Abstract 460: Cyclin Dependent Kinase Inhibitor A1 Identified as a Potential Risk Locus for Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is characterized by heterogeneous phenotypic expression, natural history, and genetic profile with numerous causative mutations. The relationship between genotype and phenotype in HCM is incompletely understood. Identifying genetic modifiers may expand understanding of the signaling pathways that are responsible for phenotypic expression. UK Biobank comprises clinical and genetic data for greater than 500,000 individuals. We compared control individuals to those with a diagnosis of HCM (identified via ICD-10 code I42.1) in a 20-to-1 fashion to identify genetic differences. Data were compared using Mixed Model Analysis for Pedigrees/Populations (MMAP) mixed-model regression. Variants were assessed using bioinformatics tools including linkage disequilibrium and Eigen scoring. Results were then compared to previously published genome-wide association datasets. Mixed-model regression identified 5 variants of cyclin-dependent kinase inhibitor 1A ( CDKN1A ) as statistically significant with one intronic variant (rs3176326) likely affecting a gene promoter region with an Eigen-PC score of 7.779. This variant was found to have a p-value of 5.08x10 -8 when contrasted to controls with a minor allele frequency of 0.199 in the affected individuals. The 4 other variants were in linkage disequilibrium (r 2 0.90-0.99) with rs3176326. The odds ratio of HCM with rs3176326 is 1.81.To our knowledge, CDKN1A has not previously been associated with HCM. By utilizing bioinformatic tools we were able to identify 5 variants that may be associated with the risk for HCM. One locus affects a promotor region and resulted in a notably high Eigan-PC score suggestive that it has an impact on HCM. When comparing these findings with previous genome-wide association studies utilizing the UK Biobank, we find that CDKN1A has a possible association with HCM, though those results were not statistically significant. CDKN1A has been previously associated with the p53 DNA repair and cell senescence pathway. Animal and human studies have implicated it in the development of fibrosis. A recent genome-wide association metanalysis identified it as a risk locus for heart failure. These findings support our conclusion that CDKN1A is a risk locus for HCM.