常见的低密度脂蛋白受体p.G116S变体对环北极因纽特人群的血浆低密度脂蛋白胆固醇有很大影响。
Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations.
作者信息
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
机构信息
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.).
出版信息
Circ Cardiovasc Genet. 2015 Feb;8(1):100-5. doi: 10.1161/CIRCGENETICS.114.000646. Epub 2014 Nov 20.
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.
背景
因纽特人被认为易患心血管疾病，因为他们的生活方式正变得越来越西化。在对脂质特征处于极端水平的因纽特人个体进行序列分析时，我们在低密度脂蛋白受体（LDLR）中鉴定出2个非同义变体，即p.G116S和p.R730W。
方法和结果
对来自阿拉斯加、加拿大和格陵兰的3324名因纽特人进行这些变体的基因分型，结果显示它们很常见，等位基因频率为10%至15%。只有p.G116S与血脂异常有关：每个等位基因的低密度脂蛋白胆固醇升高0.54 mmol/L（20.9 mg/dL）（P = 5.6×10⁻⁴⁹），这比在其他人群中其他常见变体所观察到的最大效应大小大3倍以上。p.G116S的携带者患高胆固醇血症的风险增加3.02倍（95%置信区间，2.34 - 3.90；P = 1.7×10⁻¹⁷），但不具有经典的家族性高胆固醇血症。在体外，与野生型受体相比p.G116S的配体结合活性降低了60%。相比之下，p.R730W既与低密度脂蛋白胆固醇水平无关，体外活性也未改变。
结论
因此，LDLR p.G116S是独特的：它是因纽特人中一种常见的功能失调变体，对低密度脂蛋白胆固醇有很大影响，可能对公共卫生有影响。
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