The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019

Lack of Association of the CD247 SNP rs2056626 with Systemic Sclerosis in Han Chinese



Jiucun Wang 1, 2, Lin Yi 3, 4, Xinjian Guo 3, Dongyi He 3, Hongyi Li 3, Gang Guo 6, Yi Wang 1, Hejian Zou 2, 7, Yuanhui Gu 8, Wenzhen Tu 9, Wenyu Wu 7, Li Yang 10, Rong Xiao 11, Syeling Lai 12, Shervin Assassi 3, Maureen D Mayes 3, Xiaodong Zhou *, 3
1 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, China
2 Institute of Rheumatology, Immunology, and Allergy, Fudan University, China
3 Division of Rheumatology and Clinical Immunogenetics, University of Texas Medical School at Houston, USA
4 Gansu College of Traditional Chinese Medicine, Lanzhou, Gansu, China
5 Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital, Shanghai, China
6 Yiling Hospital, Shijiazhuang, Hebei Province, China
7 Huashan Hospital, Fudan University, China
8 Gansu Provincial Hospital, Lanzhou, Gansu, China
9 Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai, China
10 Teaching Hospital of Chengdu University of TCM, Chengdu, Sichuan Province, China
11 Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
12 Department of pathology, Baylor College of Medicine, Michael E. DeBakey VA Medical Center, USA

Abstract

Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. A recent genome-wide association study (GWAS) indicated that CD247 was strongly associated with SSc, which was subsequently confirmed in a SSc cohort of European population. However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc. The studies herein aimed to examine whether the SSc-associated SNP rs2056626 of CD247 identified in Caucasian is also associated with Han Chinese SSc. A Han Chinese cohort consisting of 387 SSc patients and 523 healthy controls were examined in the studies. TaqMan assays were performed to examine the SNP. Exact p-values were obtained (Fisher’s test) from 2x2 tables of allele counts and disease status. The results showed that there was no association between rs2056626 of CD247 and SSc or any SSc subtypes of Han Chinese. The negative results are important in understanding genetics of SSc in different ethnic populations, which further suggest complex nature of genetics of SSc.

Keywords: CD247, Chinese population, genetics, polymorphism/SNP, scleroderma systemic sclerosis/SSc..


Article Information


Identifiers and Pagination:

Year: 2014
Volume: 8
First Page: 43
Last Page: 45
Publisher Id: TORJ-8-43
DOI: 10.2174/1874312901408010043

Article History:

Received Date: 14/7/2014
Revision Received Date: 5/9/2014
Acceptance Date: 11/9/2014
Electronic publication date: 2 /10/2014
Collection year: 2014

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 924
Abstract HTML Views: 1124
PDF Downloads: 218
Total Views/Downloads: 2266

Unique Statistics:

Full-Text HTML Views: 545
Abstract HTML Views: 684
PDF Downloads: 134
Total Views/Downloads: 1363
Geographical View

© Wang et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Internal Medicine, University of Texas Medical School at Houston, 6431 Fannin Street, MSB5270, Houston Texas 77030, USA; Tel: 713-500-6900; Fax: 713-500-0580; E-mail: xiaodong.zhou@uth.tmc.edu




INTRODUCTION

T-cell surface glycoprotein CD3 zeta chain (CD247), a component of T cell receptor (TCR)/CD3 complex, plays an important role in assembly and transport of the TCR/CD3 complex to the cell surface and in receptor signaling function [1Irving BA, Chan AC, Weiss A. Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain. J Exp Med 1993; 177: 1093-103.,2Sussman JJ, Bonifacino JS, Lippincott-Schwartz J , et al. Failure to synthesize the T cell CD3-zeta chain structure and function of a partial T cell receptor complex. Cell 1988; 52: 85-95.]. Somatic CD3-zeta mutations have been shown to impair immune function [3Rieux-Laucat F, Hivroz C, Lim A , et al. Inherited and somatic CD3-zeta mutations in a patient with T-cell deficiency. New Eng J Med 2006; 354: 1913,-21.]. Recently, an intronic single nucleotide polymorphism (SNP) rs2056626 of the CD247gene was reported to be associated with systemic sclerosis (SSc) in a genome-wide association study (GWAS) of European and US Caucasians [4Radstake T, Gorlova O, Rueda B , et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 2010; 42: 426-9.]. An independent study with a French Caucasian cohort (1031 patients/1014 controls) confirmed the association between rs2056626 and SSc, and further indicated that the rs2056626G minor allele was associated in a dominant pattern with a protective effect to SSc [5Dieudé P, Boileau C, Guedj M , et al. Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis 2011; 70: 1695-6.]. However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc and SSc clinical features. Chinese SSc patients have some unique serological and clinical features with high frequency of ATA and pulmonary fibrosis [6Wang J, Assassi S, Guo G , et al. Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol 2012; 32(5): 617-21.]. Association between CD247 and SSc has not been reported in Chinese SSc. Recently, we established a SSc cohort of Han Chinese through multicenter SSc consortium in China under the International Network of Scleroderma Clinical Care and Research (InSCAR) (http://www.inscar-global.org). This cohort has been extensively examined in multiple genetic association studies of SSc [7Wang J, Guo X, Yi L , et al. Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS ONE 2014; 9: e87363.-10Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581-90.]. We undertook the current study to examine whether the genotype of the CD247 rs2056626 confer susceptibility to SSc and clinical features of SSc in Han Chinese population.

