Genome-Wide Association Study of Coronary Microvascular Disease assessed by cardiac perfusion Positron Emission Tomography converges on NF-κB pathway

BackgroundCoronary Microvascular Disease (CMVD) contributes to the large burden of ischemic heart disease, and there is a need for mechanistic insight and targeted therapies. Perfusion cardiac PET allows for the quantitative assessment of myocardial blood flow reserve (MBFR), which reflects coronary microvascular function. Here we perform the first genome-wide association study (GWAS) using cardiac PET MBFR as a measure of CMVD. MethodsMBFR was measured using Rubidium-82 cardiac perfusion PET obtained as part of routine clinical care. GWAS was performed using datasets from individuals genetically similar to EUR and AFR populations within the Penn Medicine Biobank (PMBB), followed by comprehensive downstream analyses including fine-mapping and transcriptome-wide association study (TWAS). We used gene set enrichment analysis (GSEA) to investigate associated molecular pathways and TIMI Frame Count to validate the association between the identified variants and CMVD. Finally, we assessed associations between key loci and proteins in the NF-[kcy]B pathway in the UK Biobank Pharma Proteome pGWAS dataset and with individual-level OLINK proteomic data in PMBB. ResultsAmong 241 targeted CAD loci, 17 in the AFR, 14 in the EUR, and 16 shared across both populations were significant (p<2e-04). A subsequent discovery GWAS identified 1 genome-wide significant association. Fine mapping identified a signal near ERC1. Sex-stratified TWAS identified CAPN2 in females and PLA2G5 in males. GSEA identified inflammatory and NF-[kcy]B pathways as the top pathways associated with these loci, and TIMI frame count confirmed that these loci were protective. Using proteomic data, we found IL-1B was increased in individuals with CAPN2 variant, and NEMO was differentially regulated by CAPN2 and ERC1 variants. ConclusionsOur study identified variants associated with MBFR in populations of EUR and AFR ancestry and converged on two independent loci that are near genes known to regulate the NF-[kcy]B pathway. Our multi-omic analyses support a role for NF-[kcy]B pathway in CMVD.