Common Low-Density Lipoprotein Receptor p.G116S Variant Has a Large Effect on Plasma Low-Density Lipoprotein Cholesterol in Circumpolar Inuit Populations Academic Article uri icon

  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All


  • 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.


  • Dubé, Joseph B
  • Wang, Jian
  • Cao, Henian
  • McIntyre, Adam D
  • Johansen, Christopher
  • Hopkins, Scarlett E
  • Stringer, Randa
  • Hosseinzadeh, Siyavash
  • Kennedy, Brooke A
  • Ban, Matthew R
  • Young, T Kue
  • Connelly, Philip W
  • Dewailly, Eric
  • Bjerregaard, Peter
  • Boyer, Bert B
  • Hegele, Robert A

publication date

  • February 2015