Joseph B Dubé1, Jian Wang1, Henian Cao1, Adam D McIntyre1, Christopher T Johansen1, Scarlett E Hopkins1, Randa Stringer1, Siyavash Hosseinzadeh1, Brooke A Kennedy1, Matthew R Ban1, T Kue Young1, Philip W Connelly1, Eric Dewailly1, Peter Bjerregaard1, Bert B Boyer1, Robert A Hegele2. 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.
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:LDLRp.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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Authors: Emil Jørsboe; Mette K Andersen; Line Skotte; Frederik F Stæger; Nils J Færgeman; Kristian Hanghøj; Cindy G Santander; Ninna K Senftleber; Lars J Diaz; Maria Overvad; Ryan K Waples; Frank Geller; Peter Bjerregaard; Mads Melbye; Christina V L Larsen; Bjarke Feenstra; Marit E Jørgensen; Niels Grarup; Ida Moltke; Anders Albrechtsen; Torben Hansen Journal: HGG Adv Date: 2022-06-09