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Dimas, A.S.* ; Lagou, V.* ; Barker, A.* ; Knowles, J.W.* ; Mägi, R.* ; Hivert, M.F.* ; Benazzo, A.* ; Rybin, D.* ; Jackson, A.U.* ; Stringham, H.M.* ; Song, C.* ; Fischer-Rosinsky, A.* ; Boesgaard, T.W.* ; Grarup, N.* ; Abbasi, F.A.* ; Assimes, T.L.* ; Hao, K.* ; Yang, X.* ; Lecoeur, C.* ; Barroso, I.* ; Bonnycastle, L.L.* ; Böttcher, Y.* ; Bumpstead, S.* ; Chines, P.S.* ; Erdos, M.R.* ; Graessler, J.* ; Kovacs, P.* ; Morken, M.A.* ; Narisu, N.* ; Payne, F.* ; Stancáková, A.* ; Swift, A.J.* ; Tönjes, A.* ; Bornstein, S.R.* ; Cauchi, S.* ; Froguel, P.* ; Meyre, D.* ; Schwarz, P.E.* ; Häring, H.-U. ; Smith, U.* ; Boehnke, M.* ; Bergman, R.N.* ; Collins, F.S.* ; Mohlke, K.L.* ; Tuomilehto, J.* ; Quertemous, T.* ; Lind, L.* ; Hansen, T.* ; Pedersen, O.* ; Walker, M.* ; Pfeiffer, A.F.* ; Spranger, J.* ; Stumvoll, M.* ; Meigs, J.B.* ; Wareham, N.J.* ; Kuusisto, J.* ; Laakso, M.* ; Langenberg, C.* ; Dupuis, J.* ; Watanabe, R.M.* ; Florez, J.C* ; Ingelsson, E.* ; McCarthy, M.I.* ; Prokopenko, I.* ; MAGIC Investigators (Grallert, H. ; Gieger, C. ; Meisinger, C. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T.)

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Diabetes 63, 2158-2171 (2013)
Verlagsversion DOI PMC
Closed
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Beta-cell Function; Scale Association Analysis; Body-mass Index; Insulin Sensitivity; Proinsulin Levels; Common Variant; Tcf7l2 Gene; Glucose; Genome; Loci
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Zeitschrift Diabetes
Quellenangaben Band: 63, Heft: 6, Seiten: 2158-2171 Artikelnummer: , Supplement: ,
Verlag American Diabetes Association
Verlagsort Alexandria, VA.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
Research Unit Molecular Epidemiology (AME)
Institute of Genetic Epidemiology (IGE)
German Center for Diabetes Reseach (DZD)
Institute of Diabetes Research and Metabolic Diseases (IDM)
POF Topic(s) 30201 - Metabolic Health
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-521500-002
G-500700-001
G-504000-002
G-504200-002
G-503900-001
G-504000-006
G-504100-001
DOI 10.2337/db13-0949
WOS ID WOS:000336643900039
PubMed ID 24296717
Erfassungsdatum 2013-12-04
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