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Novel Locus Tied to Rheumatic Heart Disease in Black Africans

NEW YORK — A genome-wide association study has uncovered a novel genetic locus linked to rheumatic heart disease in Black African individuals.

Rheumatic heart disease affects about 40 million people around the world but sub-Saharan Africa accounts for nearly a quarter of cases. The disease stems from untreated or inadequately treated Streptococcus pyogenes infection. While treating such infections with penicillin can prevent rheumatic heart disease, this is not always possible, particularly in poorer regions. Social and economic factors play a role in rheumatic heart disease susceptibility but S. pyogenes virulence and host genetic factors are also suspected to influence disease risk.

As part of the Genetics of Rheumatic Heart Disease Network, a sub-study within the Human Heredity and Health Africa, or H3Africa, project, researchers led by McMaster University's Guillaume Paré searched for common genetic variants associated with rheumatic heart disease among Africans. As they reported in JAMA Cardiology on Wednesday, they uncovered a novel genetic locus associated with the condition that appears to be specific to Black African individuals. In addition, they discovered high polygenic heritability of rheumatic heart disease.

"This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to [rheumatic heart disease] susceptibility in African individuals," the researchers wrote in their paper.

But as Africans are underrepresented in genomic studies, the researchers were unable to replicate this finding in another cohort and had limited functional data to try to assess its relevance, which they noted underscores the need for more study.

For their project, the researchers enrolled 4,809 participants from eight African countries, including Kenya, Nigeria, and South Africa. In all, the study encompassed 2,548 African individuals, as well as a combined meta-analysis.

Within the Black African cohort, the researchers identified an association with rheumatic heart disease at the chromosome 11 locus 11q24.1. Because this locus was imputed in their analysis, the researchers directly genotyped the region in a subset of samples to confirm a high concordance between the direct and imputed genotypes.

They were unable to confirm this association within their admixed African population or within other datasets of non-African individuals, suggesting that the locus could be specific to Black African individuals.

Additional phenome-wide and other analyses using primarily European data suggested ties between rheumatic heart disease to the immune system, skeletal system, and metabolism.

Meanwhile, the GWAS of admixed African individuals and meta-analysis of Black and admixed African individuals uncovered loci with suggestive significance and replicated a finding reported in Pacific Islanders that linked an immunoglobulin heavy chain locus to rheumatic heart disease.

The researchers also estimated the heritability of rheumatic heart disease among Black Africans, gauging it to be about 49 percent heritable. A further analysis using family trios suggested that rheumatic heart disease risk is highly polygenic.

Paré and his colleagues noted, though, that their study has limitations, including its small sample size and inability to replicate the finding in Black Africans, as no independent cohort was available.

In an accompanying editorial, Harvard Medical School's Pradeep Natarajan and Elizabeth McNally from Northwestern University Feinberg School of Medicine, both editors at JAMA Cardiology, wrote that more studies and biobanks in Africa are needed to support analyses like this. "Future systematic efforts to improve the unbiased molecular and phenotypic profiling of residents of Africa are important endeavors to curb disparities and, importantly, advance genetic discovery," they added.