Cardiovascular disease (CVD) is a leading health problem, affecting over 80,000,000 individuals in the United States alone. CVD encompasses a broad range of disorders including diseases of the vasculature, the myocardium, the heart’s electrical circuit, and congenital heart disease. For nearly all of these disorders, inherited DNA sequence variants play a role in conferring risk for disease. For example, in the general population, a history of premature atherosclerotic CVD in a parent confers ~3.0-fold increase in CVD risk to offspring. The precise magnitude of the role of inheritance, however, varies by disease and by other factors such as age of disease onset and subtype of disease.
Selected examples of Mendelian diseases and insights derived from the study of causal genes
| Mendelian condition | Causal genes | Key biological and clinical insight(s) | Reference(s) |
|---|---|---|---|
| Severe hypercholesterolemia | LDLR, APOB, ABCG5, ABCG8, ARH, PCSK9 | Receptor-mediated endocytosisReceptor recyclingFeedback regulation of receptorsMolecular mechanism of intestinal cholesterol absorption and biliary cholesterol excretionHigh LDL cholesterol is sufficient to cause MI | (Abifadel et al., 2003; Brown and Goldstein, 1986; Garcia et al., 2001; Lehrman et al.,1985) |
| Familial hypobetalipoproteinemia | APOB, PCSK9, ANGPTL3 | Lifelong low LDL cholesterol (from loss of PCSK9 function) is sufficient to protect from MI despite other coronary risk factors | (Cohen et al., 2006; Musunuru et al., 2010a; Soria et al., 1989) |
| Mendelian forms of low and high blood pressure | SLC12A3, SLC12A1, KCNJ1, CLCNKB, NR3C2, SCNN1A, SCNN1B, SCNN1G CYP11B2, CYP11B1, HSD11B2, NR3C2, SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3 | Genes converge on a final common pathway of altering net renal sodium handling and balanceIdentification of new targets for the treatment of blood pressure | (Boyden et al., 2012; Chang et al., 1996; Geller et al., 2000; Geller et al., 1998; Hansson et al., 1995; Lifton et al., 1992a; Lifton et al., 1992b; Lifton et al., 2001; Mune et al., 1995; Shimkets et al., 1994; Simon et al., 1997; Simon et al., 1996a; Simon et al., 1996b; Simon et al., 1996c; Wilson et al., 2001) |
| Hypertrophic cardiomyopathy | MYH7, TNNT2, TPM1, TNNI3, MYL2, MYBPC3, ACTC, MYL3 | Mutations have expanded knowledge of the molecular mechanisms of heart muscle contractionMutations may cause increased TGF-β signaling in the myocyte with subsequent effects on neighboring fibroblasts, leading to fibrosis and scarring | (Bonne et al., 1995; Carrier et al., 1993; Geisterfer-Lowrance et al., 1990; Kimura et al., 1997; Olson et al., 2000; Poetter et al., 1996; Seidman and Seidman, 2001; Thierfelder et al., 1994; Watkins et al., 1995) |
| Marfan’s syndrome | FBN1 | Aneurysm formation is likely due to perturbations in cytokine signaling cascades and the smooth muscle contractile apparatus rather than defects in the extracellular matrixUnexpected role for TGF-β pathway in disease | (Dietz et al., 1991; Lindsay and Dietz, 2011) |
| Atrial or ventricular septal defects | NKX2-5, GATA-4, TBX5 | These transcription factors, originally discovered in flies and mice, are critical for proper heart development in humans and function in a common complex | (Basson et al., 1997; Garg et al., 2003; Schott et al., 1998) |
| Bicuspid aortic valve, Calcific aortic valve disease | NOTCH1 | NOTCH1 functions to repress a default osteoblast fate of the valve mesenchymal cellsNOTCH1 mutations likely result in a de-repression of this fate choice and subsequent differentiation of valve cells into an osteoblast-like phenotype | (Garg et al., 2005) |
