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

• Author(s) / Creator(s)

  • Dubé, Joseph B.
  • Wang, Jian
  • Cao, Henian
  • McIntyre, Adam D.
  • Johansen, Christopher T.
  • 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.

• "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." (as cited in abstract)

• Date created

  2014-11-20

• Subjects / Keywords

  • Cardiovascular diseases
  • Genetic variation
  • Low-density lipoprotein cholesterol
  • Alaska
  • Canada
  • Greenland

• Type of Item

  Article (Published)

• DOI

  https://doi.org/10.7939/r3-jez3-fh39

• License

  Attribution 4.0 International