The Open Rheumatology Journal




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

Association Between STAT4 rs7574865 Polymorphism and Rheumatoid Arthritis: Debate Unresolved



Iman Tarakji1, *, Wafa Habbal2, Fawza Monem1, 2
1 Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria
2 Clinical Laboratories Department, Al-Assad Hospital, Damascus University, P.O. Box 10769, Damascus, Syria

Abstract

Background:

STAT4 rs7574865 polymorphism has been evidently associated with susceptibility to Rheumatoid Arthritis (RA) in European and Eastern Asian populations, whereas studies in other countries reported otherwise.

Objective:

We investigated the distribution of STAT4 rs7574865 polymorphism in a group of Syrian RA patients.

Methods:

Eighty-one RA patients and forty healthy controls were enrolled and STAT4 rs7574865 was genotyped by direct sequencing. RA patients were stratified according to Anti-Citrullinated Protein Antibodies (ACPA) status for analysis.

Results:

Minor T allele frequencies were 30.4%, 16.7%, and 23.8% in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively. No significant differences in STAT4 rs7574865 allele/genotype frequencies were found between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05).

Conclusion:

STAT4 rs7574865 TT genotype showed a potential impact on ACPA positivity in Syrian RA patients. However, STAT4 rs7574865 effect on RA onset and severity is minor compared to other genetic factors such as HLA-DRB1 shared epitope alleles.

Keywords: : STAT4 rs7574865, Rheumatoid arthritis, Syria, ACPA, SNP, MHC.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 172
Last Page: 178
Publisher Id: TORJ-12-172
DOI: 10.2174/1874312901812010172

Article History:

Received Date: 31/5/2018
Revision Received Date: 28/8/2018
Acceptance Date: 01/10/2018
Electronic publication date: 24/10/2018
Collection year: 2018

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© 2018 Tarakji 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 Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus’ Syria, Tel: +963-988 387 367, E-mail: imantarakji@gmail.com




1. INTRODUCTION

Rheumatoid Arthritis (RA) is one of the most common chronic multifactorial autoimmune disorders [1O’Rielly DD, Rahman P. Pharmacogenetics of rheumatoid arthritis: Potential targets from susceptibility genes and present therapies. Pharm Genomics Pers Med 2010; 3: 15-31.[PMID: 23226040] ]. It gives rise to synovial joint deformity and loss of function leading to disabilities and early mortalities [2Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: What have we learned? Immunogenetics 2011; 63(8): 459-66.[http://dx.doi.org/10.1007/s00251-011-0528-6] [PMID: 21556860] ]. Genetic background plays a great role, side by side with environmental factors, in RA pathogenesis, etiology, prognosis and outcomes [3Kurkó J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z. Genetics of rheumatoid arthritis - A comprehensive review. Clin Rev Allergy Immunol 2013; 45(2): 170-9.[http://dx.doi.org/10.1007/s12016-012-8346-7] [PMID: 23288628] ]. HLA-DRB1 shared epitope alleles remain the major contributor to RA susceptibility [4Barton A, Worthington J. Genetic susceptibility to rheumatoid arthritis: An emerging picture. Arthritis Rheum 2009; 61(10): 1441-6.[http://dx.doi.org/10.1002/art.24672] [PMID: 19790122] ]. Their involvement has been proved to be restricted to Anti-Citrullinated Protein Antibodies (ACPA)-positive patients [5Ruyssen-Witrand A, Constantin A, Cambon-Thomsen A, Thomsen M. New insights into the genetics of immune responses in rheumatoid arthritis. Tissue Antigens 2012; 80(2): 105-18.[http://dx.doi.org/10.1111/j.1399-0039.2012.01939.x] [PMID: 22835281] ]. Beyond the Major Histocompatibility Complex (MHC) region, many Single Nucleotide Polymorphisms (SNPs) occurring within numerous genes, including STAT4 [6Martínez A, Varadé J, Márquez A, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008; 58(9): 2598-602.[http://dx.doi.org/10.1002/art.23792] [PMID: 18759272] , 7Jiang X, Zhou Z, Zhang Y, Yang H, Ren K. An updated meta-analysis of the Signal Transducer and Activator of Transcription 4 (STAT4) rs7574865 G/T polymorphism and rheumatoid arthritis risk in an Asian population. Scand J Rheumatol 2014; 43(6): 477-80.[http://dx.doi.org/10.3109/03009742.2014.918174] [PMID: 25179669] ], have been identified as candidate genetic markers associated with RA [5Ruyssen-Witrand A, Constantin A, Cambon-Thomsen A, Thomsen M. New insights into the genetics of immune responses in rheumatoid arthritis. Tissue Antigens 2012; 80(2): 105-18.[http://dx.doi.org/10.1111/j.1399-0039.2012.01939.x] [PMID: 22835281] ].