MATERIALS AND METHODS

Study Subjects

A case-control study including 387 SSc patients and 523 healthy controls of Han Chinese was performed. SSc patients were recruited from a multicenter study including hospitals and outpatient clinics in Shanghai, Hebei province, Sichuan province, and Hunan province in China [6Wang J, Assassi S, Guo G , et al. Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol 2012; 32(5): 617-21.-9Yi L, Wang JC, Guo XJ , et al. STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol 2013; 26: 473-8.]. All patients met the American College of Rheumatology (ACR) classification criteria for SSc [10Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581-90.]. None of the controls had autoimmune diseases. The studies were approved by the institutional review board, and written informed consents were obtained from all subjects.

Tests for Autoantibodies and Pulmonary Fibrosis

Patient’s sera were tested for antinuclear antibodies (ANA) by indirect immunofluorescence using HEp-2 cells as antigen substrate (Antibodies, Davis, CA). Anti-topoisomerase I (ATA) was detected by passive immunodiffusion against calf thymus extracts (INOVA, Diagnostics). Anti-centromere autoantibody (ACA) was determined by indirect immunofluorescence using HEp-2 cells. Diagnosis of pulmonary fibrosis was confirmed with either chest X-ray (41.9 %) or thorax CT (58.1 %) in different hospitals.

Genotyping Assays

The SNP genotyping for rs2056626 of CD247 was performed with TaqMan assays as we described previously [9Yi L, Wang JC, Guo XJ , et al. STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol 2013; 26: 473-8.]. A standard control DNA (Life Technology, Forster city, CA, USA) was used for quality control. The probe was purchased from the pre-designed SNP Assays of Life Technologies. The SDS2.4 was used for reading genotyping (Life Technologies).

Statistical Analysis

Exact p-values were obtained (Fisher’s test) from 2x2 tables of allele counts and disease status. The disease status includes SSc in general, SSc subtypes, and SSc with pulmonary fibrosis (PF). SSc subtypes include diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) of clinical subsets, and SSc patients with autoantibodies to DNA topoisomerase I (ATA) or autoantibodies to centromere protein (ACA). The p values less than 0.05 were considered statistically significant.

RESULTS AND DISCUSSION

SSc patients of the Han Chinese cohort were 93% positive for ANA. There were 137 limited cutaneous SSc (lcSSc) (42.4%) and 186 diffused cutaneous SSc (dcSSc) (57.6%), other were undefined. There were 349 patients examined for ATA with 167 positive (47.9%), 321 were examined for ACA with 45 positive (14.0%). In addition, there were 287 patients examined with chest X-ray and/or CT for diagnosis of pulmonary fibrosis (PF), and 210 were positive (73.2%). The high rate of PF correlates with the incidence of dcSS, and which was consistent with SSc features in Han Chinese [6Wang J, Assassi S, Guo G , et al. Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol 2012; 32(5): 617-21.].

