Department of Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
Genes Immun. 2013 Apr;14(3):187-91. doi: 10.1038/gene.2013.2. Epub 2013 Feb 7.
HLA-DRB1 codes for a major histocompatibility complex class II cell surface receptor. Genetic variants in and around this gene have been linked to numerous autoimmune diseases. Most notably, an association between HLA-DRB11501 haplotype and multiple sclerosis (MS) has been defined. Utilizing electronic health records and 4235 individuals within Marshfield Clinic's Personalized Medicine Research Project, a reverse genetic screen coined phenome-wide association study (PheWAS) tested association of rs3135388 genotype (tagging HLA-DRB11501) with 4841 phenotypes. As expected, HLA-DRB11501 was associated with MS (International Classification of Disease version 9-CM (ICD9) 340, P=0.023), whereas the strongest association was with alcohol-induced cirrhosis of the liver (ICD9 571.2, P=0.00011). HLA-DRB11501 also demonstrated association with erythematous conditions (ICD9 695, P=0.0054) and benign neoplasms of the respiratory and intrathoracic organs (ICD9 212, P=0.042), replicating previous findings. This study not only builds on the feasibility/utility of the PheWAS approach, represents the first external validation of a PheWAS, but may also demonstrate the complex etiologies associated with the HLA-DRB1*1501 loci.
HLA-DRB1 编码主要组织相容性复合体 II 类细胞表面受体。该基因内和周围的遗传变异与许多自身免疫性疾病有关。最值得注意的是，已经确定了 HLA-DRB11501 单倍型与多发性硬化症 (MS) 之间的关联。利用电子健康记录和 Marshfield 诊所个性化医学研究项目中的 4235 个人，一种称为表型全基因组关联研究 (PheWAS) 的反向遗传筛选测试了 rs3135388 基因型（标记 HLA-DRB11501）与 4841 种表型的关联。正如预期的那样，HLA-DRB11501 与 MS（国际疾病分类第 9 版（ICD9）340 相关，P=0.023）相关，而与酒精性肝硬化（ICD9 571.2，P=0.00011）的关联最强。HLA-DRB11501 还与红斑性疾病（ICD9 695，P=0.0054）和呼吸及胸内器官的良性肿瘤（ICD9 212，P=0.042）相关，这与之前的发现一致。这项研究不仅建立了 PheWAS 方法的可行性/实用性，代表了对 PheWAS 的首次外部验证，而且还可能证明与 HLA-DRB1*1501 位点相关的复杂病因。