Signal Transducer and Activator of Transcription 4 (STAT4) gene encodes for a transcription factor that lies in the signaling pathway of IL-12 and IL-23 leading to the production of IFNγ and differentiation of CD4+ T-cells into Th1 and Th17 [8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] , 9Lamana A, Balsa A, Rueda B, et al. The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis. PLoS One 2012; 7(8): e43661.[http://dx.doi.org/10.1371/journal.pone.0043661] [PMID: 22937072] ]. The pathophysiological hallmark of RA involves the exaggeration of Th1/Th17 mediated inflammatory response [8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] ] and upregulation of STAT4 gene in synovial macrophages [10Shen L, Liu R, Zhang H, Huang Y, Sun R, Tang P. Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a chinese population. Gene 2013; 526(2): 259-64.[http://dx.doi.org/10.1016/j.gene.2013.05.022] [PMID: 23727609] ]. A susceptibility haplotype formed of four SNPs in STAT4 gene and tagged by the T allele of rs7574865 has been shown to have a significant association with RA [11Kobayashi S, Ikari K, Kaneko H, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58(7): 1940-6.[http://dx.doi.org/10.1002/art.23494] [PMID: 18576330] ] evidently in Europe and Eastern Asia [6Martínez A, Varadé J, Márquez A, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008; 58(9): 2598-602.[http://dx.doi.org/10.1002/art.23792] [PMID: 18759272] , 8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] , 11Kobayashi S, Ikari K, Kaneko H, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58(7): 1940-6.[http://dx.doi.org/10.1002/art.23494] [PMID: 18576330] -19Liang YL, Wu H, Li PQ, et al. Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in northwestern chinese han population. Life Sci 2011; 89(5-6): 171-5.[http://dx.doi.org/10.1016/j.lfs.2011.05.012] [PMID: 21683716] ]. However, studies in other countries reported otherwise [20Kelley JM, Hughes LB, Malik A, et al. Genetic variants of STAT4 associated with rheumatoid arthritis in persons of asian and european ancestry do not replicate in african americans. Ann Rheum Dis 2010; 69(4): 625-6.[http://dx.doi.org/10.1136/ard.2009.113183] [PMID: 20237121] , 21Yüksel B, Ataman Ş, Evcik D, Saime A, Mumcuoglu M, Erdogan B. Is there an association between two-STAT4 gene polymorphisms and rheumatoid arthritis in turkish population? Arch Rheumatol 2014; 29(1): 20-7.[http://dx.doi.org/10.5606/tjr.2014.3967] ], which suggests the need for ethnic-specific association studies. In this preliminary study, we aimed at investigating the distribution of STAT4 rs7574865 polymorphism for the first time among a group of Syrian RA patients adding to the data that have only been scarcely collected in the Middle East.

2. MATERIALS AND METHODS

This case-control study included 81 unrelated RA Syrian patients presenting at outpatient clinics of Ibn Al-Nafis Hospital, Ministry of Health or admitted to the departments of arthrology at Al-Mowasah and Al-Assad Hospitals, Damascus University, between January 2010 and September 2011. All patients were diagnosed by an accredited arthrologist and they fulfilled the American College of Rheumatology (ACR) 1987 revised criteria [22O’Dell JR, Imboden JB, Miller LD. Rheumatoid arthritis. In: Imboden JB, Hellmann DB, Stone JH, Eds. CURRENT Diagnosis & Treatment in Rheumatology. McGraw-Hill 2013; New York, pp. 139-55.]. Patients with juvenile idiopathic arthritis or other autoimmune diseases were excluded. Patients' clinical data including disease duration, Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), Rheumatoid Factor (RF), and ACPA were obtained from their medical records.

Forty healthy unrelated controls matched for age and ethnicity were also enrolled in the study. Neither controls nor any of their first degree relatives had RA or any other autoimmune disease. An informed consent was obtained from both patients and healthy individuals whose HLA-DRB1 genotype has been analyzed previously [23Mourad J, Monem F. HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria. Rev Bras Reumatol 2013; 53(1): 47-56.[PMID: 23588515] ]. This study has been approved by the Research Ethics Committee of Damascus University.

