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

Background Coronary 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.

MBFR 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-кB pathway in the UK Biobank Pharma Proteome pGWAS dataset and with individual-level OLINK proteomic data in PMBB.

Among 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-кB 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.

Our 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-кB pathway. Our multi-omic analyses support a role for NF-кB pathway in CMVD. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by Alpha Phi Heart to Heart (MG, SSV), NHLBI R01HL175485 and BWF CAMS (MG), NHGRI T32HG000046 (RK, LG), NIH K12GM081259 (TC), Doris Duke Foundation (Award 2023-0224, MGL) and US Department of Veterans Affairs Biomedical Research and Development Award IK2-BX006551 (MGL). This article does not represent the views of the Department of Veterans Affairs or the US government. We acknowledge the Penn Medicine BioBank (PMBB) for providing data and thank the patient-participants of Penn Medicine who consented to participate in this research program. We would also like to thank the Penn Medicine BioBank team and Regeneron Genetics Center for providing genetic variant data for analysis. The PMBB is approved under IRB protocol# 813913 and supported by Perelman School of Medicine at University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award number UL1TR001878. A full list of contributors in included in Supplemental Note 1. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Pennsylvania IRB. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All summary data will be made available, and the supplemental tables include full analyses results. For review of files larger than 75MB, a link is included in the cover letter.