Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes With Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5,327 Nondiabetic Finnish Men

被引：145

作者：

Stancakova, Alena ^{[1
,2
]}

Kuulasmaa, Teemu ^{[1
,2
]}

Paananen, Jussi ^{[1
,2
]}

Jackson, Anne U. ^{[3
]}

Bonnycastle, Lori L. ^{[4
]}

Collins, Francis S. ^{[4
]}

Boehnke, Michael ^{[3
]}

Kuusisto, Johanna ^{[1
,2
]}

Laakso, Markku ^{[1
,2
]}

机构：

[1] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland

[2] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[3] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[4] NHGRI, NIH, Bethesda, MD 20892 USA

来源：

DIABETES | 2009年 / 58卷 / 09期

基金：

芬兰科学院; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; BETA-CELL FUNCTION; TCF7L2 GENE POLYMORPHISMS; POPULATION-BASED SAMPLE; GLUCOSE-TOLERANCE; INCREASED RISK; PREDIABETIC PHENOTYPES; PRO12ALA POLYMORPHISM; EUROPEAN POPULATIONS; PREVENTION PROGRAM;

D O I：

10.2337/db09-0117

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

OBJECTIVE-We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin. RESEARCH DESIGN AND METHODS-A total of 5,327 nondiabetic men (age 58 +/- 7 years, BMI 27.0 +/- 3.8 kg/m(2)) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium. RESULTS-Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, and MTNR1B) were significantly (P < 6.9 x 10(-4)) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P < 0.05) associated with early-phase insulin release, (InsAUC(0-30)/GluAUC(0-30)), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached -32% reduction in InsAUC(0-30)/GluAUC(0-30), in carriers of >= 11 vs. <= 3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, and TCF7L2) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs (KCNJ11, HHEX, and TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC(0-30)/GluAUC(0-30). Nine SNPs did not show any associations with examined traits. CONCLUSIONS-Eight type 2 diabetes-related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity. Diabetes 58:2129-2136, 2009

引用

页码：2129 / 2136

页数：8

共 49 条

[1]

[Anonymous], 1999, Definition, diagnosis, and classification of diabetes mellitus and its complications: report of a WHO consultation

[2] Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men [J].

Dahlgren, A. ;

Zethelius, B. ;

Jensevik, K. ;

Syvaenen, A.-C. ;

Berne, C. .

DIABETOLOGIA, 2007, 50 (09) :1852-1857

[3] Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene in relation to insulin sensitivity among glucose tolerant Caucasians [J].

Ek, J ;

Andersen, G ;

Urhammer, SA ;

Hansen, L ;

Carstensen, B ;

Borch-Johnsen, K ;

Drivsholm, T ;

Berglund, L ;

Hansen, T ;

Lithell, H ;

Pedersen, O .

DIABETOLOGIA, 2001, 44 (09) :1170-1176

[4] Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program [J].

Florez, J. C. ;

Jablonski, K. A. ;

McAteer, J. ;

Sandhu, M. S. ;

Wareham, N. J. ;

Barroso, I. ;

Franks, P. W. ;

Altshuler, D. ;

Knowler, W. C. .

DIABETOLOGIA, 2008, 51 (03) :451-457

[5] A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity [J].

Frayling, Timothy M. ;

Timpson, Nicholas J. ;

Weedon, Michael N. ;

Zeggini, Eleftheria ;

Freathy, Rachel M. ;

Lindgren, Cecilia M. ;

Perry, John R. B. ;

Elliott, Katherine S. ;

Lango, Hana ;

Rayner, Nigel W. ;

Shields, Beverley ;

Harries, Lorna W. ;

Barrett, Jeffrey C. ;

Ellard, Sian ;

Groves, Christopher J. ;

Knight, Bridget ;

Patch, Ann-Marie ;

Ness, Andrew R. ;

Ebrahim, Shah ;

Lawlor, Debbie A. ;

Ring, Susan M. ;

Ben-Shlomo, Yoav ;

Jarvelin, Marjo-Riitta ;

Sovio, Ulla ;

Bennett, Amanda J. ;

Melzer, David ;

Ferrucci, Luigi ;

Loos, Ruth J. F. ;

Barroso, Ines ;

Wareham, Nicholas J. ;

Karpe, Fredrik ;

Owen, Katharine R. ;

Cardon, Lon R. ;

Walker, Mark ;

Hitman, Graham A. ;

Palmer, Colin N. A. ;

Doney, Alex S. F. ;

Morris, Andrew D. ;

Smith, George Davey ;

Hattersley, Andrew T. ;

McCarthy, Mark I. .

SCIENCE, 2007, 316 (5826) :889-894

[6] Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI [J].

Freathy, Rachel M. ;

Timpson, Nicholas J. ;

Lawlor, Debbie A. ;

Pouta, Anneli ;

Ben-Shlomo, Yoav ;

Ruokonen, Aimo ;

Ebrahim, Shah ;

Shields, Beverley ;

Zeggini, Eleftheria ;

Weedon, Michael N. ;

Lindgren, Cecilia M. ;

Lango, Hana ;

Melzer, David ;

Ferrucci, Luigi ;

Paolisso, Giuseppe ;

Neville, Matthew J. ;

Karpe, Fredrik ;

Palmer, Colin N. A. ;

Morris, Andrew D. ;

Elliott, Paul ;

Jarvelin, Marjo-Riitta ;

Smith, George Davey ;

McCarthy, Mark I. ;

Hattersley, Andrew T. ;

Frayling, Timothy M. .

DIABETES, 2008, 57 (05) :1419-1426

[7] Pro12Ala polymorphism in peroxisome proliferator-activated receptorγ2 (PPARγ2):: beta-cell function and insulin sensitivity [J].

Fritsche, A ;

Madaus, A ;

Tschritter, O ;

Özeker, M ;

Wulle, EL ;

Machicao, F ;

Häring, H ;

Stumvoll, M .

DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT, 2001, 126 (20) :580-584

[8] Association of variants of the TCF7L2 gene with increases in the risk of type 2 diabetes and the proinsulin:insulin ratio in the Spanish population [J].

Gonzalez-Sanchez, J. L. ;

Martinez-Larrad, M. T. ;

Zabena, C. ;

Perez-Barba, M. ;

Serrano-Rios, M. .

DIABETOLOGIA, 2008, 51 (11) :1993-1997

[9] Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes [J].

Grarup, Niels ;

Andersen, Gitte ;

Krarup, Nikolaj T. ;

Albrechtsen, Anders ;

Schmitz, Ole ;

Jorgensen, Torben ;

Borch-Johnsen, Knut ;

Hansen, Torben ;

Pedersen, Oluf .

DIABETES, 2008, 57 (09) :2534-2540

[10] Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects -: Validation and extension of genome-wide association studies [J].

Grarup, Niels ;

Rose, Chrisian S. ;

Andersson, Ehm A. ;

Andersen, Gitte ;

Nielsen, Arne L. ;

Albrechtsen, Anders ;

Clausen, Jesper O. ;

Rasmussen, Signe S. ;

Jorgensen, Torben ;

Sandbaek, Annelli ;

Lauritzen, Torsten ;

Schmitz, Ole ;

Hansen, Torben ;

Pedersen, Oluf .

DIABETES, 2007, 56 (12) :3105-3111

← 1 2 3 4 5 →