rs4753426
badMag 3.5This is a upstream gene variant variant in the MTNR1B gene.
Key Literature Trait Associations
Gestational diabetes mellitus
The C allele of rs4753426 is enriched in women with gestational diabetes mellitus (GDM) and is associated with higher fasting plasma glucose and reduced pancreatic beta-cell function during pregnancy. A meta-analysis by Jia et al. (2020, n=17 studies) found the C allele conferred an OR of 1.75 (95% CI 1.14–2.68, p=0.01) in a recessive model, qualifying it as a GDM genetic biomarker. Multiple Chinese hospital-based studies corroborate this association, though one Polish cohort (Tarnowski et al. 2017) found no significant association, suggesting effect sizes may vary by ancestry. The C allele frequency is notably higher in GDM cases (~82%) versus controls (~73%) in East Asian populations.
Type 2 Diabetes Risk
The MTNR1B rs4753426 C allele has been associated with altered oral glucose tolerance test-derived indices of beta-cell function and higher fasting insulin levels. MTNR1B is expressed in pancreatic beta-cells; melatonin signaling through MT2 receptors inhibits insulin secretion via Gi-coupled cAMP reduction. Promoter variants that alter MTNR1B expression levels consequently dysregulate the circadian gating of insulin release.
Morning Chronotype
The MTNR1B -1193C allele (rs4753426) in the promoter region is associated with extreme morningness in a codominant model (n=814). C/C homozygotes show the earliest sleep-onset and wake times. The C allele is hypothesized to alter MTNR1B promoter activity, modifying MT2 receptor expression levels and thereby shifting the phase-advancing response to evening melatonin. Population-level analysis shows C-allele frequency is inversely correlated with annual sunshine duration worldwide, suggesting latitude-driven natural selection on circadian entrainment.
Adolescent idiopathic scoliosis
The C allele of rs4753426 in the MTNR1B promoter has been associated with susceptibility to adolescent idiopathic scoliosis (AIS), particularly in Asian populations. A systematic review and meta-analysis by Yang et al. (2015, n=2,552 cases/2,738 controls) found the C allele conferred an OR of 1.12 (95% CI 1.03–1.21, p=0.01) and the dominant model (CC+CT vs. TT) yielded OR=1.28 (p=0.009). However, a separate meta-analysis by Yang et al. (2015, n=2,395/3,645) found no significant association overall (OR=1.11, p=0.09–0.48 across models), and the positive signal was confined to Asian subgroups. The evidence is suggestive but inconsistent across ancestry groups.
Depressive symptoms
Small studies have explored rs4753426 in psychiatric phenotypes. Gałecka et al. (2011, n=330) reported that the C allele was associated with increased risk of recurrent depressive disorder (rDD) and reduced MTNR1B mRNA expression in Polish patients, with the T allele conferring apparent protection. The GWAS Catalog also lists two associations with depressive symptom measurement and stressful life event measurement (beta=0.055–0.072, p~2–4×10⁻⁷), below genome-wide significance. Evidence is limited to small candidate-gene studies and sub-threshold GWAS signals; replication in large cohorts is lacking.
▶Research that mentions this SNP (1)
▶MTNR1B gene on susceptibility to gestational diabetes mellitus: a two-stage hospital-based study in Southern ChinaAssociationN=1,429Yulong Jia et al.(2020)· Molecular Genetics and Genomics
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.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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