Carmona F David, Mackie Sarah L, Martín Jose-Ezequiel, Taylor John C, Vaglio Augusto, Eyre Stephen, Bossini-Castillo Lara, Castañeda Santos, Cid Maria C, Hernández-Rodríguez José, Prieto-González Sergio, Solans Roser, Ramentol-Sintas Marc, González-Escribano M Francisca, Ortiz-Fernández Lourdes, Morado Inmaculada C, Narváez Javier, Miranda-Filloy José A, Beretta Lorenzo, Lunardi Claudio, Cimmino Marco A, Gianfreda Davide, Santilli Daniele, Ramirez Giuseppe A, Soriano Alessandra, Muratore Francesco, Pazzola Giulia, Addimanda Olga, Wijmenga Cisca, Witte Torsten, Schirmer Jan H, Moosig Frank, Schönau Verena, Franke Andre, Palm Øyvind, Molberg Øyvind, Diamantopoulos Andreas P, Carette Simon, Cuthbertson David, Forbess Lindsy J, Hoffman Gary S, Khalidi Nader A, Koening Curry L, Langford Carol A, McAlear Carol A, Moreland Larry, Monach Paul A, Pagnoux Christian, Seo Philip, Spiera Robert, Sreih Antoine G, Warrington Kenneth J, Ytterberg Steven R, Gregersen Peter K, Pease Colin T, Gough Andrew, Green Michael, Hordon Lesley, Jarrett Stephen, Watts Richard, Levy Sarah, Patel Yusuf, Kamath Sanjeet, Dasgupta Bhaskar, Worthington Jane, Koeleman Bobby P C, de Bakker Paul I W, Barrett Jennifer H, Salvarani Carlo, Merkel Peter A, González-Gay Miguel A, Morgan Ann W, Martín Javier
Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain.
Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS7 4SA, UK.
Am J Hum Genet. 2015 Apr 2;96(4):565-80. doi: 10.1016/j.ajhg.2015.02.009. Epub 2015 Mar 26.
We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.
我们对巨细胞动脉炎（GCA）进行了大规模基因分析，GCA是一种多基因免疫介导的血管炎。通过免疫芯片阵列对一个病例对照队列进行基因分型，该队列包括1651例GCA病例受试者和来自六个不同欧洲血统国家的15306名无关对照受试者。我们还使用先前验证的归因方法推算HLA数据，以对该基因组区域进行更全面的分析。在HLA区域观察到最强的关联信号，rs477515代表最高峰（p = 4.05×10⁻⁴⁰，OR = 1.73）。一个多变量模型，包括HLA-DRβ1和HLA-DQα1的II类氨基酸以及HLA-B的一个I类氨基酸，解释了大部分HLA与GCA的关联，这与先前报道的经典HLA等位基因如HLA-DRB1（*）04的关联一致。对多态性氨基酸位置的综合检验突出显示DRβ1 13（p = 4.08×10⁻⁴³）和HLA-DQα1 47（p = 4.02×10⁻⁴⁶）、56和76（p均 = 1.84×10⁻⁴⁵）是疾病易感性的相关位置。在HLA区域之外，最显著的基因座包括PTPN22（rs2476601，p = 1.73×10⁻⁶，OR = 1.38）、LRRC32（rs10160518，p = 4.39×10⁻⁶，OR = 1.20）和REL（rs115674477，p = 1.10×10⁻⁵，OR = 1.63）。我们的研究提供了证据，证明HLA I类和II类分子对GCA易感性有很大贡献。在非HLA区域，我们证实了功能性PTPN22 rs2476601变体的关键作用，并提出了其他与GCA相关的假定风险基因座，这些基因座参与Th1、Th17和调节性T细胞功能。
