Common Low-Density Lipoprotein Receptor p.G116S Variant Has a Large Effect on Plasma Low-Density Lipoprotein Cholesterol in Circumpolar Inuit Populations. (February 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Circulation. Volume 8:Number 1(2015)
• Publication Date: 2015-02
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000646
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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 (<italic>LDLR</italic>), namely p.G116S and p.R730W.</p> </sec> <sec> <title>Methods and Results—</title> <p>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 (<italic>P</italic>=5.6×10<sup>−49</sup>), 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; <italic>P</italic>=1.7×10<sup>−17</sup>), 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.</p> </sec> <sec> <title>Conclusions—</title> <p> <italic>LDLR</italic> p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.</p> </sec> </abstract>