We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27-1.75]; P = 8.91 x 10(-7)) and CDKN2A/B (1.31 [1.12-1.54]; P = 1.0 x 10(-3)).
Of the 18 polymorphisms, the ADAMTS9, CDKAL1, CDKN2A/B-rs1412829, FTO, IGF2BP2, JAZF1, SLC30A8, TCF7L2, and WFS1 variants were associated with type 2 diabetes risk in our population.
However, genome-wide association studies are accelerating our knowledge of the genetics of complex diseases, and have identified seven other key genes in T2DM: CDKAL1, CDK5 regulatory subunit associated protein-like 1; CDKN2, cyclin-dependent kinase inhibitor 2A; FTO, fat mass and obesity associated; HHEX, haematopoietically expressed homeobox; IDE, insulin-degrading enzyme; IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2; SLC30A8, solute carrier family 30 (zinc transporter), member 8; TCF7L2, transcription factor 7-like 2 (T-cell specific, HMG-box).
None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians.
In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634).
Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function.
We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively).
In the total population, the TCF7L2 and IGF2BP2 variants most strongly associated with increased risk for type 2 diabetes/IGT and increased AUC for glucose, while the CDKAL1 polymorphism associated with decreased AUC for insulin.
The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion also reduce birth weight, and an association of low birth weight and the type 2 diabetes risk alleles at the HHEX-IDE and CDKAL1 loci were recently reported.
The combined analysis of the three ethnic groups revealed significant associations between SNPs in CDKAL1 (OR = 1.13; P = 3 x 10(-4)), CDKN2A/B (OR = 1.16; P = 9 x 10(-5)), HHEX (OR = 1.14; P = 6 x 10(-4)), and KCNQ1 (OR = 1.16-1.20; P = 3 x 10(-4) to 3 x 10(-6)) with T2DM.
Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al.
We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre-genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2).
We have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities.