Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Paris Centre de Recherche Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale, Hôpital Européen Georges Pompidou, 56, rue Leblanc, 75908 Paris, France.
Nat Commun. 2017 May 11;8:14946. doi: 10.1038/ncomms14946.
The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-6102 allele. We show each copy of IGHV4-6102 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27-1.61, P=4.1 × 10). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.
南太平洋地区的土著居民患有风湿性心脏病（RHD）的负担很重。在这里，我们报告了一项针对 RHD 易感性的全基因组关联研究（GWAS），该研究共招募了来自八个大洋洲国家的 2852 人。我们按祖先进行分层，在对另外三个祖先群体（波利尼西亚人、南亚人和混血或其他人群）中的提示性基因座进行随访之前，分析了已基因分型和已推断的美拉尼西亚人（607 例病例和 1229 例对照）中的变体。我们在免疫球蛋白重链（IGH）基因座中发现了一个新的易感信号，该信号集中在 IGHV4-61 基因片段中的非同义变异的单倍型上，该基因片段对应于 IGHV4-6102 等位基因。我们表明，IGHV4-6102 的每个拷贝都与 RHD 风险增加 1.4 倍相关（优势比 1.43，95%置信区间 1.27-1.61，P=4.1×10）。这些发现为 IGH 基因座中种系变异在疾病易感性中的作用提供了新的见解。
