szydłowska W, Rutkowski B. Uric acid excretion and dopamine-induced glomerular filtration response in patients with IgA glomerulonephritis. Am J Nephrol 2008; 28(3): 391-6.[http://dx.doi.org/10.1159/000112271] [PMID: 18063857] ]. After the combined action of MAOA and COMT, dopamine is converted to DOPAC, 3-MT and HVA, which can pass through renal tubular proximal epithelial cells. A Chinese study showed that rs4680 (V158M) of COMT gene was associated with gout [155Dong Z, Zhao D, Yang C, et al. Common variants in LRP2 and COMT genes affect the susceptibility of gout in a chinese population. PLoS One 2015; 10(7): e0131302.[http://dx.doi.org/10.1371/journal.pone.0131302] [PMID: 26147675] ], but the association was negative in a Taiwanese aborigines population [170Tu HP, Ko AM, Wang SJ, et al. Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines. Hum Genet 2010; 127(2): 223-9.[http://dx.doi.org/10.1007/s00439-009-0765-z] [PMID: 19915868] ]. In contrast, the latter identified that three other SNPs including rs1137070 (D470D), rs2283725, rs5953210 of MAOA gene were associated with gout [170Tu HP, Ko AM, Wang SJ, et al. Monoamine oxidase A gene polymorphisms and enzyme activity associated with risk of gout in Taiwan aborigines. Hum Genet 2010; 127(2): 223-9.[http://dx.doi.org/10.1007/s00439-009-0765-z] [PMID: 19915868] ].

7.6. PRKG2

Protein Kinase, cGMP-dependent 2 (PRKG2) is an important regulator of intestinal secretion and bone growth, and was found to be an inflammation exciter in gout disease [171Liao WT, You HL, Li C, Chang JG, Chang SJ, Chen CJ. Cyclic GMP-dependent protein kinase II is necessary for macrophage M1 polarization and phagocytosis via toll-like receptor 2. J Mol Med (Berl) 2015; 93(5): 523-33.[http://dx.doi.org/10.1007/s00109-014-1236-0] [PMID: 25475742] ]. Genetic reports of the association between the PRKG2 gene and gout were inconsistent. In which gout was associated with rs7688672 of PRKG2 in a Taiwanese study [172Chang SJ, Tsai MH, Ko YC, Tsai PC, Chen CJ, Lai HM. The cyclic GMP-dependent protein kinase II gene associates with gout disease: identified by genome-wide analysis and case-control study. Ann Rheum Dis 2009; 68(7): 1213-9.[http://dx.doi.org/10.1136/ard.2008.093252] [PMID: 18678579] ] and rs10033237 of PRKG2 in a study of male Chinese cohort [173Guo M, Cheng Z, Li C, et al. Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China. Gene 2015; 562(1): 50-4.[http://dx.doi.org/10.1016/j.gene.2015.02.033] [PMID: 25688884] ], but two studies could not replicate the results from each other [172Chang SJ, Tsai MH, Ko YC, Tsai PC, Chen CJ, Lai HM. The cyclic GMP-dependent protein kinase II gene associates with gout disease: identified by genome-wide analysis and case-control study. Ann Rheum Dis 2009; 68(7): 1213-9.[http://dx.doi.org/10.1136/ard.2008.093252] [PMID: 18678579] , 173Guo M, Cheng Z, Li C, et al. Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China. Gene 2015; 562(1): 50-4.[http://dx.doi.org/10.1016/j.gene.2015.02.033] [PMID: 25688884] ], and in a Japanese study, no PRKG2-gout association was found by examining four variants (rs11736177, rs10033237, rs7688672, and rs6837293) of PRKG2 [174Sakiyama M, Matsuo H, Chiba T, et al. Common variants of cGKII/PRKG2 are not associated with gout susceptibility. J Rheumatol 2014; 41(7): 1395-7.[http://dx.doi.org/10.3899/jrheum.131548] [PMID: 24882840] ].

8. GENES INVOLVED IN FUNCTIONS OF CYTOSKELETON, MYOSIN AND TRANSCRIPTION AND OTHERS

8.1. WDR1

WD-Repeat protein 1 (WDR1), also called Actin-Interacting Protein 1 (AIP1), plays a crucial role in dynamic reorganization of the actin cytoskeleton [175Ono S. Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation. Biochem Biophys Res Commun 2017 Oct 19. pii: S0006-291X(17)32074-0.]. The G allele of rs3756230 and the A allele of rs12498927 of WDR1 were reported to be gout risk in a study of a Han Chinese cohort [176Liu LJ, Zhang XY, He N, et al. Genetic variation in WDR1 is associated with gout risk and gout-related metabolic indices in the Han Chinese population. Genet Mol Res 2016; 15(2)[http://dx.doi.org/10.4238/gmr.15027381] [PMID: 27173277] ]. However, the sample size of this study was relatively small (143 gout cases and 310 controls), and there has not been any replication study.

