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

Abstract

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. RESEARCH DESIGN AND 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 × 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 β-cell dysfunction.

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

“…Larger studies have also confirmed susceptibility loci within the SLC30A8, CDKN2A/B, IGF2BP2 and KCNJ11 genes as altering beta cell function, so larger studies may refine our initial estimates [7,11,12]. In conclusion, while individual susceptibility alleles only moderately alter pancreatic beta cell function, the risk is additively increased when risk alleles are combined.…”

“…The additive effects of the three risk variants were associated with a decrease in 30 min insulin response (p=4.17×10 −7 ). This was decreased by 43% in the 3.1% of the cohort with five or more risk alleles compared with the 3.2% that carried no risk alleles ( Although the other novel genes, CDKN2A/B, IGF2BP2, SLC30A8 and KCNJ11 have been shown to be associated with indices of pancreatic beta cell function in other studies [7,11,12], they did not reach statistical significance individually in our cohort [10]. However, when we included them in our additive model the relationships between increasing number of risk alleles and decreasing 30 min insulin response and decreasing beta cell glucose sensitivity still remained significant (p<0.001 and p=0.003, respectively).…”

“…Many of the confirmed type 2 diabetes variants have since been shown in population cohorts to alter beta cell function [7][8][9][10][11][12][13]. These studies include the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study [14], where we previously showed that CDKAL1 (rs10946398) and HHEX/IDE (rs1111875) loci were associated with altered beta cell function as measured by the 30 min insulin response and pancreatic beta cell glucose sensitivity derived from an OGTT [10].…”

Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps

“…Remarkably, second-phase insulin secretion remained intact. Previously, several studies have investigated the effects of novel susceptibility loci on insulin secretion as assessed by the OGTT [2-4, 6, 7] or IVGTT [2,[4][5][6]. These studies reported that these gene variants were associated with reduced insulin secretion but not with insulin sensitivity.…”

“…Of these novel genes, FTO plays a role in childhood and adult obesity and the other five regions may play a role in pancreatic beta cell development and/or insulin secretion. Recent clinical results involving glucose tolerance tests indeed show that these variants affect insulin secretion, at least within the limitations of the tests used [2][3][4][5][6][7].…”