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Strawbridge, R.J.* ; Dupuis, J.* ; Prokopenko, I.* ; Barker, A.* ; Ahlqvist, E.* ; Rybin, D.* ; Petrie, J.R.* ; Travers, M.E.* ; Bouatia-Naji, N.* ; Dimas, A.S.* ; Nica, A.* ; Wheeler, E.* ; Chen, H.* ; Voight, B.F.* ; Taneera, J.* ; Kanoni, S.* ; Peden, J.F.* ; Turrini, F.* ; Gustafsson, S.* ; Zabena, C.* ; Almgren, P.* ; Barker, D.J.* ; Barnes, D.* ; Dennison, E.M.* ; Eriksson, J.G.* ; Eriksson, P.* ; Eury, E.* ; Folkersen, L.* ; Fox, C.S.* ; Frayling, T.M.* ; Goel, A.* ; Gu, H.F.* ; Horikoshi, M.* ; Isomaa, B.* ; Jackson, A.U.* ; Jameson, K.A.* ; Kajantie, E.* ; Kerr-Conte, J.* ; Kuulasmaa, T.* ; Kuusisto, J.* ; Loos, R.J.* ; Luan, J.* ; Makrilakis, K.* ; Manning, A.K.* ; Martinez-Larrad, M.T.* ; Narisu, N.* ; Nastase, Mannila, M.* ; Ohrvik, J.* ; Osmond, C.* ; Pascoe, L.* ; Payne, F.* ; Sayer, A.A.* ; Sennblad, B.* ; Silveira, A.* ; Stancáková, A.* ; Stirrups, K.* ; Swift, A.J.* ; Syvanen, A.C.* ; Tuomi, T.* ; van't Hooft, F.M.* ; Walker, M.* ; Weedon, M.N.* ; Xie, W.* ; Zethelius, B* ; DIAGRAM Consortium (Huth, C. ; Grallert, H. ; Gieger, C. ; Klopp, N. ; Meitinger, T. ; Petersen, A.-K. ; Wichmann, H.-E. ; Illig, T.) ; GIANT Consortium (Heid, I.M. ; Lamina, C. ; Thiering, E. ; Illig, T. ; Peters, A. ; Wichmann, H.-E. ; Grallert, H. ; Heinrich, J. ; Gieger, C.) ; MuTHER Consortium (*) ; CARDIoGRAM Consortium (Wichmann, H.-E. ; Illig, T. ; Döring, A. ; Peters, A. ; Klopp, N. ; Meisinger, C. ; Meitinger, T.) ; C4D Consortium (*) ; Ongen, H.* ; Mälarstig, A.* ; Hopewell, J.C.* ; Saleheen, D.* ; Chambers, J.* ; Parish, S.* ; Danesh, J.* ; Kooner, J.* ; Ostenson, C.G.* ; Lind, L.* ; Cooper, C.C.* ; Serrano-Rios, M.* ; Ferrannini, E.* ; Forsen, T.J.* ; Clarke, R.* ; Franzosi, M.G.* ; Seedorf, U.* ; Watkins, H.* ; Froguel, P.* ; Johnson, P.* ; Deloukas, P.* ; Collins, F.S.* ; Laakso, M.* ; Dermitzakis, E.T.* ; Boehnke, M.* ; McCarthy, M.I.* ; Wareham, N.J.* ; Groop, L.* ; Pattou, F.* ; Gloyn, A.L.* ; Dedoussis, G.V.* ; Lyssenko, V.* ; Meigs, J.B.* ; Barroso, I.* ; Watanabe, R.M.* ; Ingelsson, E.* ; Langenberg, C.* ; Hamsten, A.* ; Florez, J.C*

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

Diabetes 60, 2624-2634 (2011)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Coronary heart-disease; Beta-cell function; Susceptibility loci; Glucose-homeostasis; Insulin sensitivity; Population; TCF7L2; Risk; Obesity; Metaanalysis
Sprache englisch
Veröffentlichungsjahr 2011
HGF-Berichtsjahr 2011
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Zeitschrift Diabetes
Quellenangaben Band: 60, Heft: 10, Seiten: 2624-2634 Artikelnummer: , Supplement: ,
Verlag American Diabetes Association
Verlagsort Alexandria, VA.
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Molecular Epidemiology (AME)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504200-002
G-504000-002
G-504100-001
G-500700-001
G-503900-001
PubMed ID 21873549
DOI 10.2337/db11-0415
Scopus ID 80053405321
Erfassungsdatum 2011-12-08
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