Abstract:
The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.
摘要:
混合冷球蛋白血管炎的宿主遗传基础尚不清楚,也没有在大型队列中进行研究。在356个丙型肝炎病毒(HCV)RNA阳性的冷球蛋白相关性血管炎和447个种族匹配的个体中进行了全基因组关联研究,HCVRNA阳性对照。所有病例均有血清冷球蛋白和血管炎综合征。使用根据性别调整的逻辑回归分析了来自IlluminaHumanOmni1-Quad芯片的899641个标记,以及遗传决定的祖先。使用91例病例和180例对照进行了选择的单核苷酸多态性(SNP)的复制,根据性别和原籍国进行调整。在NOTCH4和MHCII类基因附近的6号染色体上鉴定出最重要的关联。在HLA-DRB1和DQA1之间的SNPrs9461776(比值比=2.16,P=1.16E-07)的6号染色体上检测到全基因组的显着关联:这种关联在其他独立样本中进一步复制(荟萃分析P=7.1×10(-9))。通过NOTCH4和MHCII类基因附近的SNP鉴定出与冷球蛋白相关血管炎相关的全基因组显着关联。这两个区域是相关的,并且很难在这个扩展的主要组织相容性复杂区域中解开哪个基因与混合冷球蛋白血症血管炎有关。