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 conditionCausal genesKey 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., 2003Brown and Goldstein, 1986Garcia et al., 2001Lehrman 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., 2006Musunuru et al., 2010aSoria 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., 2012Chang et al., 1996Geller et al., 2000Geller et al., 1998Hansson et al., 1995Lifton et al., 1992aLifton et al., 1992bLifton et al., 2001Mune et al., 1995Shimkets et al., 1994Simon et al., 1997Simon et al., 1996aSimon et al., 1996bSimon et al., 1996cWilson et al., 2001)
Hypertrophic cardiomyopathyMYH7, 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., 1995Carrier et al., 1993Geisterfer-Lowrance et al., 1990Kimura et al., 1997Olson et al., 2000Poetter et al., 1996Seidman and Seidman, 2001Thierfelder et al., 1994Watkins et al., 1995)
Marfan’s syndromeFBN1Aneurysm 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., 1991Lindsay 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., 1997Garg et al., 2003Schott et al., 1998)
Bicuspid aortic valve, Calcific
aortic valve disease
NOTCH1NOTCH1 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)

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Dr. Drew Sutton