Han Shizhong, Kim-Howard Xana, Deshmukh Harshal, Kamatani Yoichiro, Viswanathan Parvathi, Guthridge Joel M, Thomas Kenaz, Kaufman Kenneth M, Ojwang Joshua, Rojas-Villarraga Adriana, Baca Vicente, Orozco Lorena, Rhodes Benjamin, Choi Chan-Bum, Gregersen Peter K, Merrill Joan T, James Judith A, Gaffney Patrick M, Moser Kathy L, Jacob Chaim O, Kimberly Robert P, Harley John B, Bae Sang-Choel, Anaya Juan-Manuel, Alarcón-Riquelme Marta E, Matsuda Koichi, Vyse Timothy J, Nath Swapan K
Genetic Epidemiology Unit, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Hum Mol Genet. 2009 Mar 15;18(6):1171-80. doi: 10.1093/hmg/ddp007. Epub 2009 Jan 6.
We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele 'A') with SLE in EAs (P = 1.0 x 10(-8)) and Hispanic-Americans (P = 2.9 x 10(-5)). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 10(-50), odds ratio = 1.83, 95% confidence interval = 1.69-1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.
我们最近在整合素α-M（ITGAM）基因的第3外显子中鉴定出一种新的非同义变异rs1143679，该变异与欧美裔（EA）和非裔美国人的系统性红斑狼疮（SLE）易感性相关。通过全基因组关联研究方法，其他三项研究也独立报告了SLE易感性与ITGAM或ITGAM-ITGAX区域之间的关联。本研究的主要目的是评估同一基因或任何附近基因中的单个或多个因果变异是否与SLE易感性有关，并在九个独立数据集（n = 8211）中确认ITGAM与SLE之间的强关联。首先，我们证实了之前报道的rs1143679（风险等位基因“A”）与EA（P = 1.0×10⁻⁸）和西班牙裔美国人（P = 2.9×10⁻⁵）的SLE之间的关联。其次，通过全面的基于归因的关联测试，我们发现ITGAM是SLE的主要非人类白细胞抗原易感基因之一，并且EA的最强关联是相同编码变异rs1143679（log₁₀贝叶斯因子 = 20，P = 6.17×10⁻²⁴）。第三，我们在另外三个病例对照样本中确定了rs1143679与SLE关联的稳健性，包括英国（P = 6.2×10⁻⁸）、哥伦比亚（P = 3.6×10⁻⁷）、墨西哥（P = 0.002），以及来自英国（P（传递不平衡检验）= 1.4×10⁻⁵）和墨西哥（P（传递不平衡检验）= 0.015）的两组独立三联体。对所有独立数据集进行的荟萃分析大大加强了这种关联（P（荟萃分析）= 7.1×10⁻⁵⁰，优势比 = 1.83，95%置信区间 = 1.69 - 1.98，n = 10046）。然而，在韩国或日本样本中未观察到这种ITGAM关联，其中rs1143679对于非风险等位基因（G）是单态的。结合我们早期的研究结果，这些结果表明编码变异rs1143679最能解释ITGAM与SLE的关联，特别是在欧洲和非洲裔人群中，但在亚洲人群中并非如此。