DNAs extracted from whole blood samples were genotyped for STAT4 rs7574865 by direct DNA sequencing. A 182 bp-fragment was amplified using a forward primer 5'-GGT GTG GAT GGA GGT AAG GA-3' and a reverse primer 5'-ATC CCC TGA AAT TCC ACT GA-3' [24Su Y, Zhao Y, Liu X, et al. Variation in STAT4 is associated with systemic lupus erythematosus in chinese northern han population. Chin Med J (Engl) 2010; 123(22): 3173-7.[PMID: 21163111] ] manufactured by VBC Biotech Service (Vienna, Austria). 25-µL PCRs, including 2.5 µL DNA and 0.5 µM of each primer, were performed using a HotStar PCR SuperMix kit (GeneDirex, Las Vegas, NV) on the MasterCycler® Pro S (Eppendorf, Hamburg, Germany). Thermal cycling was initiated at 94°C for 2 min, followed by 45 cycles of denaturation at 94°C for 2 min, annealing at 55°C for 30 sec and extension at 72°C for 2 min, and a final extension at 72°C for 7 min. Agarose gel electrophoresis (2.5%) was used for DNA visualization.

PCR products were purified using a High Pure PCR Product Purification Kit (Roche Diagnostics, Mannheim, Germany) and sequenced using the forward primer and a BigDye® Terminator v3.1 Cycle Sequencing Kit on the ABI PRISM® 3100-AvantTM Genetic Analyzer (Applied Biosystems, Foster City, CA) according to the manufacturers' instructions. STAT4 rs7574865 genotypes GG, GT and TT were considered as wild-type, heterozygote mutant, and homozygote mutant, respectively.

Samples were analyzed for Hardy-Weinberg Equilibrium (HWE) using a chi-square goodness-of-fit test of SNPStats [25Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: A web tool for the analysis of association studies. Bioinformatics 2006; 22(15): 1928-9.[http://dx.doi.org/10.1093/bioinformatics/btl268] [PMID: 16720584] ]. Differences of allele/genotype distribution of both STAT4 rs7574865 and HLA-DRB1 among study groups were analyzed using Kruskal-Wallis H and Mann-Whitney U tests. Whenever a significant difference was inferred, Kendall's tau-b correlation coefficient and Odds Ratio (OR) were calculated to test the strength and direction of the association between relevant variables. Statistical analyses were performed using IBM SPSS Statistics 19.0 software (International Business Machines Crop., New York, USA) and MedCalc for Windows, version 17.7.1 (MedCalc Software, Ostend, Belgium) and P-value <0.05 was considered significant.

3. RESULTS

Our study included 65 (80.25%) females and 16 (19.75%) males aged 41.4±10.6 years, and whose RA disease lasted for 11.3±6.3 years with ESR and CRP values of 56.7±29.7 mm/hr and 31.1±38.4 mg/L, respectively. In addition, 55 of 81 (67.90%) RA patients were positive for RF and 51 of 81 (62.96%) RA patients were positive for ACPA with values of 160.7±92.4 RU/mL. On the other hand, healthy controls included 26 (65%) females and 14 (35%) males aged 39.42 ±10.90 years.

The frequencies of presumably Risky (R) HLA-DRB1 alleles (DRB*01, *04, and *10) were 59 of 102 (57.8%), 20 of 60 (33.3%), and 16 of 80 (20%), while the frequencies of presumably protective (P) HLA-DRB1 alleles (DRB*11 and *13) were 17 of 102 (16.7%), 16 of 60 (26.7%), and 34 of 80 (42.5%) in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively Table 1.

Table 1
Distribution of HLA-DRB1 alleles/genotypes among Syrian rheumatoid arthritis patients and healthy controls.


The frequencies of STAT4 rs7574865 G allele were 71 of 102 (69.6%), 50 of 60 (83.3%), and 61 of 80 (76.3%), while the frequencies of STAT4 rs7574865 T allele were 31 of 102 (30.4%), 10 of 60 (16.7%), and 19 of 80 (23.8%) in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively Table 2.

The frequencies of STAT4 rs7574865 GG genotype (wild-type) were 26 of 51 (51%), 20 of 30 (66.7%), and 25 of 40 (62.5%), the frequencies of STAT4 rs7574865 GT genotype (heterozygote mutant) were 19 of 51 (37.3%), 10 of 30 (33.3%), and 11 of 40 (27.5%), and the frequencies of STAT4 rs7574865 TT genotype (homozygote mutant) were 6 of 51 (11.8%), 0 of 30 (0%), and 4 of 40 (10%) in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively Table 2.

Table 2
Distribution of STAT4 rs7574865 alleles/genotypes among Syrian rheumatoid arthritis patients and healthy controls.


