rs4753426 — MTNR1B

Promoter variant in the melatonin receptor 1B gene that alters MTNR1B expression, affecting circadian rhythm, morningness chronotype, and fasting glucose through impaired insulin secretion

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MTNR1B -1193T>C — The Promoter Variant That Shifts Your Clock Toward Morning

The MTNR1B gene encodes the melatonin receptor 1B11 melatonin receptor 1B
Also known as MT2, one of two G-protein-coupled receptors for melatonin. MT2 is expressed in the brain (especially the suprachiasmatic nucleus), retina, and pancreatic beta cells, where it mediates melatonin's effects on circadian timing and insulin secretion (MT2), a receptor that links the hormone of darkness to both your sleep-wake cycle and your glucose metabolism. The platform already carries the well-studied rs10830963 — a strong GWAS hit deep within the MTNR1B intron. The rs4753426 variant is different: it sits approximately 1,193 base pairs upstream of the gene's transcription start site, in the promoter, where it directly modulates how much MTNR1B is produced.

The two variants are correlated but not identical. Their linkage disequilibrium is high at the haplotype level (D' = 0.969) but moderate in terms of allele correlation (r² = 0.414), meaning they frequently travel together on chromosomes yet capture partly distinct information. A person who tests positive for one does not necessarily carry the other. The rs4753426 C allele has been independently associated with altered fasting glucose and insulin secretion22 altered fasting glucose and insulin secretion
Staiger H et al. Polymorphisms within the Novel Type 2 Diabetes Risk Locus MTNR1B Determine β-Cell Function. PLoS One, 2008 as well as with a specific circadian phenotype — a preference for mornings and reduced social jetlag — that rs10830963 does not directly capture.

The Mechanism

Promoter variants modulate gene expression rather than protein structure. The -1193 position falls within a region of the MTNR1B promoter that contains binding sites for BMAL1/CLOCK33 BMAL1/CLOCK
The core transcriptional activators of the circadian clock. BMAL1 and CLOCK form a heterodimer that binds E-box elements in circadian gene promoters to drive rhythmic gene expression, the core circadian transcription factor complex. The C variant at this position alters the binding affinity at or near this element, changing the amplitude of MTNR1B's circadian transcriptional drive. Tissue-level expression data from GTEx indicates that the C allele is associated with altered MTNR1B expression in esophageal mucosa, consistent with a transcriptional rather than protein-level effect.

The downstream consequence mirrors what is seen with rs10830963: elevated MT2 receptor levels in beta cells prolong the window during which melatonin suppresses glucose-stimulated insulin secretion44 glucose-stimulated insulin secretion
Melatonin inhibits insulin release by activating inhibitory Gi-proteins on beta cells, reducing cAMP. This is adaptive during sleep but harmful when eating occurs while melatonin is still elevated. The C allele has also been found to modulate circadian entrainment to photoperiod — the frequency of the C allele across human populations correlates with sunshine duration, suggesting an adaptive role in populations at different latitudes.

The Evidence

The original beta-cell function study55 original beta-cell function study
Staiger H et al. Polymorphisms within the Novel Type 2 Diabetes Risk Locus MTNR1B Determine β-Cell Function. PLoS One, 2008 of 1,578 non-diabetic subjects found rs4753426 C allele carriers had significantly higher fasting plasma glucose (p < 0.0001) and approximately 20% reductions in IVGTT-derived insulin secretion compared to TT homozygotes. The effect was present alongside — and partially independent from — the rs10830963 signal, reflecting the partial LD between the two variants.

The circadian dimension was established by Pereira e Silva and colleagues66 Pereira e Silva and colleagues
Pereira e Silva AC et al. Melatonin receptor 1B -1193T>C polymorphism is associated with diurnal preference and sleep habits. Sleep Medicine, 2019 in 814 subjects, who found the C allele associated with extreme morningness phenotype across codominant, recessive, and allele models, with a negative correlation between the C allele and social jetlag scores. Carriers of the T allele tended to spend more time in bed on weekends — a proxy for accumulated sleep debt and delayed preference.

In gestational diabetes mellitus (GDM), a meta-analysis77 meta-analysis
Jia G et al. Effects of MTNR1B Genetic Variants on Individual Susceptibility to Gestational Diabetes Mellitus. Am J Perinatol, 2020 of 17 studies found rs4753426 associated with GDM risk in recessive (OR 1.75) and allele models (OR 0.69), though the associations were less consistent than those for rs10830963, which showed significance across all genetic models.

