Rare pathogenic variants in G-protein coupled receptor genes involved in gut-to-host communication are associated with cardiovascular disease risk

BackgroundGut microbial metabolites called short-chain fatty acids (SCFA) confer protective effects against cardiovascular disease and high blood pressure. Proposed mechanisms include anti-inflammatory signalling mediated by SCFA-sensing G-protein-coupled receptors (GPCR), particularly GPR41, GPR43, and GPR109a, as suggested by knockout mouse models. We aimed to determine if rare pathogenic variants (RPVs) affecting GPCR genes in humans increase the risk of hypertension (HTN) and major adverse cardiac events (MACEs), including acute coronary syndrome, heart failure, and ischemic stroke. MethodsUsing UK Biobank whole-exome sequencing data from 393,649 European participants, we identified rare (minor allele frequency <1%) pathogenic variants with predicted high-impact functional consequences in GPCR genes, based on Ensembl Variant Effect Predictor annotations. For missense variants, pathogenicity likelihood scores from AlphaMissense, Mendelian Clinically Applicable Pathogenicity, and Combined Annotation Dependent Depletion were assessed. Multivariable logistic regression models, adjusted for age, sex, BMI, genetic ancestry, and other potential confounders, were conducted to compare RPV prevalence between cases and controls. ResultsWe identified a total of 158 RPVs in SCFA-sensing GPCR genes. The prevalence of RPV carriers was significantly higher in patients with HTN (OR=1.12, P=0.014) and MACEs (OR=1.18, P=0.009) than controls. In single GPCR gene analyses, RPVs in the FFAR2 gene (encoding GPR43) were associated with an increased risk of HTN (OR=1.23, P=0.005). RPVs in the HCAR2 gene (encoding GPR109A) were associated with a markedly increased risk of heart failure (OR=1.57, P=0.012). ConclusionsThese findings confirm and extend previous results from knockout animal models in a large population-based cohort, highlighting the potential of GPCRs as therapeutic targets for HTN and cardiovascular diseases in humans.