rs4607517

This association study examined 43 diabetes-related SNPs in relation to diastolic dysfunction and cardiovascular disease across two Swedish cohorts. HNF1B rs757210 (T-allele) was the main finding, associated with prevalent diastolic dysfunction in both the discovery cohort (MPP-RES; OR 1.21, P=0.024) and replication cohort (VARA; OR 1.38, P=0.042), and with increased risk of incident CVD (HR 1.05, P=0.042) but not CHF over 30+ years of follow-up.

Meta-analysis of 34,748 European ancestry adults from 11 CHARGE Consortium cohorts examining sugar-sweetened beverage (SSB) intake associations with glycemic traits. SSB intake was associated with higher fasting glucose (β=0.014 mmol/l, p=1.5×10⁻³) and fasting insulin (β=0.030 log pmol/l, p=2.0×10⁻¹⁰). Although a suggestive interaction between SSB and KLB-rs1542423 was observed in discovery cohorts for fasting insulin (p=0.006), this was not confirmed in replication analysis.

A case-control study of 674 GDM patients and 690 controls combined with a meta-analysis found that the G allele of rs10830963 and T allele of rs1387153 in MTNR1B are significantly associated with increased risk of gestational diabetes mellitus (GDM). Meta-analysis of 6 studies showed rs10830963 G allele increased GDM risk in co-dominant model (OR 1.62, 95% CI 1.34-1.94) and rs1387153 T allele increased risk in co-dominant model (OR 1.53, 95% CI 1.26-1.86).

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.

Transethnic genome-wide meta-analysis in 159,940 individuals identified 60 common genetic variants associated with HbA1c levels. Variants were classified as glycemic (19), erythrocytic (22), or unclassified (19) based on their biological mechanisms. Glycemic variants were associated with higher type 2 diabetes risk (OR=1.05 per allele, p=3×10⁻²⁹), while erythrocytic variants were not. The X-linked G6PD G202A variant showed a large effect in African Americans (0.81% HbA1c reduction per allele) but minimal effects in other ancestries, potentially causing 2% of African American T2D cases to remain undiagnosed when using HbA1c screening.

This case-control study investigated 25 T2DM-associated SNPs in a multi-ethnic Hawaiian cohort (291 GDM cases, 734 controls) and found ethnicity-specific associations with gestational diabetes. Key findings in Filipinos included rs1113132 (EXT2, OR=1.52, p=0.028), rs1111875 (HHEX, OR=1.5, p=0.047), rs2237892 (KCNQ1, OR=0.49, p<0.001), rs10830963 (MTNR1B, OR=0.63, p=0.025), and rs13266634 (SLC30A8, OR=0.58, p=0.011). In Japanese women, rs4402960 (IGFBP2, OR=0.5, p=0.031) and rs2237892 (KCNQ1, OR=0.5, p=0.03) were significant. Pacific Islanders showed associations with rs10830963 (MTNR1B, OR=0.52, p=0.037) and rs13266634 (SLC30A8, OR=2.43, p=0.03). No SNPs showed consistent associations across all three ethnic groups.

This study examined genetic variants associated with fasting glucose from previously identified GWAS loci in four ethnic groups (Caucasian, African American, Hispanic, and Chinese descent) from the Multi-Ethnic Study of Atherosclerosis (MESA). The analysis focused on three gene regions (MTNR1B, GCK, and G6PC2) and found that rs10830963 in MTNR1B and rs4607517 in GCK demonstrated consistent magnitude of association with fasting glucose across ethnic groups (p = 1.29E-12 and p = 1.0E-7, respectively in meta-analysis), with effect sizes ranging from 1.22-1.66 mg/dl and -1.19 to -1.06 mg/dl respectively.

Replication study in Japanese (n=4,813) and Sri Lankan (n=2,319) populations confirmed association of five common variants at four loci (GCK rs1799884, GCKR rs780094, G6PC2-ABCB11 rs560887, MTNR1B rs1387153 and rs10830963) with fasting plasma glucose levels (p<0.05). Fine-mapping identified a novel independent SNP rs3755157 in the G6PC2-ABCB11 region with stronger association (β=0.055-0.069 mmol/l, p=2.6×10⁻⁸ in Japanese) and confirmed allelic heterogeneity. Type 2 diabetes association was replicated in case-control studies (OR 1.09-1.28).

This GWAS of fasting glucose in the ARIC study examined 5,782-8,372 individuals across four longitudinal visits and identified five genomic regions significantly associated with fasting glucose (p < 5×10⁻⁸): GCKR, G6PC2, GCK, SLC30A8, and MTNR1B. The study demonstrated that averaging fasting glucose measures across visits improved statistical power and detected additional signals (GCKR rs780094, SLC30A8 rs13266634) not visible in single-visit analyses. Analysis of candidate SNPs revealed significant interactions with diabetes status: associations with fasting glucose were stronger in non-diabetic individuals than in those with prevalent diabetes for multiple SNPs including rs10830963 (MTNR1B), rs560887 (G6PC2), rs4607517 (GCK), and rs780094 (GCKR).

This is a comprehensive mutation review of the glucokinase (GCK) gene, documenting 620 mutations identified in 1,441 families that cause maturity-onset diabetes of the young (GCK-MODY), permanent neonatal diabetes mellitus (PNDM), and hyperinsulinemic hypoglycemia (GCK-HH). The paper reviews heterozygous inactivating GCK mutations causing mild fasting hyperglycemia in GCK-MODY, homozygous mutations causing severe PNDM, and activating mutations clustering in the allosteric activator site causing inappropriate insulin secretion. The GCK polymorphism rs4607517 is associated with increased fasting plasma glucose but not type 2 diabetes susceptibility.