Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations

Circ Cardiovasc Genet. 2015 Feb;8(1):100-5. doi: 10.1161/CIRCGENETICS.114.000646. Epub 2014 Nov 20.


Background: Inuit are considered to be vulnerable to cardiovascular disease because their lifestyles are becoming more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified 2 nonsynonymous variants in low-density lipoprotein receptor (LDLR), namely p.G116S and p.R730W.

Methods and results: Genotyping these variants in 3324 Inuit from Alaska, Canada, and Greenland showed they were common, with allele frequencies 10% to 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× larger than the largest effect sizes seen with other common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (95% confidence interval, 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 with wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol level nor altered in vitro activity.

Conclusions: LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.

Keywords: cardiovascular diseases; genetic variation; low-density lipoprotein cholesterol.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alaska / ethnology
  • Alleles*
  • Canada / ethnology
  • Cardiovascular Diseases* / blood
  • Cardiovascular Diseases* / ethnology
  • Cardiovascular Diseases* / genetics
  • Cholesterol, LDL / blood*
  • Female
  • Gene Frequency*
  • Greenland / ethnology
  • Humans
  • Inuits / genetics*
  • Male
  • Middle Aged
  • Receptors, LDL* / genetics
  • Receptors, LDL* / metabolism


  • Cholesterol, LDL
  • Receptors, LDL