Association of HLA-DPB1 with Scleroderma and Its Clinical Features in Chinese Population

Citation: Wang J, Guo X, Yi L, Guo G, Tu W, et al. ( Association of HLA-DPB1 with Scleroderma and Its Clinical Features in Chinese Population Jiucun Wang 0 Xinjian Guo 0 Lin Yi 0 Gang Guo 0 Wenzhen Tu 0 Wenyu Wu 0 Li Yang 0 Rong Xiao 0 Yuan Li 0 Haiyan Chu 0 Dongyi He 0 Li Jin 0 Maureen D. Mayes 0 Hejian Zou 0 Xiaodong Zhou 0 Masataka Kuwana, Keio University School of Medicine, Japan 0 1 Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University , Shanghai , China , 2 Institute of Rheumatology, Immunology and Allergy, Fudan University , Shanghai , China , 3 Division of Rheumatology and Clinical Immunogenetics, The University of Texas Medical School at Houston , Houston , Texas, United States of America, 4 Gansu College of Traditional Chinese Medicine , Lanzhou, Gansu , China , 5 Yiling Hospital , Shijiazhuang, Hebei Province , China , 6 Shanghai Traditional Chinese Medicine-Integrated Hospital , Shanghai , China , 7 Division of Dermatology, Huashan Hospital, Fudan University , Shanghai , China , 8 Division of Rheumatology, Teaching Hospital of Chengdu University of TCM , Chengdu, Sichuan Province , China , 9 Department of Dermatology, Second Xiangya Hospital, Central South University , Changsha, Hunan Province , China , 10 Department of Rheumatology, Shanghai Guanghua Hospital , Shanghai , China , 11 Division of Rheumatology, Huashan Hospital, Fudan University , Shanghai , China Human leukocyte antigen DPB1 was reported to contain singly nucleotide polymorphisms conferring the strongest susceptibility to systemic sclerosis in Korean population. However, associations of specific DPB1 alleles with SSc vary in different ethnic populations. The aim of this study was to profile DPB1 alleles in Chinese population and to identify specific DPB1 alleles in association with SSc and clinical and serological features of SSc in Han Chinese. A cohort containing 338 patients with SSc and 480 gender-matched and unrelated controls were examined in the study. The HLA-DPB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher's test) from 262 tables of allele counts or allele carriers and disease status. Thirty eight DPB1 alleles were found in the cohort. DPB1*05:01 was the most common allele in this cohort. DPB1*03:01 and *13:01 were significantly increased in SSc. DPB1*13:01 association had already been described in other ethnic populations, whereas DPB1*03:01 was specific to Han Chinese patients with SSc. In addition, comparisons between SSc subsets indicated that patients carrying DPB1*03:01 were more likely to develop pulmonary fibrosis, DPB1*04 carriers were increased in SSc patients with anti-centromere autoantibodies and in contrast, SSc patients with homozygous DPB1*05:01 showed an opposite association with marginal significance. - Funding: The studies were supported by research grants from the US NIH NIAID UO1, 1U01AI09090 and the Science and Technology Committee of Shanghai Municipality (11410701800), International S&T Cooperation Program of China (2013DFA30870), the National Basic Research Program (2012CB944600), Ministry of Science and Technology (2011BAI09B00), Ministry of Health (201002007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Systemic sclerosis (SSc) or scleroderma is a rare and complex immune-mediated disease. It is clinically characterized by fibrosis of skin and internal organs. Based on the extent of skin fibrosis, SSc can be classified into two clinical subsets: limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) SSc. The latter subset is characterized by more rapid progression of skin and visceral involvement, as well as poorer prognosis [1]. SSc patients also are characterized by the presence of a group of autoantibodies in circulation, and which classify SSc patients into specific autoantibody subsets. The most common of these autoantibodies are directed against DNA topoisomerase I (ATA), centromeric proteins (ACA) and RNA polymerases III (anti-RNAP3) [2,3]. Genetic studies of SSc indicated that specific genotypes of multiple genes contributing to susceptibility to SSc and its clinical presentations [4,5,6]. A recent genome wide association study (GWAS) in a Korean SSc cohort revealed that the specific single nucleotide polymorphisms (SNPs) of human leukocyte antigen (HLA) DPB1 conferred the strongest susceptibility to SSc, and HLA-DPB1*13:01 and DPB1*09:01 were the most susceptible alleles to Korean SSc [6]. Studies of US Caucasian population supported DPB1*13:01, but not DPB1*09:01, as a major susceptibility allele to SSc, and especially to ATA positive SSc [7], which was consistent with the reports of a SSc cohort of UK Caucasians [8]. Studies of South Africans indicated that DPB1*13:01 was significantly increased in dcSSc, but not in lcSSc [9]. On the other hand, a Japanese SSc cohort supported only DPB1*09:01 in association with SSc [10]. However, AfricanAmerican and Hispanic SSc of US cohorts did not show any association with HLA-DPB1 [7]. Chinese SSc patients have unique serological and clinical features with high frequency of ATA, dcSSc and pulmonary fibrosis but low in anti-RNAP3 [11]. Associations between the HLA alleles and SSc have 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). The goal of the present study is to OR = odds ratio; CI = confidence interval; nominal significance p value,0.05; Bonferroni correction for significance was calculated as p,0.0013. doi:10.1371/journal.pone.0087363.t001 investigate the HLA-DPB1 alleles in association with potential risk to or protection from SSc in Han Chinese. Materials and Methods Patient enrollment SSc patients were recruited from a multicenter study including hospitals and outpatient clinics in Shanghai, Hebei province, Sichuan province, and Hunan province in China. All patients met the American College of Rheumatology (ACR) classification criteria for SSc [12], or had at least 3 out of 5 CREST features (Calcinosis, Raynauds phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) with sclerodactyly being mandatory [13]. A total of 338 patients with SSc and 480 gendermatched and unrelated controls were examined in the studies. None of the controls had autoimmune diseases. There were 129 lcSSc and 159 dcSSc, others were undefined. The studies were approved by the institutional review boards of the University of Texas Health Science Center at Houston, United States of American and Fudan University, Shanghai, China. Written informed consent was obtained from each study subj (...truncated)