Islet ATAC-seq peaks overlap with 13 SNPs associated with T2D (e.g. rs7903146, rs2237897, rs757209, rs11708067 and rs878521 near TCF7L2, KCNQ1, HNF1B, ADCY5 and GCK, respectively) and with additional 67 SNPs in LD with known T2D SNPs (e.g.
Mean C-peptide at diagnosis was higher for HNF4A-MODY than for T1D (1.8 vs 0.9 ng/mL; P < 0.01); 36.4% of patients with HNF4A-MODY and 65.7% of patients with HNF1B-MODY were treated with insulin, whereas 20.5% and 8.6% received oral antidiabetics only (P < 0.05 and P < 0.01 vs T2D).
Mutations in hepatocyte nuclear factor-1β gene result in a multisystemic syndrome where a monogenic form of diabetes (maturity-onset diabetes of young type 5; MODY 5) and renal anomalies, usually bilateral multiple cysts are the most characteristic findings.
Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.
After adjusting for multiple covariates, SNPs in or near CDKAL1, CDKN2BAS, KCNQ1, TCF7L2, CDC123/CAMK1D, HHEX, and TCF2 were associated with the risk for lean T2D, and SNPs in or near KCNQ1 and FTO were associated with the risk for obese T2D.
We have detected the interactions of hsa-miR-214-5p/hsa-miR-550a-5p and the 3'UTR SNP of the HNF1B gene by in vitro luciferase reporter assays, and propose that the binding of such miRNAs regulates the expression of the HNF1B gene and the susceptibility of T2DM.
Genetic variants of WFS1, CDKAL1, CDKN2BAS, TCF7L2, HHEX, KCNQ1, TSPAN8/LGR5, FTO, and TCF2 were associated with the risk for T2D with MetS, as well as the risk for development of T2D with at least one of the MetS components (P < 0.05).
Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1Brs4430796 in influencing risk of type 2 diabetes (p < 0.05).
We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10(-18)<P<8.5×10(-3)), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09.
hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50-1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46-2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30-1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under the curve = 0.84).