Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania
Parks T., Mirabel MM., Kado J., Auckland K., Nowak J., Rautanen A., Mentzer AJ., Marijon E., Jouven X., Perman ML., Cua T., Kauwe JK., Allen JB., Taylor H., Robson KJ., Deane CM., Steer AC., Hill AVS., Allen L., Allen M., Braunstein C., Colquhoun SM., Jewine A., Ah Kee M., Kumar R., John Martin W., Mataika R., Nadra M., Nadu S., Naseri T., Noël B., Simon N., Ward B.
AbstractThe 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 theIGHV4-61gene segment corresponding to theIGHV4-61*02 allele. We show each copy ofIGHV4-61*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.