Abstract
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 IGHV4-61*02 allele. We show each copy of IGHV4-61*02 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 × 10−9). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.
Highlights
The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD)
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 IGHV4-61*02 allele
Our study was undertaken using a collection of 3,412 DNA samples from individuals recruited in eight Oceanian countries established by the Pacific Islands RHD Genetics Network (Fig. 1a)
Summary
The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). We report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. We show each copy of IGHV4-61*02 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 1⁄4 4.1 Â 10 À 9) These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility. We report a genome-wide association study (GWAS) of RHD susceptibility in the endemic settings of Oceania, where the disease remains a leading cause of premature death and disability[9]. Set in populations hitherto largely overlooked by genetics research, to the best of our knowledge, our study is the first GWAS of RHD, providing much needed insight into the pathogenesis of this devastating disease. As the only study from the GWAS era that we are aware of linking germline coding variants in the IGH locus to disease susceptibility, our study suggests further consideration should be given to the role of IGH polymorphism in autoimmune disease
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