In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.35.suppl_1.608
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1494427-3
Permalink