TY - JOUR
T1 - Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations
AU - Dubé, Joseph B.
AU - Wang, Jian
AU - Cao, Henian
AU - McIntyre, Adam D.
AU - Johansen, Christopher T.
AU - Hopkins, Scarlett E.
AU - Stringer, Randa
AU - Hosseinzadeh, Siyavash
AU - Kennedy, Brooke A.
AU - Ban, Matthew R.
AU - Young, T. Kue
AU - Connelly, Philip W.
AU - Dewailly, Eric
AU - Bjerregaard, Peter
AU - Boyer, Bert B.
AU - Hegele, Robert A.
N1 - Publisher Copyright:
© 2014 American Heart Association, Inc.
PY - 2015/2/4
Y1 - 2015/2/4
N2 - 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.
AB - 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.
KW - Cardiovascular diseases
KW - Genetic variation
KW - Low-density lipoprotein cholesterol
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U2 - 10.1161/CIRCGENETICS.114.000646
DO - 10.1161/CIRCGENETICS.114.000646
M3 - Article
C2 - 25414273
AN - SCOPUS:84924611929
SN - 1942-325X
VL - 8
SP - 100
EP - 105
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 1
ER -