-Inuit are considered to be vulnerable to cardiovascular disease (CVD) as their lifestyles become more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified two nonsynonymous variants in LDLR encoding the low-density lipoprotein (LDL) receptor, namely p.G116S and p.R730W.
-Genotyping these variants in 3,324 Inuit from Alaska, Canada and Greenland showed they were common, with allele frequencies 10-15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P = 5.6 × 10(-49)), which was >3-times larger than the largest effect sizes seen with common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (CI 2.34 - 3.90, P = 1.7 × 10(-17)), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand binding activity compared to wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol nor altered in vitro activity.
-LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.