The Genetic Control of the Rheumatic Heart: Closing the Genotype-Phenotype Gap

Abstract

Rheumatic heart disease (RHD) is a heritable inflammatory condition characterized by carditis, arthritis, and systemic disease. Although remaining neglected, the last 3 years has seen some promising advances in RHD research. Whilst it is clear that RHD can be triggered by recurrent group A streptococcal infections, the mechanisms driving clinical progression are still poorly understood. This review summarizes our current understanding of the genetics implicated in this process and the genetic determinants that predispose some people to RHD. The evidence demonstrating the importance of individual cell types and cellular states in delineating causal genetic variants is discussed, highlighting phenotype/genotype correlations where possible. Genetic fine mapping and functional studies in extreme phenotypes, together with large-scale omics studies including genomics, transcriptomics, epigenomics, and metabolomics, are expected to provide new information not only on RHD but also on the mechanisms of other autoimmune diseases and facilitate future clinical translation.

Keywords: autoimmune diseases; exome sequencing; genetic association; group A streptococcus; rheumatic heart.