rs1470579

Of 40 SNPs previously associated with type 2 diabetes, 19 (48%) introduce or remove CpG sites. In 84 human pancreatic islet donors, all 16 analyzed CpG-SNPs showed statistically significant differential DNA methylation (p≤2.3×10⁻⁵). Several CpG-SNPs including rs391300 (SRR), rs5945326 (DUSP9), rs11708067 (ADCY5), rs5015480 (HHEX), rs13266634 (SLC30A8), rs1801214 (WFS1), rs564398 (CDKN2A), and rs2237895 (KCNQ1) were associated with differential gene expression, alternative splicing, or hormone secretion, suggesting DNA methylation-mediated mechanisms linking genetic variants to type 2 diabetes pathogenesis.

This association study identified rs10811661 near CDKN2A/B on chromosome 9p21, a type 2 diabetes risk SNP, as significantly associated with diabetic nephropathy in 2,963 type 1 diabetes patients (OR 1.33, p=0.00045). The association was replicated in meta-analysis across four cohorts (n>5,000; OR 1.15, p=0.011) and was particularly strong for end-stage renal disease (OR 1.35, p=0.00038). The SNP was also associated with severe retinopathy but not cardiovascular disease.

This case-control study analyzed 7 SNPs in 6 genes previously associated with type 2 diabetes (T2DM) in 235 kidney transplant patients medicated with tacrolimus to determine their effect on new-onset diabetes after transplantation (NODAT). While no individual SNP showed significant association with NODAT, patients carrying >7 of the 14 'diabetogenic' alleles had significantly higher NODAT risk (OR 2.17, 95% CI 1.18–3.99, p=0.015), particularly for late-onset NODAT (OR 1.37 per allele, 95% CI 1.05–1.78, p=0.017).

The D.E.S.I.R. prospective cohort study (N=4,707) validated 22 SNPs from genome-wide association studies for type 2 diabetes effects on glucose homeostasis. Risk alleles in SLC30A8 (rs13266634, P=0.0003), NGN3 (rs10823406, P=0.01), and MMP26 (rs2499953, P=0.04) were associated with elevated fasting glucose, while CDKAL1 variants (rs7756992, P=0.003) showed reduced fasting insulin. However, associations with type 2 diabetes incidence were modest (HRs ranging 1.25-2.03), and only SLC30A8 remained significant after Bonferroni correction for HOMA-B.

This case-control association study in 864 Japanese type 2 diabetes patients and 864 controls confirmed that three SNPs in HHEX (rs5015480 OR=1.46, rs7923837 OR=1.40, rs1111875 OR=1.30) were significantly associated with type 2 diabetes across ethnic groups. SNPs in FTO, CDKAL1, CDKN2B, and SLC30A8 showed nominal associations, while several SNPs were associated with impaired pancreatic beta cell function measured by HOMA-beta index.