rs10830963

This is a Turkish-language personalized nutrigenetics and epigenetics coaching report for individual Mehmet Efe Yildirim (Report No. 1332, dated 2023-11-21). The report analyzes the individual's genetic polymorphisms related to nutritional metabolism, food sensitivities, detoxification pathways, and other health-related traits, providing personalized dietary and lifestyle recommendations based on cited scientific literature. This is a direct-to-consumer genetic test report, not a peer-reviewed research study.

Two-stage case-control study of 1,429 pregnant women in Southern China examining MTNR1B gene variants and gestational diabetes mellitus (GDM) susceptibility. SNP rs10830963 was significantly associated with increased GDM risk in the combined analysis (additive model OR=1.36, 95%CI=1.17-1.59, P<0.001; dominant model OR=1.45, 95%CI=1.15-1.83, P=0.005). The rs10830963 variant showed interaction with maternal age and BMI in contributing to GDM risk.

This genome-wide interaction analysis in 6,224 African Americans identified CMIP rs17197883 as a novel type 2 diabetes susceptibility locus through interaction with the insulin secretion variant MTNR1B rs10830963. The CMIP variant showed antagonistic interaction (P_INTXN = 1.43×10^-8) with opposite effects depending on MTNR1B carrier status: OR = 2.29 (95% CI 1.59-3.28) in AIRg-lowering allele carriers vs. OR = 0.78 (95% CI 0.67-0.90) in non-carriers.

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.

This study tested whether insomnia mediates or modifies the association between MTNR1B variant rs10830963 and glucose levels in the DILGOM discovery cohort (n=4,691) and Health 2000 replication cohort (n=5,981). The rs10830963 G allele strongly associates with fasting blood glucose (β=0.189, p=2.39×10⁻¹⁸ in discovery), but the nominal associations with insomnia and the interaction between insomnia and rs10830963 on glucose were not replicated. The authors conclude that rs10830963 associates with glucose metabolism rather than sleep phenotypes, and insomnia does not mediate this association.

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).

This case-control study of 314 Euro-Brazilian pregnant women (134 with gestational diabetes, 180 controls) investigated the association of two polymorphisms with gestational diabetes: rs7799039 in the LEP gene and rs13266634 in the SLC30A8 gene. Neither polymorphism showed a statistically significant association with gestational diabetes (LEP rs7799039 p=0.627, SLC30A8 rs13266634 p=0.522), and genotype frequencies did not differ between groups.

A prospective cohort study of 16,499 Swedish participants from the GLACIER study examined season-dependent associations between circadian rhythm-regulating SNPs (CRY1 rs8192440, CRY2 rs11605924, MTNR1B rs10830963) and glucose homeostasis. The CRY1 A-allele was associated with lower fasting glucose only during the light season (β=-0.04 mmol/l, p=0.02), while CRY2 and MTNR1B variants showed associations with 2h glucose only during the dark season. Results suggest biologically plausible season-dependent effects on glucose metabolism related to extreme seasonal daylight variation at high latitude.

A pharmacogenomics study of 456 hypertensive participants examining whether fasting glucose GWAS variants predict glucose response to antihypertensive medications. The primary finding was that PROX1 rs340874 (C allele) was significantly associated with greater glucose elevation after 9 weeks of atenolol monotherapy (p=0.0013, beta = +2.39 mg/dL per allele). Two additional SNPs showed nominal associations: ARAP1 rs11603334 with atenolol response and SLC2A2 rs11920090 with HCTZ response.

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.

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.

A population-based association study in 5,722 non-diabetic Danish individuals from the Inter99 cohort examined the rs7172432 A allele in the VPS13C/C2CD4A/C2CD4B locus (previously associated with type 2 diabetes risk). The diabetes-associated A allele showed strong association with impaired glucose-stimulated insulin response (GSIR), with effect sizes of 3-8% reduction in GSIR per allele (β = -0.039 to -0.057, p = 2×10⁻⁷ to 9×10⁻⁹). The variant also associated with 0.60 cm higher waist circumference and 0.037 mmol/l higher fasting plasma glucose. Conditional analyses showed rs7172432 has superior effect compared to other regional SNPs (rs11071657, rs17271305), suggesting impaired beta cell function as the intermediary mechanism for type 2 diabetes risk.

A case-control study nested within the Nord-Trøndelag Health Study investigated whether the MTNR1B variant rs10830963 mediates the association between sleep disturbances and type 2 diabetes in 1,322 prevalent cases and 1,447 controls. The rs10830963 risk allele showed a weak association with type 2 diabetes (OR 1.12, 95% CI 1.00-1.27, p=0.0579) and a tendency toward association with early morning awakening, but adjustment for the variant did not alter the sleep-diabetes association (OR 1.69, 95% CI 1.23-2.34, p=0.0014), indicating the MTNR1B variant does not mediate this relationship.

Population-based study of 6,733 non-diabetic Finnish men examining associations between 19 confirmed type 2 diabetes risk loci and tissue-specific insulin resistance indices. Type 2 diabetes risk SNPs in KCNJ11 (rs5219) and HHEX (rs1111875) showed significant associations with lower liver insulin resistance (p<0.0013 and p=5.4×10⁻⁵, respectively), while the Pro12 allele of PPARG2 (rs1801282) was significantly associated with higher adipocyte insulin resistance (p=6.2×10⁻⁵).

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 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).

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 study examined associations between rs10830963 in the MTNR1B gene and measures of insulin secretion and glucose metabolism in 1,276 healthy European individuals from the RISC study. The minor G allele was significantly associated with higher fasting glucose (beta=0.17, p=5.8×10⁻⁵) and impaired early insulin response (beta=-0.19, p=1.7×10⁻⁵), but showed no association with whole-body insulin sensitivity measured by euglycaemic-hyperinsulinaemic clamp.

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 replicated the association between rs10830963 in MTNR1B (melatonin receptor 1B) and type 2 diabetes in Han Chinese individuals, previously reported in European populations. The risk allele (G) was associated with increased type 2 diabetes risk (OR 1.16, 95% CI 1.03-1.31, p=0.015) and elevated fasting plasma glucose (0.068 mmol/l per allele, p=4×10⁻⁵), suggesting this is a cross-population effect.