☆ 4.0 Article

Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: Association with the functional IRAK1 196Phe/532Ser haplotype

ARTHRITIS AND RHEUMATISM (2011)

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ARTHRITIS AND RHEUMATISM

卷 63, 期 12, 页码 3979-3987

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WILEY

DOI: 10.1002/art.30640

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Rheumatology

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Agence Nationale de la Recherche [R070994KS]
Societe Francaise de Rhumatologie
Association des Sclerodermiques de France
Groupe Francais de Recherche sur la Sclerodermie
INSERM
German Federal Ministry for Education and Research [01 GM 0310, 01 GM 0634]
Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Neuherberg, Germany
German National Genome Research Network [01GS0834]
University of Ulm
Ludwig-Maximilian University Munich (LMU, Munich Center of Health Sciences)
European Union [HEALTH-F4-2007-201550]
Actelion
GlaxoSmithKline
BSP Pharma
Celgene

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Objective Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. Methods. We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). Results. An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06- 1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06- 2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti- topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51- 3.66], P = 1.56 x 10(-4), OR 2.84 [95% CI 1.87- 4.32], P = 1.07 x 10(-6), and OR 2.09 [95% CI 1.35- 3.24], P = 9.05 x 10(-4), respectively). Conclusion. Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.

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Association of GTF2I, NFKB1, and TYK2 Regional Polymorphisms With Systemic Sclerosis in a Chinese Han Population

Chenxi Liu, Songxin Yan, Haizhen Chen, Ziyan Wu, Liubing Li, Linlin Cheng, Haolong Li, Yongzhe Li

Summary: This study found that the GTF2I rs117026326 and rs73366469 SNPs were strongly associated with SSc in the Chinese Han population, while NFKB1 rs1599961 showed a suggestive association with SSc. However, TYK2 rs2304256 was not significantly associated with SSc in this particular population.

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