Background: Rheumatic heart disease (RHD) is a major cause of death and disability worldwide. Accordingly, to aid development of vaccines and novel therapeutics, we sought to identify common host genetic variants associated with susceptibility to this neglected disease.
Methods: We pooled the results of genome-wide association studies from four prior studies of susceptibility to RHD undertaken across diverse populations in Africa (Black Africans, Admixed South Africans), Australia (Aboriginal Australians), South Asia (Northern Indians), Europe (UK Caucasians) and the Pacific region (Melanesians, Polynesians, Fijian Indians, Admixed Pacific Islanders). Cases had an echocardiographic diagnosis of RHD, except in the UK Biobank cohort where inclusion was based on a medical record diagnosis of mitral stenosis. Association statistics for variants present at minor allele frequency of 5% or more in any three populations from each population were combined using inverse-variance weighted fixed effects meta-analysis.
Results: We combined association statistics from more than 11 million variants derived from a total of 4284 cases and 7160 controls. Two regions reached our threshold for genome-wide significance (p<5x10-8): the complement factor H region on chromosome 1 (rs10489456, OR, 1.29, p= 1.7x10-12) and the immunoglobulin heavy chain locus on chromosome 14 (rs11846409, OR 1.23, p=9.4x10-10). In addition, the strongest signal within the major histocompatibility locus on chromosome 6 mapped to the class III region, neighbouring genes for complement factor 4 and complement factor B (rs389512, p=7.0x10-7).
Conclusions: Large-scale unbiased assessment of host genetic susceptibility indicate dysregulation of the complement system is a key feature of RHD pathogenesis. This provides an invaluable new therapeutic target, potentially accessible through drug repurposing.