rs564398

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 genome-wide association study identified four genes influencing theta band event-related oscillations, a heritable neuroelectrical trait associated with alcohol dependence. The strongest association for alcohol dependence risk was rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10⁻⁴), with a recessive effect (OR = 1.32–1.37, P = 0.031–0.042). Other significant markers included rs4907240 in ARID5A (P = 3.68 × 10⁻⁶), rs13831 in GNAS1, and non-synonymous rs2294015 in ANXA13.

The HERITAGE Family Study examined eight type 2 diabetes susceptibility variants in 481 sedentary individuals undergoing 20-week endurance training. PPARG rs1801282 (Pro12Ala) was the only significant finding: Ala carriers showed greater improvements in glucose tolerance (p=0.0008), glucose effectiveness (p=0.004), and disposition index (p=0.003) in response to exercise training, though no associations were found with other recently identified GWAS variants.

This case-control study in 869 Korean women with gestational diabetes mellitus (GDM) and 632 non-diabetic controls examined whether type 2 diabetes-associated genetic variants discovered in recent GWAS are also associated with GDM. Multiple variants showed significant associations with GDM, including rs7756992 and rs7754840 in CDKAL1 (OR 1.55, p=4.17×10⁻⁹), rs10811661 in CDKN2A-CDKN2B (OR 1.49, p=1.05×10⁻⁷), variants in HHEX, rs4402960 in IGF2BP2 (OR 1.18, p=0.03), rs13266634 in SLC30A8 (OR 1.24, p=0.005), and rs7903146 in TCF7L2 (OR 1.58, p=0.038).

This study identified seven SNPs on chromosome 9p21.3 associated with atherosclerotic stroke risk in 4,376 cases and 4,305 controls from Europe and North America. The lead SNP rs1537378 had a pooled odds ratio of 1.21 (95% CI=1.07-1.37, p=0.002) with a population attributable risk of 20.1% for atherosclerotic stroke. The associated variants are located in a region spanning over 100 kb that overlaps genes encoding ANRIL (antisense noncoding RNA), MTAP, CDKN2A, and CDKN2B, implicating this locus in vascular disease pathogenesis.

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.

A replication study of genome-wide association findings in the CDKN2A/CDKN2B region on chromosome 9p in 3,093 French Europids (1,455 cases, 1,638 controls). The study confirms a strong association of rs10811661 with type 2 diabetes (p=3.8×10⁻⁷, OR 1.43 [95% CI 1.24-1.64]) and identifies rs3218018 as a secondary signal surviving Bonferroni correction (p=0.002). The rs564398 variant did not reach significance in this population.

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.