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

Tom Parks, Mariana M. Mirabel, Joseph Kado, Kathryn Auckland, Jaroslaw Nowak, Anna Rautanen, Alexander J. Mentzer, Eloi Marijon, Xavier Jouven, Mai Ling Perman, Tuliana Cua, John K. Kauwe, John B. Allen, Henry Taylor, Kathryn J. Robson, Charlotte M. Deane, Andrew C. Steer () and Adrian V. S. Hill ()
Additional contact information
Tom Parks: Wellcome Trust Centre for Human Genetics, University of Oxford
Mariana M. Mirabel: Paris Centre de Recherche Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale, Hôpital Européen Georges Pompidou
Joseph Kado: Ministry of Health and Medical Services, Colonial War Memorial Hospital
Kathryn Auckland: Wellcome Trust Centre for Human Genetics, University of Oxford
Jaroslaw Nowak: University of Oxford
Anna Rautanen: Wellcome Trust Centre for Human Genetics, University of Oxford
Alexander J. Mentzer: Wellcome Trust Centre for Human Genetics, University of Oxford
Eloi Marijon: Paris Centre de Recherche Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale, Hôpital Européen Georges Pompidou
Xavier Jouven: Paris Centre de Recherche Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale, Hôpital Européen Georges Pompidou
Mai Ling Perman: College of Medicine, Nursing & Health Sciences, Fiji National University
Tuliana Cua: Rheumatic Heart Disease Control Programme, Ministry of Health and Medical Services, Colonial War Memorial Hospital
John K. Kauwe: College of Life Sciences, Brigham Young University
John B. Allen: College of Life Sciences, Brigham Young University
Henry Taylor: Rheumatic Heart Disease Control Programme, Samoa Ministry of Health
Kathryn J. Robson: MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington
Charlotte M. Deane: University of Oxford
Andrew C. Steer: Centre for International Child Health, University of Melbourne
Adrian V. S. Hill: Wellcome Trust Centre for Human Genetics, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14946

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