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Disruption of the aortic elastic lamina and medial calcification share genetic determinants in mice.

ABSTRACT: Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans.We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F(2) mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE(-/-)) nullgene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification.Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.

SUBMITTER: Wang SS

PROVIDER: S-EPMC2836127 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Disruption of the aortic elastic lamina and medial calcification share genetic determinants in mice.

Wang Susanna S SS Martin Lisa J LJ Schadt Eric E EE Meng Haijin H Wang Xuping X Zhao Wei W Ingram-Drake Leslie L Nebohacova Martina M Mehrabian Margarete M Drake Thomas A TA Lusis Aldons J AJ

Circulation. Cardiovascular genetics 20091019 6

<h4>Background</h4>Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans.<h4>Methods and results</h4>We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F(2) mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE(-/-)) null<h4>Background</h4>gene, known to mediate myo ...[more]

PMID: 20031637

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Project description:BACKGROUND:Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS:We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS:One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS:Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

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Disruption of the aortic elastic lamina and medial calcification share genetic determinants in mice.

Publications

Disruption of the aortic elastic lamina and medial calcification share genetic determinants in mice.

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