No deviation from Hardy-Weinberg equilibrium was found in the control group (P=0.18). HLA-DRB1 allele/genotype frequencies were significantly different between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P=0.00), where R allele was weakly correlated with ACPA positivity (τ=0.38, P=0.00) and P allele was weakly correlated with healthy status (τ=0.33, P=0.00). Moreover, ACPA positivity was 6.8 and 4.7 times more likely to occur in patients with R allele compared with healthy controls (OR 6.8, 95% CI:2.7-17.5, P=0.0001) and ACPA-negative patients (OR 4.7, 95% CI:1.7-12.7, P=0.002), respectively. In addition, healthy status was 4.5 and 7.2 times more likely to be maintained in individuals with P allele compared with ACPA-negative patients (OR 4.5, 95% CI:1.6-12.5, P=0.004) and ACPA-positive patients (OR 7.2, 95% CI:2.8-18.4, P<0.0001), respectively. When compared in pairs in terms of HLA-DRB1 alleles, R alleles were not significantly different between ACPA-negative RA patients and healthy controls (P=0.21) and P alleles were not significantly different between ACPA-positive RA patients and ACPA-negative RA patients (P=0.24) Table 1.

No significant differences in STAT4 rs7574865 allele/genotype frequencies were found between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05). When compared in pairs in terms of STAT4 rs7574865 genotype, homozygote mutant and wild-type genotypes were solely significantly different between ACPA-positive RA patients and ACPA-negative RA patients (P=0.041), where ACPA-positivity was not necessarily associated with TT genotype (OR 10.06, 95% CI:0.5-189, P=0.123) albeit weakly correlated (τ=0.278, P=0.045) Table 2. However, no significant correlation was found between STAT4 rs7574865 and HLA-DRB1 alleles/genotypes in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05).

