Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease

Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in theABCG5orABCG8genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8—as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.Methods:We first recruited 9 sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency ABCG5orABCG8.Results:In sitosterolemia families, 7 pedigrees harbored causative LoF variants inABCG5and 2 pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8was ≈0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35];P=1.1×10−6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35];P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.Conclusions:Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.