Circulation. Cardiovascular genetics
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Circ Cardiovasc Genet · Jun 2012
Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension.
Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9. Approximately 25% of heritable cases lack identifiable mutations in any of these genes. ⋯ Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology, as well as PAH-directed therapeutic development.
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Circ Cardiovasc Genet · Apr 2012
Literature-based genetic risk scores for coronary heart disease: the Cardiovascular Registry Maastricht (CAREMA) prospective cohort study.
Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD. ⋯ A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.
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Circ Cardiovasc Genet · Feb 2012
Case ReportsCharacterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.
Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, loss-of-function mutations were found among individuals in the lowest quartile of plasma triglycerides in population studies. Recently, 4 related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 loss-of-function mutations. ⋯ Complete ANGPTL3 deficiency caused by loss-of-function mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, changes in subclasses of high-density lipoprotein, and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of low-density lipoprotein.
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Circ Cardiovasc Genet · Oct 2011
The coronary artery disease-associated 9p21 variant and later life 20-year survival to cohort extinction.
Common variation at chromosome 9p21 (marked by rs10757278 or rs1333049) is associated with coronary artery disease (CAD) and peripheral vascular disease. A decreasing effect at older age was suggested, and effects on long-term mortality are unclear. We estimated 9p21 associations with CAD and all-cause mortality in a CAD diagnosis-free older population. We also estimated classification gains on adding the variant to the Framingham Risk Score (FRS) for CAD. ⋯ In 71- to 80-year-old subjects free of CAD diagnoses, 9p21 is associated with excess mortality, mainly attributed to CAD mortality. Adding 9p21 to the FRS may improve the targeting of CAD prevention in older people, but validation in independent samples is needed for confirmation.
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Circ Cardiovasc Genet · Oct 2011
Racial/ethnic variation in the association of lipid-related genetic variants with blood lipids in the US adult population.
Genome-wide association studies (GWAS) have identified a number of single-nucleotide polymorphisms (SNPs) associated with serum lipid level in populations of European descent. The individual and the cumulative effect of these SNPs on blood lipids are largely unclear for the US population. ⋯ Our findings show that the combined association of SNPs, based on a GRS, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the United States, which may help in identifying subgroups with a high risk for an unfavorable lipid profile.