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

TY - JOUR

T1 - Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

AU - Boesgaard, T W

AU - Grarup, N

AU - Jørgensen, Torben

AU - Borch-Johnsen, Knut

AU - Hansen, T

AU - Pedersen, Oluf

AU - Meta-Analysis of Glucose and Insulin-Related Trait Consortium (MAGIC)

PY - 2010/8/1

Y1 - 2010/8/1

N2 - Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/ interpretation: 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.

AB - Aims/hypothesis: 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. Methods: 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. Results: 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. Conclusions/ interpretation: 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.

KW - Denmark

KW - Diacylglycerol Kinase

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Glucose

KW - Humans

KW - Insulin-Secreting Cells

KW - Male

KW - Middle Aged

KW - Receptors, Adrenergic, alpha-2

KW - Transcription Factors

U2 - 10.1007/s00125-010-1753-5

DO - 10.1007/s00125-010-1753-5

M3 - Journal article

C2 - 20419449

SN - 0012-186X

VL - 53

SP - 1647

EP - 1655

JO - Diabetologia

JF - Diabetologia

IS - 8

ER -