4. DISCUSSION

The Minor Allele Frequency (MAF) of STAT4 rs7574865 among RA patients in Syria (25.3%) seems consistent with Tunisians (25%) [26Ben Hamad M, Cornelis F, Mbarek H, et al. Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders. Clin Exp Rheumatol 2011; 29(2): 269-74.[PMID: 21418779] ] and Europeans (24%-30%) [6Martínez A, Varadé J, Márquez A, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008; 58(9): 2598-602.[http://dx.doi.org/10.1002/art.23792] [PMID: 18759272] , 8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] , 12Stark K, Rovenský J, Blazicková S, et al. Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a slovak population using osteoarthritis patients as controls. Arthritis Res Ther 2009; 11(3): R70.[http://dx.doi.org/10.1186/ar2699] [PMID: 19445664] -14Daha NA, Kurreeman FA, Marques RB, et al. Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum 2009; 60(5): 1255-60.[http://dx.doi.org/10.1002/art.24503] [PMID: 19404967] , 17Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357(10): 977-86.[http://dx.doi.org/10.1056/NEJMoa073003] [PMID: 17804842] , 27Seddighzadeh M, Gonzalez A, Ding B, et al. Variants within STAT genes reveal association with anticitrullinated protein antibody-negative rheumatoid arthritis in 2 European populations. J Rheumatol 2012; 39(8): 1509-16.[http://dx.doi.org/10.3899/jrheum.111284] [PMID: 22753649] , 28Zervou MI, Sidiropoulos P, Petraki E, et al. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum Immunol 2008; 69(9): 567-71.[http://dx.doi.org/10.1016/j.humimm.2008.06.006] [PMID: 18625278] ] but higher than African Americans (15%) [20Kelley JM, Hughes LB, Malik A, et al. Genetic variants of STAT4 associated with rheumatoid arthritis in persons of asian and european ancestry do not replicate in african americans. Ann Rheum Dis 2010; 69(4): 625-6.[http://dx.doi.org/10.1136/ard.2009.113183] [PMID: 20237121] ] and lower than Iranians (50%) [29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] ], Eastern Asians (35%-42%) [11Kobayashi S, Ikari K, Kaneko H, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58(7): 1940-6.[http://dx.doi.org/10.1002/art.23494] [PMID: 18576330] , 15Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 2007; 13(9-10): 455-60.[http://dx.doi.org/10.2119/2007-00072.Lee] [PMID: 17932559] , 16Zhao Y, Liu X, Liu X, et al. Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern chinese Han subpopulation. Int J Rheum Dis 2013; 16(2): 178-84.[http://dx.doi.org/10.1111/1756-185X.12093] [PMID: 23773642] , 19Liang YL, Wu H, Li PQ, et al. Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in northwestern chinese han population. Life Sci 2011; 89(5-6): 171-5.[http://dx.doi.org/10.1016/j.lfs.2011.05.012] [PMID: 21683716] ], and Colombians (38%) [18Palomino-Morales RJ, Rojas-Villarraga A, González CI, Ramírez G, Anaya JM, Martín J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in colombians. Genes Immun 2008; 9(4): 379-82.[http://dx.doi.org/10.1038/gene.2008.30] [PMID: 18432273] ]. On the contrary, the MAF among healthy controls in Syria (23.8%) seems higher than Tunisians (17%) [26Ben Hamad M, Cornelis F, Mbarek H, et al. Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders. Clin Exp Rheumatol 2011; 29(2): 269-74.[PMID: 21418779] ] and Europeans (17%-23%) [6Martínez A, Varadé J, Márquez A, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008; 58(9): 2598-602.[http://dx.doi.org/10.1002/art.23792] [PMID: 18759272] , 8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] , 12Stark K, Rovenský J, Blazicková S, et al. Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a slovak population using osteoarthritis patients as controls. Arthritis Res Ther 2009; 11(3): R70.[http://dx.doi.org/10.1186/ar2699] [PMID: 19445664] -14Daha NA, Kurreeman FA, Marques RB, et al. Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum 2009; 60(5): 1255-60.[http://dx.doi.org/10.1002/art.24503] [PMID: 19404967] , 17Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357(10): 977-86.[http://dx.doi.org/10.1056/NEJMoa073003] [PMID: 17804842] , 27Seddighzadeh M, Gonzalez A, Ding B, et al. Variants within STAT genes reveal association with anticitrullinated protein antibody-negative rheumatoid arthritis in 2 European populations. J Rheumatol 2012; 39(8): 1509-16.[http://dx.doi.org/10.3899/jrheum.111284] [PMID: 22753649] , 28Zervou MI, Sidiropoulos P, Petraki E, et al. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum Immunol 2008; 69(9): 567-71.[http://dx.doi.org/10.1016/j.humimm.2008.06.006] [PMID: 18625278] ] and still higher than African Americans (13%) [20Kelley JM, Hughes LB, Malik A, et al. Genetic variants of STAT4 associated with rheumatoid arthritis in persons of asian and european ancestry do not replicate in african americans. Ann Rheum Dis 2010; 69(4): 625-6.[http://dx.doi.org/10.1136/ard.2009.113183] [PMID: 20237121] ] and lower than Iranians (50%) [29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] ], Eastern Asians (31%-33%) [11Kobayashi S, Ikari K, Kaneko H, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58(7): 1940-6.[http://dx.doi.org/10.1002/art.23494] [PMID: 18576330] , 15Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 2007; 13(9-10): 455-60.[http://dx.doi.org/10.2119/2007-00072.Lee] [PMID: 17932559] , 16Zhao Y, Liu X, Liu X, et al. Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern chinese Han subpopulation. Int J Rheum Dis 2013; 16(2): 178-84.[http://dx.doi.org/10.1111/1756-185X.12093] [PMID: 23773642] , 19Liang YL, Wu H, Li PQ, et al. Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in northwestern chinese han population. Life Sci 2011; 89(5-6): 171-5.[http://dx.doi.org/10.1016/j.lfs.2011.05.012] [PMID: 21683716] ], and Colombians (31%) [18Palomino-Morales RJ, Rojas-Villarraga A, González CI, Ramírez G, Anaya JM, Martín J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in colombians. Genes Immun 2008; 9(4): 379-82.[http://dx.doi.org/10.1038/gene.2008.30] [PMID: 18432273] ]. Regarding the neighboring countries, the MAF of STAT4 rs7574865 has only been reported in Egypt. Albeit diverse among both RA patients (8% and 37%) and healthy controls (5% and 17%), Egyptian MAFs were inconsistent with those of our study [30Mohamed RH, Pasha HF, El-Shahawy EE. Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in egyptian population. Cell Immunol 2012; 273(1): 67-72.[http://dx.doi.org/10.1016/j.cellimm.2011.11.005] [PMID: 22196377] , 31El-Saadanya HM, Amerb WH, Khalilb HS, Gaberc RA, Elshweikh SA. Association of STAT4 polymorphism with susceptibility and severity of rheumatoid arthritis and systemic lupus erythematosus in egyptian patients. Egyptian Rheumatol 2016; 38(1): 21-7.[http://dx.doi.org/10.1016/j.ejr.2015.04.003] ].