Practical Implications

The C allele's dual phenotype — morningness plus elevated fasting glucose — suggests that CC carriers wake early (melatonin falls fast) but may still carry some degree of beta-cell vulnerability through the promoter's effect on MTNR1B expression. For CC individuals, the actionable insight is to leverage their natural morning preference: front-loading calories to breakfast and lunch, when their insulin sensitivity is at its best, directly addresses the metabolic vulnerability.

CT heterozygotes have an intermediate profile. The meal-timing principle still applies but with less urgency than for CC homozygotes.

For the circadian angle: CC individuals who experience reduced social jetlag can treat this as a structural advantage — their internal clock is more closely aligned with social time compared to evening chronotypes, reducing the chronic circadian misalignment that independently impairs metabolic function.

Interactions

rs4753426 and rs10830963 operate in partial linkage disequilibrium within the MTNR1B locus. Their D' = 0.969 indicates they rarely appear on different haplotypes, but their r² = 0.414 means they are not interchangeable — carriers of the rs10830963 G allele who are also CC at rs4753426 face compounded promoter-level and intronic expression effects on beta-cell MT2 receptor abundance. The clinical implication is additive: combined, both variants likely produce greater suppression of glucose-stimulated insulin secretion than either alone.

Genotype Interpretations

What each possible genotype means for this variant.

TT Standard Expression Normal

Normal MTNR1B promoter activity — no altered circadian or glucose risk from this variant

The TT genotype produces baseline MTNR1B promoter activity. In the Staiger et al. (2008) study of 1,578 non-diabetic subjects, TT individuals served as the reference group with the lowest fasting glucose and the highest OGTT- and IVGTT-derived insulin secretion among the three genotypes. Insulin secretion for TT individuals was approximately 20% higher than minor-allele carriers in IVGTT C-peptide measurements.

In the circadian phenotype study by Pereira e Silva et al. (2019), the T allele was associated with greater time spent in bed on weekends compared to C allele carriers, consistent with more evening-leaning or flexible chronotype tendencies.

CT Intermediate Expression Intermediate

One copy of the promoter variant — modest elevation in MTNR1B expression and slight morningness shift

With one C allele, beta-cell MT2 receptor levels are intermediate between TT and CC. The Staiger et al. (2008) study found intermediate effects on fasting glucose and insulin secretion for heterozygous carriers, consistent with the codominant inheritance pattern observed across MTNR1B variants.

The circadian phenotype study found the codominant model (comparing each genotype) was significant for morningness association, placing CT individuals between TT and CC. Research on the correlation between the C allele frequency and sunshine duration across worldwide populations suggests the C allele confers a circadian advantage in high-sunshine environments, where earlier rising aligns better with photoperiod. For CT individuals in modern environments, this may manifest as modest morningness tendencies without the full glucose risk profile of CC homozygotes.

Because the LD between rs4753426 and rs10830963 is moderate (r² = 0.414), CT individuals may or may not also carry the rs10830963 G allele — the risks of the two variants are additive if both are present but should be assessed separately.

CC Elevated Expression High Risk

Two copies of the promoter variant — elevated MTNR1B expression, impaired insulin secretion, and pronounced morningness

The CC genotype is associated with the strongest elevations in fasting plasma glucose and the greatest reductions in insulin secretion. In Staiger et al. (2008), CC carriers had significantly higher fasting glucose than TT carriers (p < 0.0001), with approximately 20% reductions in IVGTT C-peptide output, a direct measure of beta-cell insulin secretory capacity.

In gestational diabetes mellitus, a meta-analysis of 17 studies found the CC genotype associated with GDM risk at OR 1.75 in the recessive model. This is clinically meaningful for women of childbearing age — the metabolic stress of pregnancy can unmask the beta-cell limitation imposed by elevated MTNR1B expression.

Paradoxically, the CC genotype is also the most strongly associated with morningness and reduced social jetlag. This means CC individuals' melatonin falls sharply in the morning, which may limit the melatonin-glucose collision at breakfast time — but the promoter-driven elevation in beta-cell MT2 receptors still confers metabolic risk, particularly when melatonin levels are elevated (evening hours).

The promoter variant at -1193 affects BMAL1/CLOCK-driven transcription of MTNR1B — the same circadian machinery that drives the rhythmic melatonin peak. CC individuals may have a more sharply defined, tightly entrained circadian cycle with a steeper melatonin ramp and faster morning clearance, explaining both the morningness phenotype and the preserved (relatively) morning insulin response.