Abstract 608: A locus on Chromosome 6 in Diversity Outbred Mice Suggests Osteogenic Regulation of Dystrophic Cardiac Calcinosis
Introduction: Dystrophic cardiac calcinosis (DCC) is an age-related cardiomyopathy that involves myocardial injury, necrosis, and calcification. The genetic factors contributing to myocardial calcification are complex, and several loci for DCC have been identified. However, only 1 gene, Abcc6, has been cloned and confirmed to regulate DCC. Our current studies were designed to study the genetic architecture of DCC.
Methods and Results: Recently, the Diversity Outbred (DO) population was developed from 8 inbred strains of mice. The DO mice are mosaics of 8 progenitor strains: C57BL6/J, A/J, NOD/ShiLtJ, NZO/HiLtJ, WSB/EiJ, CAST/EiJ, PWK/PhJ and 129S1/SvImJ. Our initial studies examined the effects of diet and genetic background on the development of DCC in the 8 progenitor strains. At 24 weeks of age, the hearts of mice from these 8 strains were collected, and a colorimetric assay was used to measure calcium levels in heart tissue. ANOVA tests indicated a significant effect (p < 0.05) of the underlying genetics on DCC.
To identify genes and pathways contributing to DCC, we next performed QTL mapping using 300 DO mice. Our QTL mapping analysis was carried out using a genetic model that incorporates reconstructed haplotypes and accounts for population structure. We identify a significant (LOD 7.10) QTL on chromosome 6 (94.7 Mb - 97.3 Mb) associated with DCC. Detailed analysis identified the CAST/EiJ and PWK/PhJ founder alleles as the greatest genetic contributors to the chromosome 6 peak. Myocardial calcification involves a highly regulated process of mineralization similar to osteogenesis, and several of the positional candidates mediate calcification, including: Fam19a4, Fam19a1, Eogt, and Arl6ip5.
Conclusions: This data identifies genes that may regulate the mineralization underlying both DCC and osteogenesis. They may yield new therapeutic targets for DCC and serve as indicators of atherosclerosis.
Author Disclosures: M. Elnagheeb: None. T. Smallwood: None. A. O’Connor: None. B. Bennett: None.
- © 2015 by American Heart Association, Inc.