While the MAFs among ACPA-positive patients (30.4%; 60%) were perceptibly higher versus ACPA-negative patients (16.7%; 39.4%) in Syria and Iran [29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] ], respectively, they appeared comparable in the European [8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] , 13Orozco G, Alizadeh BZ, Delgado-Vega AM, et al. Association of STAT4 with rheumatoid arthritis: A replication study in three european populations. Arthritis Rheum 2008; 58(7): 1974-80.[http://dx.doi.org/10.1002/art.23549] [PMID: 18576336] , 14Daha NA, Kurreeman FA, Marques RB, et al. Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum 2009; 60(5): 1255-60.[http://dx.doi.org/10.1002/art.24503] [PMID: 19404967] ] and Eastern Asian [15Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 2007; 13(9-10): 455-60.[http://dx.doi.org/10.2119/2007-00072.Lee] [PMID: 17932559] ] populations. Moreover, the TT genotype among ACPA-negative patients was exclusively nil in Syria and Egypt [31El-Saadanya HM, Amerb WH, Khalilb HS, Gaberc RA, Elshweikh SA. Association of STAT4 polymorphism with susceptibility and severity of rheumatoid arthritis and systemic lupus erythematosus in egyptian patients. Egyptian Rheumatol 2016; 38(1): 21-7.[http://dx.doi.org/10.1016/j.ejr.2015.04.003] ], a phenomenon unseen in other populations such as Turkey [21Yüksel B, Ataman Ş, Evcik D, Saime A, Mumcuoglu M, Erdogan B. Is there an association between two-STAT4 gene polymorphisms and rheumatoid arthritis in turkish population? Arch Rheumatol 2014; 29(1): 20-7.[http://dx.doi.org/10.5606/tjr.2014.3967] ], Iran [29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] ], Europe [13Orozco G, Alizadeh BZ, Delgado-Vega AM, et al. Association of STAT4 with rheumatoid arthritis: A replication study in three european populations. Arthritis Rheum 2008; 58(7): 1974-80.[http://dx.doi.org/10.1002/art.23549] [PMID: 18576336] ], and Eastern Asia [16Zhao Y, Liu X, Liu X, et al. Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern chinese Han subpopulation. Int J Rheum Dis 2013; 16(2): 178-84.[http://dx.doi.org/10.1111/1756-185X.12093] [PMID: 23773642] , 19Liang YL, Wu H, Li PQ, et al. Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in northwestern chinese han population. Life Sci 2011; 89(5-6): 171-5.[http://dx.doi.org/10.1016/j.lfs.2011.05.012] [PMID: 21683716] ].

In discord with more than twenty studies conducted in Europe [6Martínez A, Varadé J, Márquez A, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008; 58(9): 2598-602.[http://dx.doi.org/10.1002/art.23792] [PMID: 18759272] , 8Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17(15): 2274-9.[http://dx.doi.org/10.1093/hmg/ddn128] [PMID: 18434327] , 12Stark K, Rovenský J, Blazicková S, et al. Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a slovak population using osteoarthritis patients as controls. Arthritis Res Ther 2009; 11(3): R70.[http://dx.doi.org/10.1186/ar2699] [PMID: 19445664] -14Daha NA, Kurreeman FA, Marques RB, et al. Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum 2009; 60(5): 1255-60.[http://dx.doi.org/10.1002/art.24503] [PMID: 19404967] , 17Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357(10): 977-86.[http://dx.doi.org/10.1056/NEJMoa073003] [PMID: 17804842] , 27Seddighzadeh M, Gonzalez A, Ding B, et al. Variants within STAT genes reveal association with anticitrullinated protein antibody-negative rheumatoid arthritis in 2 European populations. J Rheumatol 2012; 39(8): 1509-16.[http://dx.doi.org/10.3899/jrheum.111284] [PMID: 22753649] , 28Zervou MI, Sidiropoulos P, Petraki E, et al. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum Immunol 2008; 69(9): 567-71.[http://dx.doi.org/10.1016/j.humimm.2008.06.006] [PMID: 18625278] ], Eastern Asia [10Shen L, Liu R, Zhang H, Huang Y, Sun R, Tang P. Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a chinese population. Gene 2013; 526(2): 259-64.[http://dx.doi.org/10.1016/j.gene.2013.05.022] [PMID: 23727609] , 11Kobayashi S, Ikari K, Kaneko H, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58(7): 1940-6.[http://dx.doi.org/10.1002/art.23494] [PMID: 18576330] , 15Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 2007; 13(9-10): 455-60.[http://dx.doi.org/10.2119/2007-00072.Lee] [PMID: 17932559] , 16Zhao Y, Liu X, Liu X, et al. Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern chinese Han subpopulation. Int J Rheum Dis 2013; 16(2): 178-84.[http://dx.doi.org/10.1111/1756-185X.12093] [PMID: 23773642] , 19Liang YL, Wu H, Li PQ, et al. Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in northwestern chinese han population. Life Sci 2011; 89(5-6): 171-5.[http://dx.doi.org/10.1016/j.lfs.2011.05.012] [PMID: 21683716] ], Colombia [18Palomino-Morales RJ, Rojas-Villarraga A, González CI, Ramírez G, Anaya JM, Martín J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in colombians. Genes Immun 2008; 9(4): 379-82.[http://dx.doi.org/10.1038/gene.2008.30] [PMID: 18432273] ], Tunisia [26Ben Hamad M, Cornelis F, Mbarek H, et al. Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders. Clin Exp Rheumatol 2011; 29(2): 269-74.[PMID: 21418779] ], and Egypt [30Mohamed RH, Pasha HF, El-Shahawy EE. Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in egyptian population. Cell Immunol 2012; 273(1): 67-72.[http://dx.doi.org/10.1016/j.cellimm.2011.11.005] [PMID: 22196377] , 31El-Saadanya HM, Amerb WH, Khalilb HS, Gaberc RA, Elshweikh SA. Association of STAT4 polymorphism with susceptibility and severity of rheumatoid arthritis and systemic lupus erythematosus in egyptian patients. Egyptian Rheumatol 2016; 38(1): 21-7.[http://dx.doi.org/10.1016/j.ejr.2015.04.003] ], the minor T allele of STAT4 rs7574865 was not associated with RA in Syria (p>.05) as well as in Turkish [21Yüksel B, Ataman Ş, Evcik D, Saime A, Mumcuoglu M, Erdogan B. Is there an association between two-STAT4 gene polymorphisms and rheumatoid arthritis in turkish population? Arch Rheumatol 2014; 29(1): 20-7.[http://dx.doi.org/10.5606/tjr.2014.3967] ], Iranian [29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] ], and African American [20Kelley JM, Hughes LB, Malik A, et al. Genetic variants of STAT4 associated with rheumatoid arthritis in persons of asian and european ancestry do not replicate in african americans. Ann Rheum Dis 2010; 69(4): 625-6.[http://dx.doi.org/10.1136/ard.2009.113183] [PMID: 20237121] ] populations. This might be interpreted by the ethnicity impact which is underlined by intra-population consistency and inter-population inconsistency perceived in these studies. In addition, the average odds of having RA was only 1.5 (1.15-1.9) times higher in the presence of the minor T allele, which does not indicate a considerable effect despite the reported significant association in certain populations.

