Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania

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.

A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus

“…To date, few diseases have been robustly associated to IGH 22,23,70,71 . We previously suggested this was due to sparse locus coverage of genotyping arrays and an inability of array SNPs to tag functional IGH variants 4,20 .…”

“…We explored the potential advantage of our genotyping approach compared to array genotyping and imputation. We applied our long-read capture method to a sample selected from a recent rheumatic heart disease (RHD) GWAS 22 , which identified IGH as the primary risk locus. Direct genotyping in this sample was carried out previously using the HumanCore-24 BeadChip (n=14 SNVs) and targeted Sanger sequencing (n=8 SNVs); genotypes at additional SNVs were imputed with IMPUTE2 59 , using a combination of 1KGP and population-specific sequencing data as a reference set.…”

“…As a result, IGH has been largely overlooked by genome-wide studies, leaving our understanding of the contribution of IGH polymorphism to antibody-mediated immunity incomplete 4,20,21 . While early studies uncovered associations to disease susceptibility within IGH, few links have been made by genome-wide association studies (GWAS) and whole genome sequencing (WGS) 20,22,23 . Moreover, little is known about the genetic regulation of the human Ab response, despite evidence that features of the Ab repertoire are heritable 12,19,[24][25][26][27][28][29] To define the role of IGH variation in Ab function and disease, all classes of variation must be resolved 3,12,15,19,29,30 .…”

Polymorphisms in immunoglobulin heavy chain variable genes and their upstream regions

“…Some allelic variants have been associated with increased disease susceptibility 27, 28 , yet the impact of immunoglobulin gene variation on disease risks is still unknown 29 . These regions have not been sufficiently covered in the numerous genome wide association studies performed to date.…”

Bernard and Joan Marshall Awards at the autumn meeting of the British Society for Cardiovascular Research 2017

“…The top three applicants are invited to present their work at the Autumn Meeting, to compete for the Bernard and Joan Marshall Young Investigator Prize. In 2017, the three candidates selected to present were Dr Tom Parks from the University of Oxford who discussed his paper entitled ‘Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania’1; Dr Eylem Levelt from the University of Leicester who presented her work on ‘Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type two diabetes mellitus’2; and Dr Johannes Bargehr from the University of Cambridge (figure 1)  who presented his data on ‘Human embryonic stem cell-derived epicardial cells augment cardiomyocyte-driven heart regeneration’ (under review). All three talks were stimulating and informative and resulted in lively question-and-answer sessions.…”