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
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
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DOI：
10.1136/ard.2009.111906
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发表时间：
2010-05-01
影响因子：
27.4
通讯作者：
Reveille, John D.
中科院分区：
文献类型：
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作者：
Arnett, Frank C.;Gourh, Pravitt;Reveille, John D.
目的采用病例对照研究方法对1300例硬皮病患者(白人961例，黑人178例，拉美裔161例)的临床皮肤形态(局限性与弥漫性)、SSC特异性自身抗体(抗皮肤红斑(ACA)、抗拓扑异构酶I(ATA)、抗RNA聚合酶III(ARA)、抗U3核糖核蛋白(纤毛蛋白)等)进行基因分型，以确定人类白细胞抗原II类(DRB1、DQB1、DQA1和DPB1)等与硬皮病(SSC)相关的等位基因、单倍型和共有表位。结果在白人和西班牙裔人群中，与SSC关联最强的是DRB1*1104、DQA1*0501、DQB1*0301单倍型和编码26位非亮氨酸残基的DQB1*0301等位基因(DQB1 26 Epi)，而DRB1*0701、DQA1*0201、DQB1*0202单倍型和DRB1*1501单倍型分别与SSC呈负相关，可能在显性和隐性模型中具有保护性。这些关联并不区分局限性和弥漫性SSc。黑人SSc与DRB1*0804、DQA1*0501、DQB1*0301等位基因相关。DPB1*1301显示ATA的优势比最高(OR=14)。此外，与DR/DQ没有连锁不平衡或基因互作。在白人和西班牙裔人群中，DQB1*0501和DQB1*26等位基因对ACA的解释最好，DRB1*0404、DRB1*11和DQB1*03等位基因对ARA的解释最好，而在黑人人群中DRB1*08对ACA的解释效果最好。结论HLAII类基因在SSC中具有独特的多重效应，尤其是对不同亚型自身抗体标志物的影响。
Objective To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case-control association study.Patients and methods 1300 SSc cases (961 white, 178 black and 161 Hispanic subjects) characterised for clinical skin forms (limited vs diffuse), SSc-specific autoantibodies (anticentromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 ribonucleoprotein (fibrillarin)) and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modelling for dominant, additive and recessive effects from HLA.Results The strongest positive class II associations with SSc in white and Hispanic subjects were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701,DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate between limited and diffuse SSc. SSc in black subjects was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR = 14). Moreover, it showed no linkage disequilibrium or gene interaction with DR/DQ. ACA was best explained by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in white and Hispanic subjects but DRB1*08 in black subjects.Conclusion These data indicate unique and multiple HLA-class II effects in SSc, especially on autoantibody markers of different subphenotypes.