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Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations.
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.
Afiliação
  • Dubé JB; 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 Na
  • Wang J; 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 Na
  • Cao H; 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 Na
  • McIntyre AD; 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 Na
  • Johansen CT; 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 Na
  • Hopkins SE; 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 Na
  • Stringer R; 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 Na
  • Hosseinzadeh S; 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 Na
  • Kennedy BA; 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 Na
  • Ban MR; 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 Na
  • Young TK; 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 Na
  • Connelly PW; 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 Na
  • Dewailly E; 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 Na
  • Bjerregaard P; 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 Na
  • Boyer BB; 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 Na
  • Hegele RA; 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 Na
Circ Cardiovasc Genet ; 8(1): 100-5, 2015 Feb.
Article em En | MEDLINE | ID: mdl-25414273
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de LDL / Doenças Cardiovasculares / Inuíte / Alelos / Frequência do Gene / LDL-Colesterol Tipo de estudo: Clinical_trials Limite: Adult / Female / Humans / Male / Middle aged País como assunto: America do norte / Europa Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de LDL / Doenças Cardiovasculares / Inuíte / Alelos / Frequência do Gene / LDL-Colesterol Tipo de estudo: Clinical_trials Limite: Adult / Female / Humans / Male / Middle aged País como assunto: America do norte / Europa Idioma: En Ano de publicação: 2015 Tipo de documento: Article