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

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 12; pp. 3105 - 3111
• Main Authors: GRARUP, Niels, ROSE, Chrisian S, LAURITZEN, Torsten, SCHMITZ, Ole, HANSEN, Torben, PEDERSEN, Oluf, ANDERSSON, Ehm A, ANDERSEN, Gitte, NIELSEN, Arne L, ALBRECHTSEN, Anders, CLAUSEN, Jesper O, RASMUSSEN, Signe S, JØRGENSEN, Torben, SANDBAEK, Annelli
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2007
• Subjects: Adult; Biological and medical sciences; Cohort Studies; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Denmark; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; European Continental Ancestry Group - genetics; Genetic aspects; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Genomes; Genotype & phenotype; Glucose; Glucose Intolerance - genetics; Health aspects; Health care; Homeodomain Proteins - genetics; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Like Growth Factor Binding Protein 2 - genetics; Introns; Medical sciences; Metabolism; Middle age; Middle Aged; Reference Values; Reproducibility of Results; Research design; Transcription Factors - genetics; Type 2 diabetes; Denmark; Endocrinopathy; Type 2 diabetes; Human; Variant; Pancreatic hormone; Association; Gene; Metabolic diseases; Danish; Genome; Insulin; Release
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db07-0856

In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed to characterize quantitative metabolic risk phenotypes of the four variants. The variants were genotyped in the population-based Inter99 cohort (n = 5,970), the ADDITION Study (n = 1,626), a population-based sample of young healthy subjects (n = 377), and in additional type 2 diabetic case (n = 2,111) and glucose-tolerant (n = 521) subjects. The case-control studies involved a total of 4,089 type 2 diabetic patients and 5,043 glucose-tolerant control subjects. We validated association of variants near HHEX/KIF11/IDE, CDKN2A/B, and IGF2BP2 with type 2 diabetes. Interestingly, in middle-aged people, the rs1111875 C-allele of HHEX/KIF11/IDE strongly associated with lower acute insulin response during an oral glucose tolerance test (P = 6 x 10(-7)). In addition, decreased insulin release following intravenous tolbutamide injection was observed in young healthy subjects (P = 0.02). Also, a reduced insulin release was observed for the CDKN2A/B rs10811661 T-allele after both oral and intravenous glucose challenges (P = 0.001 and P = 0.009, respectively). We validate that variants in the proximity of the HHEX/KIF11/IDE, CDKN2A/B, and IFG2BP2 loci associate with type 2 diabetes. Importantly, variations within the HHEX/KIF11/IDE and CDKN2A/B loci confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects, suggesting a role for these variants in the pathogenesis of pancreatic beta-cell dysfunction.