Common nonsynonymous variants in PCSK1 confer risk of obesity

被引：220

作者：

Benzinou, Michael ^{[1
,2
]}

Creemers, John W. M. ^{[3
]}

Choquet, Helene ^{[2
]}

Lobbens, Stephane ^{[2
]}

Dina, Christian ^{[2
]}

Durand, Emmanuelle ^{[2
]}

Guerardel, Audrey ^{[2
]}

Boutin, Philippe ^{[2
]}

Jouret, Beatrice ^{[4
]}

Heude, Barbara ^{[5
]}

Balkau, Beverley ^{[5
]}

Tichet, Jean ^{[6
]}

Marre, Michel ^{[7
,8
]}

Potoczna, Natascha ^{[6
]}

Horber, Fritz ^{[9
]}

Le Stunff, Catherine ^{[10
]}

Czernichow, Sebastien ^{[11
]}

Sandbaek, Annelli ^{[12
]}

Lauritzen, Torsten ^{[12
]}

Borch-Johnsen, Knut ^{[13
,14
]}

Andersen, Gitte ^{[13
]}

Kiess, Wieland ^{[15
]}

Koerner, Antje ^{[15
]}

Kovacs, Peter ^{[16
]}

Jacobson, Peter ^{[17
]}

Carlsson, Lena M. S. ^{[17
]}

Walley, Andrew J. ^{[1
]}

Jorgensen, Torben ^{[13
]}

Hansen, Torben ^{[13
,18
]}

Pedersen, Oluf ^{[14
]}

Meyre, David ^{[2
]}

Froguel, Philippe ^{[1
,2
]}

机构：

[1] Hammersmith Hosp, Imperial Coll London, London W12 0NN, England

[2] CNRS 8090, Inst Biol, Inst Pasteur, F-59000 Lille, France

[3] Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium

[4] Childrens Hosp, INSERM, U563, Inst Nacl Sante & Rech Med, F-31000 Toulouse, France

[5] INSERM, U780, IFR69, Villejuif, France

[6] Reg Inst Hlth, F-37000 Tours, France

[7] INSERM, U695, F-75018 Paris, France

[8] Hop Bichat Claude Bernard, Dept Endocrinol Diabetol & Nutr, F-75870 Paris, France

[9] Klin Lindberg, CH-8400 Winterthur, Switzerland

[10] Univ Paris 05, Hop St Vincent de Paul, Dept Pediat Endocrinol, F-75014 Paris, France

[11] Univ Paris 13, INSERM, U557, Inst Sci Rech Agronom INRA,U1125,CNAM EA3200, F-93017 Bobigny, France

[12] Univ Aarhus, Dept Gen Practice, DK-8000 Aarhus, Denmark

[13] Steno Diabet Ctr, DK-2820 Copenhagen, Denmark

[14] Univ Aarhus, Fac Hlth Sci, DK-8000 Aarhus, Denmark

[15] Univ Leipzig, Univ Hosp Children & Adolescents, D-04109 Leipzig, Germany

[16] Univ Leipzig, Interdisciplinary Ctr Clin Res, Dept Internal Med 3, D-04109 Leipzig, Germany

[17] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, SE-431 Gothenburg, Sweden

[18] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark

来源：

NATURE GENETICS | 2008年 / 40卷 / 08期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1038/ng.177

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.

引用

页码：943 / 945

页数：3

共 10 条

[1]

Balkau B, 1996, REV EPIDEMIOL SANTE, V44, P373

[2] Genome-wide linkage analysis for severe obesity in French Caucasians finds significant susceptibility locus on chromosome 19q [J].

Bell, CG ;

Benzinou, M ;

Siddiq, A ;

Lecoeur, C ;

Dina, C ;

Lemainque, A ;

Clément, K ;

Basdevant, A ;

Guy-Grand, B ;

Mein, CA ;

Meyre, D ;

Froguel, P .

DIABETES, 2004, 53 (07) :1857-1865

[3] Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE [J].

Chagnon, YC ;

Rice, T ;

Pérusse, L ;

Borecki, IB ;

Ho-Kim, MA ;

Lacaille, M ;

Paré, C ;

Bouchard, L ;

Gagnon, J ;

Leon, AS ;

Skinner, JS ;

Wilmore, JH ;

Rao, DC ;

Bouchard, C .

JOURNAL OF APPLIED PHYSIOLOGY, 2001, 90 (05) :1777-1787

[4] A genome-wide scan for quantitative trait loci linked to obesity phenotypes among West Africans [J].

Chen, G ;

Adeyemo, AA ;

Johnson, T ;

Zhou, J ;

Amoah, A ;

Owusu, S ;

Acheampong, J ;

Agyenim-Boateng, K ;

Eghan, BA ;

Oli, J ;

Okafor, G ;

Abbiyesuku, F ;

Dunston, GM ;

Chen, Y ;

Collins, F ;

Rotimi, C .

INTERNATIONAL JOURNAL OF OBESITY, 2005, 29 (03) :255-259

[5] Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3 [J].

Farooqi, I. Sadaf ;

Volders, Karolien ;

Stanhope, Richard ;

Heuschkel, Robert ;

White, Anne ;

Lank, Emma ;

Keogh, Julia ;

O'Rahilly, Stephen ;

Creemers, John W. M. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2007, 92 (09) :3369-3373

[6] A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10 [J].

Hager, J ;

Dina, C ;

Francke, S ;

Dubois, S ;

Houari, M ;

Vatin, V ;

Vaillant, E ;

Lorentz, N ;

Basdevant, A ;

Clement, K ;

Guy-Grand, B ;

Froguel, P .

NATURE GENETICS, 1998, 20 (03) :304-308

[7] Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency [J].

Jackson, RS ;

Creemers, JWM ;

Farooqi, IS ;

Raffin-Sanson, ML ;

Varro, A ;

Dockray, GJ ;

Holst, JJ ;

Brubaker, PL ;

Corvol, P ;

Polonsky, KS ;

Ostrega, D ;

Becker, KL ;

Bertagna, X ;

Hutton, JC ;

White, A ;

Dattani, MT ;

Hussain, K ;

Middleton, SJ ;

Nicole, TM ;

Milla, PJ ;

Lindley, KJ ;

O'Rahilly, S .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (10) :1550-1560

[8] Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene [J].

Jackson, RS ;

Creemers, JWM ;

Ohagi, S ;

RaffinSanson, ML ;

Sanders, L ;

Montague, CT ;

Hutton, JC ;

ORahilly, S .

NATURE GENETICS, 1997, 16 (03) :303-306

[9] Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice [J].

Lloyd, David J. ;

Bohan, Sandy ;

Gekakis, Nicholas .

HUMAN MOLECULAR GENETICS, 2006, 15 (11) :1884-1893

[10]

ZHOU Y, 1994, J BIOL CHEM, V269, P18408

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