Dube, J. B.3; Wang, J.3; Cao, H.3; McIntyre, A. D.3; Johansen, C. T.3; Hopkins, S. E.3; Stringer, R.3; Hosseinzadeh, S.3; Kennedy, B. A.3; Ban, M. R.3; Young, T. K.3; Connelly, P. W.3; Dewailly, E.3; Bjerregaard, Peter4; Boyer, B. B.3; Hegele, R. A.3
1 Health in Greenland, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU2 Research Programme on Adult Health and Health-related Behaviour, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU3 unknown4 Health in Greenland, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU
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.
Circulation: Cardiovascular Genetics, 2015, Vol 8, p. 100-105