Department of Cell Biology, Fukuoka University, Fukuoka, Japan.
J Hum Genet. 2011 Nov;56(11):772-8. doi: 10.1038/jhg.2011.99. Epub 2011 Sep 8.
To identify genetic variants that confer the risk of Graves' disease (GD) in the Japanese population, we conducted a two-stage genome-wide association study (GWAS) using 1119 Japanese individuals with GD and 2718 unrelated controls, and a subsequent replication study using independent 432 GD cases and 1157 controls. We identified 34 single nucleotide polymorphisms (SNPs) to be significantly associated with GD in the GWAS phase. Twenty-two out of 34 SNPs remained positive in the replication study. All 22 SNPs were located within the major histocompatibility complex (MHC) locus on chromosome 6p21. No strong long-range linkage disequilibrium (LD) was observed among the 22 SNPs, indicating independent involvement of multiple loci within the MHC with the risk of GD. Multivariate stepwise logistic regression analysis selected rs3893464, rs4313034, rs3132613, rs4248154, rs2273017, rs9394159 and rs4713693, as markers for independent risk loci for GD. The analysis of LD between these seven SNPs and tagging SNPs for GD-associated human leukocyte antigen (HLA) alleles in the Japanese population (HLA-DPB1()0501 and HLA-A()0206) demonstrated that all of and five of seven SNPs were not in strong LD with HLA-DPB1()0501 and HLA-A()0206, respectively. Although causal variants remain to be identified, our results demonstrate the existence of multiple GD susceptibility loci within the MHC region.
为了鉴定日本人群中 Graves 病（GD）的风险相关遗传变异，我们采用全基因组关联研究（GWAS）方法，对 1119 例 GD 患者和 2718 例无关对照进行了两阶段研究，并采用独立的 432 例 GD 病例和 1157 例对照进行了后续的重复研究。在 GWAS 阶段，我们鉴定到 34 个单核苷酸多态性（SNP）与 GD 显著相关。在重复研究中，有 22 个 SNP 仍然为阳性。这 34 个 SNP 中的 22 个均位于染色体 6p21 上的主要组织相容性复合体（MHC）区域。在这 22 个 SNP 之间未观察到强的长程连锁不平衡（LD），提示 MHC 内的多个独立位点与 GD 风险相关。多变量逐步逻辑回归分析选择 rs3893464、rs4313034、rs3132613、rs4248154、rs2273017、rs9394159 和 rs4713693 作为 GD 独立风险位点的标记。在日本人群中，对这 7 个 SNP 与 GD 相关的人类白细胞抗原（HLA）等位基因的标记 SNP（HLA-DPB1()0501 和 HLA-A()0206）之间的 LD 进行分析，结果表明，这 7 个 SNP 中的所有 SNP 和其中 5 个 SNP 与 HLA-DPB1()0501 和 HLA-A()0206 均不存在强 LD。尽管尚需鉴定因果变异，但我们的结果表明，MHC 区域内存在多个 GD 易感性位点。