On the other hand, the reports on the effect of TT genotype showed vast disparity. While no effect was evidenced in seven studies [10Shen L, Liu R, Zhang H, Huang Y, Sun R, Tang P. Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a chinese population. Gene 2013; 526(2): 259-64.[http://dx.doi.org/10.1016/j.gene.2013.05.022] [PMID: 23727609] , 13Orozco G, Alizadeh BZ, Delgado-Vega AM, et al. Association of STAT4 with rheumatoid arthritis: A replication study in three european populations. Arthritis Rheum 2008; 58(7): 1974-80.[http://dx.doi.org/10.1002/art.23549] [PMID: 18576336] , 16Zhao Y, Liu X, Liu X, et al. Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern chinese Han subpopulation. Int J Rheum Dis 2013; 16(2): 178-84.[http://dx.doi.org/10.1111/1756-185X.12093] [PMID: 23773642] , 18Palomino-Morales RJ, Rojas-Villarraga A, González CI, Ramírez G, Anaya JM, Martín J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in colombians. Genes Immun 2008; 9(4): 379-82.[http://dx.doi.org/10.1038/gene.2008.30] [PMID: 18432273] , 29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] , 30Mohamed RH, Pasha HF, El-Shahawy EE. Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in egyptian population. Cell Immunol 2012; 273(1): 67-72.[http://dx.doi.org/10.1016/j.cellimm.2011.11.005] [PMID: 22196377] ] including ours, the average odds of having RA was 1.5, 4.9, and 8.4 higher in five European and Eastern Asian [11Kobayashi S, Ikari K, Kaneko H, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum 2008; 58(7): 1940-6.[http://dx.doi.org/10.1002/art.23494] [PMID: 18576330] , 13Orozco G, Alizadeh BZ, Delgado-Vega AM, et al. Association of STAT4 with rheumatoid arthritis: A replication study in three european populations. Arthritis Rheum 2008; 58(7): 1974-80.[http://dx.doi.org/10.1002/art.23549] [PMID: 18576336] , 15Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC, Gregersen PK. Association of STAT4 with rheumatoid arthritis in the Korean population. Mol Med 2007; 13(9-10): 455-60.[http://dx.doi.org/10.2119/2007-00072.Lee] [PMID: 17932559] , 27Seddighzadeh M, Gonzalez A, Ding B, et al. Variants within STAT genes reveal association with anticitrullinated protein antibody-negative rheumatoid arthritis in 2 European populations. J Rheumatol 2012; 39(8): 1509-16.[http://dx.doi.org/10.3899/jrheum.111284] [PMID: 22753649] ], one Egyptian [31El-Saadanya HM, Amerb WH, Khalilb HS, Gaberc RA, Elshweikh SA. Association of STAT4 polymorphism with susceptibility and severity of rheumatoid arthritis and systemic lupus erythematosus in egyptian patients. Egyptian Rheumatol 2016; 38(1): 21-7.[http://dx.doi.org/10.1016/j.ejr.2015.04.003] ], and one Tunisian [26Ben Hamad M, Cornelis F, Mbarek H, et al. Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders. Clin Exp Rheumatol 2011; 29(2): 269-74.[PMID: 21418779] ] studies, respectively. Although our study does not prove the effect of TT genotype on having RA, our data suggest a potential effect of TT genotype on ACPA status; our RA patients with TT genotype were more likely to be ACPA-positive indicating a higher severity.

