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

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.G...

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Bibliographic Details
Published in:Circulation: Cardiovascular Genetics
Main Authors: Dube, 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, Peter, Boyer, B. B., Hegele, R. A.
Format: Article in Journal/Newspaper
Language:English
Published: 2015
Subjects:
Cardiovascular diseases
Genetic variation
Low-density lipoprotein cholesterol
Canada
Greenland
inuit
Alaska
Online Access:https://portal.findresearcher.sdu.dk/da/publications/3c2cd81a-e67e-4cb6-92a1-2dfcf2e54a5d
https://doi.org/10.1161/circgenetics.114.000646
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Summary: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=5.6x10(-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=1.7x10(-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.

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