Abstract 468: Previously Unrecognized Intronic Variants in the Dystrophin Gene Identified as Possible Contributors to Dilated Cardiomyopathy

Abstract

Nonischemic dilated cardiomyopathy (DCM) often has a genetic etiology, however, its prevalence and etiologies are not completely understood. The UK Biobank comprises clinical and genetic data for greater than 500,000 individuals with enrollees 40-69 years of age. Our group created a custom phenotype of heart failure using ICD-10 codes for several subtypes of heart failure diagnoses including DCM. We then compared the individuals included in the custom heart failure phenotype to control individuals in a 20-to-1 fashion to identify genetic differences. Data were compared using Mixed Model Analysis for Pedigrees/Populations (MMAP) mixed-model regression. We identified 8 unlinked intronic variants in the dystrophin gene ( DMD ) that, when separated by self-identified race, occurred with a combined minor allele frequency of 0.15 in individuals with heart failure who identified as being of African descent. The combined minor allele frequency of these variants was 0.05 in individuals who self-identified as being of European descent. One variant of DMD in particular (rs139029250), was identified with a minor allele frequency of 0.05 in African British with DCM. The unadjusted odds ratio of a diagnosis of heart failure in individuals with rs129029250 was 4.65. When separated by gender, the unadjusted odds ratios are 2.02 for females and 6.44 for males. DMD is most notably known for its role in Duchenne and Becker muscular dystrophy, both of which are known to cause dilated cardiomyopathy in affected individuals. However, none of the individuals (36 female and 43 male) identified in our analysis with rs129029250 have been diagnosed with Duchenne muscular dystrophy, Becker muscular dystrophy, or a primary disorder of muscle (ICD code G70). Additionally, these individuals have an intronic variant of DMD , while Duchene and Becker muscular dystrophy are both due to exonic mutations. These findings suggest a possible common variant in the DMD gene that may contribute to DCM in individuals of African descent.