Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

被引：80

作者：

Boesgaard, T. W. ^{[1
]}

Grarup, N. ^{[1
]}

Jorgensen, T. ^{[2
]}

Borch-Johnsen, K. ^{[4
,5
]}

Hansen, T. ^{[1
,6
]}

Pedersen, O. ^{[1
,3
,5
]}

机构：

[1] Hagedorn Res Inst, DK-2820 Gentofte, Denmark

[2] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[3] Univ Copenhagen, Fac Hlth Sci, Inst Biomed Sci, Copenhagen, Denmark

[4] Steno Diabet Ctr, Copenhagen, Denmark

[5] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark

[6] Univ So Denmark, Fac Hlth Sci, Odense, Denmark

来源：

DIABETOLOGIA | 2010年 / 53卷 / 08期

关键词：

Association study; Beta cell dysfunction; Beta cell function; Genetic epidemiology; Glucose homeostasis; Glucose-stimulated insulin release; Type; 2; diabetes; FASTING PLASMA-GLUCOSE; INSULIN SENSITIVITY; RESISTANCE; RELEASE; RISK; POLYMORPHISM; POPULATION; GENE; HOMEOSTASIS; ADAMTS9;

D O I：

10.1007/s00125-010-1753-5

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

A meta-analysis of 21 genome-wide association studies identified 11 novel genetic loci implicated in fasting glucose homeostasis. We aimed to evaluate the impact of these variants on insulin release and insulin sensitivity estimated from OGTTs. Eleven variants in or near DGKB/TMEM195, ADCY5, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B and IGF1 were genotyped in 6,784 middle-aged participants of the population-based Inter99 cohort. Association studies of quantitative estimates of insulin release and insulin sensitivity were performed in 5,722 non-diabetic Danish participants on whom an OGTT was performed. Assuming an additive genetic model, carriers of the alleles increasing fasting glucose in DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B showed decreased glucose-stimulated insulin release as assessed by the BIGTT-acute insulin response index (2.7-3.5%; p < 0.005 for all) and by corrected insulin response (2.8-5.9%; p < 0.03 for all). In addition, the PROX1 glucose-raising allele showed a 2.9% decreased corrected insulin response (p = 0.03), while the hyperglycaemic allele of variants in or near ADRA2A, FADS1, CRY2 and C2CD4B were associated with a 2.6% to 9.3% decrease in one or both of two different OGTT-based disposition indices (p < 0.02 for all). After correction for multiple testing, variants in the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with estimates of beta cell function. We found that the lead variants at the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response. This association underlines the importance of pancreatic beta cell dysfunction in the genetic predisposition to hyperglycaemia and type 2 diabetes.

引用

页码：1647 / 1655

页数：9