8.2. ALPK1

Alpha-Kinase 1 (ALPK1) is a component of raft-carrying apical vesicles that functions in the phosphorylation of myosin I in the apical trafficking of raft-associated sucrose-isomaltase [177Heine M, Cramm-Behrens CI, Ansari A, et al. Alpha-kinase 1, a new component in apical protein transport. J Biol Chem 2005; 280(27): 25637-43.[http://dx.doi.org/10.1074/jbc.M502265200] [PMID: 15883161] ]. Rs11726117and rs231247 of the ALPK1 gene were associated with gout in a study including a Taiwan aborigines cohort and a Han Chinese cohort [178Ko AM, Tu HP, Liu TT, et al. ALPK1 genetic regulation and risk in relation to gout. Int J Epidemiol 2013; 42(2): 466-74.[http://dx.doi.org/10.1093/ije/dyt028] [PMID: 23569188] ]. Another SNP rs231253 was only associated with gout in the Taiwan aborigines cohort [178Ko AM, Tu HP, Liu TT, et al. ALPK1 genetic regulation and risk in relation to gout. Int J Epidemiol 2013; 42(2): 466-74.[http://dx.doi.org/10.1093/ije/dyt028] [PMID: 23569188] ]. However, rs11726117 was not associated with gout in a Japanese male cohort [179Chiba T, Matsuo H, Sakiyama M, et al. Common variant of ALPK1 is not associated with gout: A replication study. Hum Cell 2015; 28(1): 1-4.[http://dx.doi.org/10.1007/s13577-014-0103-1] [PMID: 25326865] ].

8.3. CARMIL (LRRC16A)

Capping protein ARP2/3 and Myosin-I Linker (CARMIL), or Leucine-Rich Repeat-Containing 16A (LRRC16A) plays an important role in cell-shape changes and motility. Two studies of Japanese male cohorts showed that rs742132 of the LRRC16A gene was associated with gout [180Sakiyama M, Matsuo H, Shimizu S, et al. Common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility. Hum Cell 2014; 27(1): 1-4.[http://dx.doi.org/10.1007/s13577-013-0081-8] [PMID: 24318514] , 181Ogata H, Matsuo H, Sakiyama M, et al. Meta-analysis confirms an association between gout and a common variant of LRRC16A locus. Mod Rheumatol 2017; 27(3): 553-5.[http://dx.doi.org/10.1080/14397595.2016.1218413] [PMID: 27585540] ], but the results appeared to be conflict in Han Chinese and Germany cohorts [40Zhou ZW, Cui LL, Han L, et al. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC Med Genet 2015; 16: 66.[http://dx.doi.org/10.1186/s12881-015-0208-8] [PMID: 26290326] , 41Stark K, Reinhard W, Grassl M, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009; 4(11): e7729.[http://dx.doi.org/10.1371/journal.pone.0007729] [PMID: 19890391] ].

8.4. RFX3

Regulatory factor X 3 (RFX3) is a transcription factor involved in the formation of thalamocortical tract [182Magnani D, Morlé L, Hasenpusch-Theil K, et al. The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating the patterning of prethalamus and ventral telencephalon. Hum Mol Genet 2015; 24(9): 2578-93.[http://dx.doi.org/10.1093/hmg/ddv021] [PMID: 25631876] ], beta-cell [183Ait-Lounis A, Bonal C, Seguín-Estévez Q, et al. The transcription factor Rfx3 regulates beta-cell differentiation, function, and glucokinase expression. Diabetes 2010; 59(7): 1674-85.[http://dx.doi.org/10.2337/db09-0986] [PMID: 20413507] ] and the expression of glucokinase [182Magnani D, Morlé L, Hasenpusch-Theil K, et al. The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating the patterning of prethalamus and ventral telencephalon. Hum Mol Genet 2015; 24(9): 2578-93.[http://dx.doi.org/10.1093/hmg/ddv021] [PMID: 25631876] ]. Rs12236871 of RFX3 gene was associated with gout in a Han Chinese male cohort [107Li C, Li Z, Liu S, et al. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese. Nat Commun 2015; 6: 7041.[http://dx.doi.org/10.1038/ncomms8041] [PMID: 25967671] ].

