We found a significant association of rs7756992, rs7754840 and rs10946398 in CDKAL1 with type 2 diabetes (odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.07-1.23, P < 0.0001; OR = 1.14, 95%CI = 1.06-1.24, P = 0.001, and OR = 1.12, 95%CI = 1.07-1.18, P < 0.0001, respectively).
Five risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples.
In Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs) as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008) for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003) for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009) for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005) for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03) for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 x 10(-4)) for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046) for FTO-rs8050136 after adjustment for age, gender, and body mass index.
Cyclin- dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) rs10946398, a novel body mass index (BMI)-associated locus specifically in the Asian population, may impair insulin secretion and may be associated with insulin resistance and type 2 diabetes.
In addition, we also confirmed that three SNPs (rs1111875, rs7923837 and rs5015480) in HHEX , one SNP (rs10946398) in CDKAL1, and three SNPs (rs13266634, rs3802177 and rs11558471) in SLC30A8 were significantly associated with T2D in the population being studied.
Taken together, our findings provide evidence for a significant contribution of CDKN2A/B gene rs10811661 and CDKAL1 gene rs7756992 and rs10946398 to type 2 diabetes.
Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P<or=0.05), of whom the three first would stand correction for multiple testing: CDKN2A/B rs10811661, OR: 1.26 (1.12-1.43) P = 1.8*10(-4); CDKAL1 rs10946398, OR: 1.23 (1.09-1.39); P = 7.1*10(-4), and TCF7L2 rs7903146, OR: 1.61 (1.19-2.18) P = 2.3 * 10(-3).
We found a significant association between CDKAL1 polymorphisms (rs4712523, OR 1.42, p = 9.44 × 10-5; rs4712524, OR 1.38, p = 3.28 × 10-4; rs10946398, OR 1.43, p = 6.21 × 10-5; rs7754840, OR 1.43, p = 6.33 × 10-5; rs35612982, OR 1.34, p = 0.0010; and rs10440833, OR 1.32, p = 0.0018) and T2D risk among the Han population from Northwest China.
We found a lower risk of prediabetes and type 2 diabetes combined with coffee intake among individuals with the GT/TT of IGF2BP2 rs4402960, GG/GC of CDKAL1 rs7754840, or CC of KCNJ11 rs5215, which are known to be related to type 2 diabetes in East Asians.
We found a significant association of rs7756992, rs7754840 and rs10946398 in CDKAL1 with type 2 diabetes (odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.07-1.23, P < 0.0001; OR = 1.14, 95%CI = 1.06-1.24, P = 0.001, and OR = 1.12, 95%CI = 1.07-1.18, P < 0.0001, respectively).
Three SNPs-rs7756992 (P = .007), rs7754840 (P = .015), and rs6931514 (P = .029)-of the CDKAL1, rs7020996 (P = .003) of the CDKN2A/B gene, rs7923837 (P = .038) of the HHEX gene, and rs12056034 (P = .033) of the BAZ1B gene were associated with T2D in our population.
Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P=6.65×10(-16)).
Meanwhile PPARG-2 Pro12Ala, CDKN2A/2B rs10811661, IGF2BP2 rs4402960, HHEX rs7923837, CDKAL1 rs7754840, EXT2 rs1113132 and SLC30A8 rs13266634 were found to have no significant association with T2D among Arabs.
We found a significant association between CDKAL1 polymorphisms (rs4712523, OR 1.42, p = 9.44 × 10-5; rs4712524, OR 1.38, p = 3.28 × 10-4; rs10946398, OR 1.43, p = 6.21 × 10-5; rs7754840, OR 1.43, p = 6.33 × 10-5; rs35612982, OR 1.34, p = 0.0010; and rs10440833, OR 1.32, p = 0.0018) and T2D risk among the Han population from Northwest China.
HbA1c reduction after use of DPP-4 inhibitors for 3 months was significantly greater in patients with a risk allele for type 2 diabetes (GG -0.4%, CG -0.5%, CC -0.8%, p = 0.02 for rs7754840 and AA -0.4%, AG -0.5%, GG -0.8%, p = 0.01 for rs7756992).
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).
In meta-regression analyses, age was found to exert a significant influence on the association between rs10811661 and type 2 diabetes (P=0.003), as well as between rs7754840 and gender (P=0.034).
A total of 15 SNPs were genotyped.Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [odds ratio (OR) = 1.16 (95% confidence interval (CI) 1.05-1.27); P = 4.5 x 10(-3)] in SLC30A8; rs1111875 [OR = 1.27 (95% CI 1.14-1.40); P = 1.4 x 10(-5)] and rs7923837 [OR = 1.27 (95% CI 1.13-1.43); P = 1.0 x 10(-4)] in HHEX; rs10811661 [OR = 1.27 (95% CI 1.15-1.40); P = 1.9 x 10(-6)] in CDKN2B; rs4402960 [OR = 1.23 (95% CI 1.11-1.36); P = 8.1 x 10(-5)] and rs1470579 [OR = 1.18 (95% CI 1.07-1.31); P = 8.3 x 10(-4)] in IGF2BP2; and rs7754840 [OR = 1.28 (95% CI 1.17-1.41); P = 4.5 x 10(-7)] and rs7756992 [OR = 1.27 (95% CI 1.15-1.40); P = 9.8 x 10(-7)] in CDKAL1.
In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes.