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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Grarup
Niels
N
Steno Diabetes Center, Niels Steensens Vej 1, NLC2.14, 2820 Gentofte, Denmark. ngrp@steno.dk
Rose
Chrisian S
CS
Andersson
Ehm A
EA
Andersen
Gitte
G
Nielsen
Arne L
AL
Albrechtsen
Anders
A
Clausen
Jesper O
JO
Rasmussen
Signe S
SS
Jørgensen
Torben
T
Sandbaek
Annelli
A
Lauritzen
Torsten
T
Schmitz
Ole
O
Hansen
Torben
T
Pedersen
Oluf
O
D000328:Adult; D015331:Cohort Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D018149:Glucose Intolerance / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics*; D007438:Introns; D008875:Middle Aged; D012016:Reference Values; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics