rs1799884

A literature review of 70 studies examining single nucleotide polymorphisms (SNPs) associated with obesity in Mexican populations published 2011-2021. The authors identified SNPs with differential behavior in Mexican compared to Caucasian populations, including rs17782313 (MC4R), rs6548238 (TMEM18), rs6265 (BDNF), rs7498665 (SH2B1), and notably rs6232 (PCSK1) associated with early-onset obesity in Mexican youth. The review emphasizes ethnicity-dependent genetic effects on BMI heritability (40-70%) and highlights genes involved in cholesterol metabolism and adipokine signaling pathways.

This comprehensive review synthesizes literature on gestational diabetes mellitus (GDM), demonstrating its complex multifactorial etiology involving genetic factors (SNPs in GCKR, KCNQ1, MTNR1B, TCF7L2), epigenetic modifications (DNA methylation and microRNA expression), and alterations in microbial composition across multiple body sites. While certain SNP variants are associated with GDM phenotypes globally, genetic predisposition alone does not explain disease development; lifestyle factors can modify epigenetic signatures and microbiota composition to modulate risk. Evidence indicates genes, epigenetic alterations, and microbiota can transfer from mother to offspring with long-term health consequences.

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.

The GCKR rs780092 T-allele variant shows opposite effects on metabolic traits in a Chinese cohort: associated with 17% lower risk of incident type 2 diabetes (HR 0.83 [95% CI 0.73-0.95]) but 36% higher risk of hypertriacylglycerolaemia (OR 1.36 [95% CI 1.08-1.72]). Both baseline and longitudinal changes in triglyceride levels mediate the association between this variant and diabetes risk.

This study examined the association between the GCK -30G>A polymorphism (rs1799884) and gestational diabetes mellitus (GDM) susceptibility through a case-control study of 948 GDM cases and 975 controls in a Chinese population, followed by meta-analysis of 6 studies (2,959 cases, 8,535 controls). The A-allele was significantly associated with increased GDM risk in the case-control study (OR=1.41, 95% CI 1.16-1.71) and remained significantly associated in the meta-analysis overall (OR=1.28, 95% CI 1.17-1.39, P<0.001), with stronger effects in Asian populations (OR=1.37) compared to Caucasians (OR=1.24).

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 association study of 4,213 Danish individuals examined 25 type 2 diabetes risk variants and their association with birthweight. The study found that type 2 diabetes risk alleles near ADCY5 (rs11708067, β = -33 g, p = 0.004), CDKAL1 (rs7756992, β = -22 g, p = 0.04), and HHEX-IDE (rs1111875, β = -16 g in meta-analysis, p = 8×10⁻⁵, n = 25,164) were associated with reduced birthweight, supporting the fetal insulin hypothesis. Meta-analyses confirmed these associations and showed no strong general effect on birthweight from the 25 common type 2 diabetes risk alleles combined.

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 longitudinal study of 4,554 participants from the Busselton Health Survey examined associations between four SNPs in APOA5, LPL, and GCK genes with glucose and lipid traits over time. Cross-sectional analyses confirmed that GCK rs1799884 was associated with fasting glucose (beta=0.01, p=0.003), APOA5 rs662799 and rs3135506 with triacylglycerol levels (p<0.0001), and LPL rs328 with reduced triacylglycerol and raised HDL-C. Longitudinal analyses (n=2,864) showed these genetic effects on lipid and glucose traits remain stable with age during adulthood.

This population-based association study of 3,210 Han Chinese individuals examined GCKR rs780094 and GCK rs1799884 variants and their associations with type 2 diabetes. The GCKR rs780094 A allele was significantly associated with reduced risk of type 2 diabetes and IFG combined (OR 0.86, 95% CI 0.77-0.96, p=0.0032), as well as decreased fasting glucose and increased beta cell function (HOMA-B). The effect on type 2 diabetes was mediated through beta cell function rather than obesity. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B but not diabetes risk.

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.

This study of 16,853 Danes validates the association between GCKR rs780094 A-allele and elevated fasting triacylglycerol (p=6×10⁻¹⁴) while showing reduced fasting (p=0.001) and OGTT-related insulin (p=3×10⁻⁶), improved insulin sensitivity (HOMA-IR p=0.0004), increased dyslipidemia risk (p=6×10⁻⁹), and modestly decreased type 2 diabetes risk (OR=0.92, p=0.01). An additive interaction with GCK -30G>A was demonstrated for fasting insulin (p=0.0002).

This case-control study of 1,880 Scandinavian women (648 with gestational diabetes mellitus [GDM] and 1,232 controls) examined common variants in MODY genes. The GCK -30G→A polymorphism (rs1799884) showed increased GDM risk in an additive model (OR 1.28, 95% CI 1.06–1.53, p=0.008) and recessive model (OR 2.12, p=0.009). The HNF1A I27L polymorphism (rs1169288) showed modest increased risk with a dominant model (OR 1.31, p=0.007). Three HNF4A variants (rs2144908, rs2425637, rs1885088) were not associated with GDM risk.