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

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

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 >3x 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.

Original languageEnglish (US)
Pages (from-to)100-105
Number of pages6
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number1
DOIs
StatePublished - Feb 4 2015

Keywords

  • Cardiovascular diseases
  • Genetic variation
  • Low-density lipoprotein cholesterol

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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    Dubé, J. B., Wang, J., Cao, H., McIntyre, A. D., Johansen, C. T., Hopkins, S. E., Stringer, R., Hosseinzadeh, S., Kennedy, B. A., Ban, M. R., Young, T. K., Connelly, P. W., Dewailly, E., Bjerregaard, P., Boyer, B. B., & Hegele, R. A. (2015). Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations. Circulation: Cardiovascular Genetics, 8(1), 100-105. https://doi.org/10.1161/CIRCGENETICS.114.000646