8.5. BCAS3

Breast Cancer Amplified Sequence 3 (BCAS3) is a cytoskeletal protein involved in human embryogenesis and tumor angiogenesis [184Siva K, Venu P, Mahadevan A, S K S, Inamdar MS. Human BCAS3 expression in embryonic stem cells and vascular precursors suggests a role in human embryogenesis and tumor angiogenesis. PLoS One 2007; 2(11): e1202.[http://dx.doi.org/10.1371/journal.pone.0001202] [PMID: 18030336] ]. Three BCAS3 SNPs, rs9895661, rs9905274, rs11653176, were associated with gout in Han Chinese male populations [62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] , 107Li C, Li Z, Liu S, et al. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese. Nat Commun 2015; 6: 7041.[http://dx.doi.org/10.1038/ncomms8041] [PMID: 25967671] ].

8.6. CNIH-2

Cornichon-2 (CNIH-2) is a α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-associated

protein that regulates the function of AMPA receptors through the transmembrane AMPA receptor regulatory protein (TARP) isoform composition within the receptor complex [185Gill MB, Kato AS, Wang H, Bredt DS. AMPA receptor modulation by cornichon-2 dictated by transmembrane AMPA receptor regulatory protein isoform. Eur J Neurosci 2012; 35(2): 182-94.[http://dx.doi.org/10.1111/j.1460-9568.2011.07948.x] [PMID: 22211840] , 186Herring BE, Shi Y, Suh YH, et al. Cornichon proteins determine the subunit composition of synaptic AMPA receptors. Neuron 2013; 77(6): 1083-96.[http://dx.doi.org/10.1016/j.neuron.2013.01.017] [PMID: 23522044] ]. Rs4073582 of CNIH-2 gene was associated with gout in three independent cohorts including two Japanese male and a Han Chinese male [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] , 62Li Z, Zhou Z, Hou X, et al. Replication of gout/urate concentrations GWAS susceptibility loci associated with gout in a han chinese population. Sci Rep 2017; 7(1): 4094.[http://dx.doi.org/10.1038/s41598-017-04127-4] [PMID: 28642574] , 71Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.[http://dx.doi.org/10.1136/annrheumdis-2014-206191] [PMID: 25646370] ].

8.7. FAM35A

FAM35A is a protein whose function is totally unknown. Rs7903456 of FAM35A gene was associated with renal underexcretion gout [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ]. The cytosolic immunoreactivity of FAM35A is mainly in the distal tubule showed that the distal nephron is involved in urate handling in humans [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] ].

8.8. MYL2-CUX2

Myosin light chain-2 (MYL2) is a member of EF-hand calcium binding protein superfamily [187Sheikh F, Lyon RC, Chen J. Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease. Gene 2015; 569(1): 14-20.[http://dx.doi.org/10.1016/j.gene.2015.06.027] [PMID: 26074085] ]. A GWAS showed that MYL2 was associated with high-density lipoprotein cholesterol metabolism [188Kim YJ, Go MJ, Hu C, et al. Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. Nat Genet 2011; 43(10): 990-5.[http://dx.doi.org/10.1038/ng.939] [PMID: 21909109] ]. Cut-like homeobox 2 (CUX2) is an accessory factor in the repair of DNA damage [189Pal R, Ramdzan ZM, Kaur S, et al. CUX2 protein functions as an accessory factor in the repair of oxidative DNA damage. J Biol Chem 2015; 290(37): 22520-31.[http://dx.doi.org/10.1074/jbc.M115.651042] [PMID: 26221032] ]. An intergenic SNP rs2188380 located between MYL2 and CUX2 gene, and rs4766566 of CUX2 gene were associated with gout in two reports of Japanese male population [2Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis 2017; 76(5): 869-77.[http://dx.doi.org/10.1136/annrheumdis-2016-209632] [PMID: 27899376] , 71Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis 2016; 75(4): 652-9.[http://dx.doi.org/10.1136/annrheumdis-2014-206191] [PMID: 25646370] ].

CONCLUSION AND FUTURE DIRECTIONS

In summary, genetic studies have identified a number of genes with polymorphisms conferring susceptibility to or protection from gout. Among them, specific polymorphisms of membrane transporters, especially solute carrier family, and inflammatory responding genes appeared to be the major ones, and some of them also were linked to functional changes of the corresponding genes. On the other hand, some of the reported associations were inconsistent in different studies. The discordance may result from several aspects. First, the distribution of alleles and genotypes of some polymorphic loci vary greatly among different ethnic populations; second, the sample size of some studies is too small to reach acceptable statistic power, which may induce bias; third, lack of consideration of disease subtypes (such as ROL and RUE gout) and gender of gout patients in some studies may lead to mask the true association of the studied alleles. In addition, although overall studies have found multiple gout-related genetic loci, functional studies of many of these loci have not been conducted. Therefore, exploring functional significances of the identified polymorphisms is also one of the directions of the study on gout in the future.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

This study was supported by the project of studying abroad for young and Middle-aged teachers of Nanchang University.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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