In contrast to the previous reports in other ethnic populations, SSc patients of Han Chinese showed no association between rs2056626 and SSc or any subtypes of SSc including lcSSc, dcSSc, ATA, ACA and PF (Table 1). Each genotype of the rs2056626 showed similar frequency between cases and controls. The rs2056626G minor allele did not show protective effect from SSc in this cohort that was reported in the French SSc studies [5Dieudé P, Boileau C, Guedj M , et al. Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis 2011; 70: 1695-6.]. It is worth noting that this Han Chinese cohort has been examined in multiple genetic studies of SSc [7Wang J, Guo X, Yi L , et al. Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS ONE 2014; 9: e87363.-9Yi L, Wang JC, Guo XJ , et al. STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol 2013; 26: 473-8.]. In the studies of STAT4, another SSc-associated gene, the corresponding polymorphism was found to be strongly associated with Chinese SSc in this cohort [9Yi L, Wang JC, Guo XJ , et al. STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol 2013; 26: 473-8.], which was consistent with the reports in Caucasian population [4Radstake T, Gorlova O, Rueda B , et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 2010; 42: 426-9., 11Rueda B, Broen J, Simeon C , et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet 2009; 18: 2071-7., 12Dieudé P, Guedj M, Wipff J , et al. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum 2009; 60: 2472-9.]. In the studies of HLA-DPB1 and –DQB1, the specific HLA alleles in this Chinese cohort were associated with SSc, and that was also consistent with Caucasian population [13Arnett FC, Gourh P, Shete S , et al. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010; 69: 822-7.]. For instance, HLA-DPB1*13:01 was strongly associated with ATA positive SSc [7Wang J, Guo X, Yi L , et al. Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS ONE 2014; 9: e87363.,13Arnett FC, Gourh P, Shete S , et al. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010; 69: 822-7.], and HLA-DQB1*05:01 with ACA positive SSc in both Han Chinese and US Caucasian cohorts [8Zhou XD, Yi L, Guo XJ , et al. Association of HLA-DQB1*0501 with scleroderma and its clinical features in Chinese population. Int J Immunopathol Pharmacol 2013; 26: 747-51.,13Arnett FC, Gourh P, Shete S , et al. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010; 69: 822-7.]. On the other hand, DQB1*06:01 appeared more common in ATA positive Chinese SSc, which was not reported in US SSc, but was consistent with a report of Japanese SSc cohort [14Kuwana M, Kaburaki J, Okano Y, Inoko H, Tsuji K. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest 1993; 92: 1296-301.]. Moreover, two previously reported SSc-protective alleles DQB1*02:02 and *06:02 in US Caucasian [13Arnett FC, Gourh P, Shete S , et al. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010; 69: 822-7.] did not show association with Han Chinese SSc, but which appeared in consistent with SSc of US Hispanics and Africa Americans [13Arnett FC, Gourh P, Shete S , et al. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010; 69: 822-7.]. Therefore, one possible explanation of the discrepancies may be genetic heterogeneity between Han Chinese and other ethnic populations, especially Caucasian population, which may significantly impact the complex trait of SSc.

Table 1

Association studies of the rs2056626 of the CD247 gene with SSc of Han Chinese population.




This is the first report of studying CD247 in Han Chinese SSc, and the first time to demonstrate a discrepancy in genetic association between the SNP of CD247 and SSc. It revealed different genetic aspects of SSc, and suggested that previously reported association of the CD247 polymorphism may be ethnic specific, and further verification in different ethnic populations may be necessary.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The studies were supported by research grants from the US NIH NIAID UO1, 1U01AI09090 and the Science and Technology Committee of Shanghai Municipality (114107 01800, 11DJ1400102), International S&T Cooperation Program of China (2013DFA30870), the National Basic Research Program (2012CB944600), Ministry of Science and Technology (2011BAI09B00), Ministry of Health (201002007). Key projects of Shanghai Municipal Health Bureau (2011027), The National Natural Science Funds (81273979), National Science Foundation of China (NSFC): Oversea Collaboration Project 81328001.

REFERENCES

[1] Irving BA, Chan AC, Weiss A. Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain. J Exp Med 1993; 177: 1093-103.
[2] Sussman JJ, Bonifacino JS, Lippincott-Schwartz J , et al. Failure to synthesize the T cell CD3-zeta chain structure and function of a partial T cell receptor complex. Cell 1988; 52: 85-95.
[3] Rieux-Laucat F, Hivroz C, Lim A , et al. Inherited and somatic CD3-zeta mutations in a patient with T-cell deficiency. New Eng J Med 2006; 354: 1913,-21.
[4] Radstake T, Gorlova O, Rueda B , et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 2010; 42: 426-9.
[5] Dieudé P, Boileau C, Guedj M , et al. Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis 2011; 70: 1695-6.
[6] Wang J, Assassi S, Guo G , et al. Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol 2012; 32(5): 617-21.
[7] Wang J, Guo X, Yi L , et al. Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS ONE 2014; 9: e87363.
[8] Zhou XD, Yi L, Guo XJ , et al. Association of HLA-DQB1*0501 with scleroderma and its clinical features in Chinese population. Int J Immunopathol Pharmacol 2013; 26: 747-51.
[9] Yi L, Wang JC, Guo XJ , et al. STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol 2013; 26: 473-8.
[10] Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581-90.
[11] Rueda B, Broen J, Simeon C , et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet 2009; 18: 2071-7.
[12] Dieudé P, Guedj M, Wipff J , et al. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum 2009; 60: 2472-9.
[13] Arnett FC, Gourh P, Shete S , et al. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis 2010; 69: 822-7.
[14] Kuwana M, Kaburaki J, Okano Y, Inoko H, Tsuji K. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest 1993; 92: 1296-301.

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)


SCImago Journal Ranking

SCImago Journal & Country Rank

Browse Contents



Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open