Being located in the third intron of STAT4 gene, rs7574865 SNP biological impact is still debated. Whereas it does not disrupt any transcription factor binding site [28Zervou MI, Sidiropoulos P, Petraki E, et al. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum Immunol 2008; 69(9): 567-71.[http://dx.doi.org/10.1016/j.humimm.2008.06.006] [PMID: 18625278] ], alternative splicing mechanism was suggested and STAT4 gene upregulation was established [32Lamana A, López-Santalla M, Castillo-González R, et al. The Minor Allele of rs7574865 in the STAT4 Gene Is associated with increased mRNA and Protein expression. PLoS One 2015; 10(11): e0142683.[http://dx.doi.org/10.1371/journal.pone.0142683] [PMID: 26569609] ]. Collectively, functional and statistical studies hitherto refer to the small effect size of STAT4 rs7574865 SNP regarding both RA onset and severity. The remarkable discrepancies among different populations in terms of minor T allele frequency, TT genotype frequency, presence/absence of association with RA status, and strength of association denote the higher impact of other genetic and environmental factors. HLA-DRB1 alleles/genotypes, for instance, were weakly-to-moderately correlated with RA onset and ACPA status. In addition, the odds of having RA with positive ACPA was as high as 7 times in the presence of an HLA-DRB1 shared epitope allele (DRB*01, *04, and *10).

The reported average onset of RA usually ranges between the ages of 30 and 60; hence case-control studies with young adult healthy controls might get biased. Furthermore, the larger the sample size the higher the statistical power. However, the presence/absence of an association between minor T allele and RA does not seem relevant to the sample size and age as much as the ethnicity of subjects enrolled in the published studies [26Ben Hamad M, Cornelis F, Mbarek H, et al. Signal transducer and activator of transcription and the risk of rheumatoid arthritis and thyroid autoimmune disorders. Clin Exp Rheumatol 2011; 29(2): 269-74.[PMID: 21418779] , 29Nezaratian N, Kazemi Nezhad SR, Hajjari M, Akhoond MR. Lack of association between STAT4 rs7574865 polymorphism and autoimmune diseases including rheumatoid arthritis and systemic sclerosis in Southwest Iran. Meta Gene 2017; 14: 64-8.[http://dx.doi.org/10.1016/j.mgene.2017.08.002] -31El-Saadanya HM, Amerb WH, Khalilb HS, Gaberc RA, Elshweikh SA. Association of STAT4 polymorphism with susceptibility and severity of rheumatoid arthritis and systemic lupus erythematosus in egyptian patients. Egyptian Rheumatol 2016; 38(1): 21-7.[http://dx.doi.org/10.1016/j.ejr.2015.04.003] ]. Moreover, the inference of our statistical analyses remained unchanged when confined to healthy controls over 40 years of age (data not shown).

CONCLUSION

Our preliminary study points to a potential impact of STAT4 rs7574865 TT genotype on ACPA positivity and a more significant impact of HLA-DRB1 shared epitope alleles on RA onset and ACPA status. However, we failed to pinpoint an association between STAT4 rs7574865 minor T allele and RA susceptibility. More studies are recommended to be conducted repeatedly in different ethnic groups so that the debate on such an association might be resolved. Being involved in the RA-associated inflammatory response, STAT4 gene might exhibit other variations to be investigated alike in future studies.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

This study has been approved by the Research Ethics Committee of Damascus University.

HUMAN AND ANIMAL RIGHTS

No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

A written informed consent was obtained from all patients when they were enrolled.

CONFLICT OF INTEREST

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

ACKNOWLEDGEMENTS

Declared none.

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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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