Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity
Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity
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DOI：
10.1016/j.ajhg.2014.02.013
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发表时间：
2014-04-03
影响因子：
9.8
通讯作者：
Raychaudhuri, Soumya
中科院分区：
文献类型：
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作者：
Han, Buhm;Diogo, Dorothee;Raychaudhuri, Soumya
尽管在确定抗瓜氨酸化蛋白-自身抗体阳性（ACPA(+)）类风湿性关节炎（RA）的人类白细胞抗原（HLA）等位基因方面取得了进展，但由于临床队列中的临床异质性，确定ACPA-阴性（ACPA(-)）类风湿性关节炎的HLA等位基因一直具有挑战性。我们在2406例ACPA(-) RA病例和13930例对照个体中，从免疫芯片数据中推算出8961个经典HLA等位基因、氨基酸和snp。我们开发了一种统计方法来识别和调整ACPA RA的临床异质性，并观察到HLA-DR β 1中11位的丝氨酸和亮氨酸（p = 1.4 x 10(13)，优势比[OR] = 1.30）和HLA-B中9位的天冬氨酸（p = 2.7 x 10(-12), OR = 1.39）在肽结合槽内的独立关联。这些氨基酸位置诱导了HLA-DRB1*03（编码丝氨酸11）和HLA-B*08（编码天冬氨酸9）的关联。我们在一组独立的427例ACPA（-）病例受试者中验证了这些发现，这些受试者使用高灵敏度的ACPA检测进行了仔细的表型分析，以及1,691名对照受试者(HLA-DR β 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28；HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34)。虽然这两个氨基酸位点都驱动ACPA（+）和ACPA（-）疾病的风险，但HLA-DR β 1位点11的单个残基的影响是不同的（p < 2.9 x 10(-107)）。我们还在7279例ACPA(+) RA病例和15870例对照中发现了HLA-A位置77与ACPA(+) RA的关联（p = 2.7 x 10(-8), OR = 0.85）。这些结果提供了越来越多的证据，证明ACPA（+）和ACPA(-) RA在遗传上是不同的，并且可能有不同的自身抗原参与发病机制。我们期望我们的方法在分析主要组织相容性复合体（MHC）和非MHC区域异质性的临床条件方面具有广泛的应用。
Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.