rs560887

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.

Transethnic fine-mapping study of glycaemic traits in 26,760 participants (Hispanic/Latino, African, Asian, and Native American) using the Metabochip. Replicated 31/39 fasting glucose and 14/17 fasting insulin loci from European GWAS. Identified two novel secondary signals at G6PC2-rs477224 and GCK-rs2908290, a population-specific signal at G6PC2-rs77719485 in African ancestry, and one novel locus at SLC17A2-rs75862513 for fasting insulin.

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

This study identifies multiple functional polymorphisms in the G6PC2 gene that contribute to fasting plasma glucose (FPG) levels. The rs560887-G allele enhances G6PC2 pre-mRNA splicing, while the rs2232316-A allele enhances G6PC2 transcription (β=0.04 mmol/l, p=4.3×10⁻³), and the rs2232321-G allele also promotes exon 4 inclusion. All three SNPs are identified as potentially causative variants that contribute to the association between G6PC2 and elevated FPG in pancreatic beta cells.

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.

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.

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 study found that rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose (OR 1.26, 95% CI 1.08-1.47 for impaired fasting glucose risk, p=0.002) and increased basal hepatic glucose production in elderly twins (p=0.04). The variant also associates with increased insulin release after oral and intravenous glucose loads, but shows no association with type 2 diabetes (OR 0.93, p=0.2) or metabolic syndrome.

This case-control association study of 3,676 Shanghai Chinese individuals (1,876 cases, 1,800 controls) identified rs16856187 in G6PC2 as associated with type 2 diabetes (p=0.0009, OR=1.191) and fasting plasma glucose level (β=0.067 mmol/l per C allele, p=0.0002). This SNP differs from the European-associated variants rs560887 and rs563694, suggesting population-specific genetic architecture in G6PC2.

This study examined the combined effects of SNPs in four genes (GCK, GCKR, G6PC2, and MTNR1B) on fasting plasma glucose (FPG) levels and type 2 diabetes risk in 4,669 Dutch participants. A risk allele score combining GCK, G6PC2, and MTNR1B variants showed a significant association with FPG (0.05 mmol/l per additional risk allele, p=2×10⁻¹³) and type 2 diabetes, where carriers with >5 risk alleles had OR 2.05 (p=4×10⁻⁶) compared to the reference group with 4 risk alleles.