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

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

Author information

1
From the Molecular Medicine Group, Robarts Research Institute (J.B.D., J.W., H.C., A.M., C.T.J., R.S., S.H., B.A.K., M.R.B., R.A.H.) and Department of Medicine (C.T.J., R.A.H.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada; The Center for Alaska Native Health Research, Institute of Arctic Biology, University of Alaska Fairbanks (S.E.H., B.B.B.); The Dalla Lana School of Public Health (T.K.Y.) and The Keenan Research Centre for Biomedical Science of St. Michael's Hospital (P.W.C.), and Department of Medicine, University of Toronto, Toronto, ON, Canada; Département de médecine sociale et preventive, Axe Santé des Populations et Pratiques Optimales en Santé, Centre de Recherche du CHU de Québec, Université Laval, QC, Canada (E.D.); and National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark (P.B.).
2
From the Molecular Medicine Group, Robarts Research Institute (J.B.D., J.W., H.C., A.M., C.T.J., R.S., S.H., B.A.K., M.R.B., R.A.H.) and Department of Medicine (C.T.J., R.A.H.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada; The Center for Alaska Native Health Research, Institute of Arctic Biology, University of Alaska Fairbanks (S.E.H., B.B.B.); The Dalla Lana School of Public Health (T.K.Y.) and The Keenan Research Centre for Biomedical Science of St. Michael's Hospital (P.W.C.), and Department of Medicine, University of Toronto, Toronto, ON, Canada; Département de médecine sociale et preventive, Axe Santé des Populations et Pratiques Optimales en Santé, Centre de Recherche du CHU de Québec, Université Laval, QC, Canada (E.D.); and National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark (P.B.). hegele@robarts.ca.

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 >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

PMID:
25414273
PMCID:
PMC4560235
DOI:
10.1161/CIRCGENETICS.114.000646
[Indexed for MEDLINE]
Free PMC Article

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