rs3749474

mixedMag 3.5

This is a 3 prime utr variant variant in the CLOCK gene.

Key Literature Trait Associations

Overweight and obesity

The CLOCK rs3749474 T allele has been associated with increased overweight and obesity risk across multiple populations and age groups. In a cross-sectional study of 300 Turkish adolescents (ages 11–18), minor T allele carriers had a significantly elevated risk of being overweight or obese (OR=2.106, p=0.003). A population genetics analysis of 2,504 individuals from the 1000 Genomes Project found the T allele frequency varies widely (31% in Africa to 81% in East Asia), and T allele carriers show greater weight loss on low-carbohydrate or low-fat diets compared to CC carriers, suggesting the risk is diet-modifiable. In children aged 6–8 (n=1,268), the association appeared sex-dependent, with female minor allele carriers showing lower BMI — highlighting that age and sex may modulate the T...

Özata Uyar G et al. “Association between CLOCK gene polymorphisms with circadian rhythm, chrononutrition, dietary intake, and metabolic parameters in adolescents.” Frontiers in Public Health (2024)
Allele T
OR 2.11
p 3.0e-3
N 300
Candidate gene study
Turkish
Roco-Videla Á et al. “[Variability of the genetic marker CLOCK rs3749474 and its impact on research and clinical trials on obesity and circadian rhythm].” Nutricion Hospitalaria (2022)
Allele T
OR —
p 5.0e-2
N 2,504
Preliminary work
multi-ancestry
Vales-Villamarín C et al. “Sex-dependent relationship of polymorphisms in CLOCK and REV-ERBα genes with body mass index and lipid levels in children.” Scientific Reports (2023)
Allele T
OR —
p 5.0e-2
N 1,268
Preliminary work
European (Spanish)

Energy Intake / Appetite

The CLOCK gene regulates circadian rhythms that govern sleep-wake cycles, appetite, and metabolism. The rs3749474 T allele in the 3' UTR is associated with higher total energy intake across all macronutrients (OR 1.33 for high energy intake). T allele carriers also show altered circadian hormone patterns with higher ghrelin and lower leptin levels. However, the same allele predicts a greater weight-loss response to fat-restricted diets, suggesting potential for genotype-guided dietary interventions.

Espinosa-Salinas I et al. “Polymorphic Appetite Effects on Waist Circumference Depend on rs3749474 CLOCK Gene Variant.” Nutrients (2020)
Allele T
OR —
β 14.100
p 1.0e-3
N 442
Candidate gene study
European (Spanish)
Garaulet M et al. “Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors in overweight subjects (GOLDN population).” European Journal of Human Genetics : Ejhg 18(3):364-369 (2010)
Allele T
OR 1.33
p 3.5e-2
Candidate gene study
Camblor Murube M et al. “Polymorphism of CLOCK Gene rs3749474 as a Modulator of the Circadian Evening Carbohydrate Intake Impact on Nutritional Status in an Adult Sample.” Nutrients (2020)
Allele T
OR —
β 0.338
p 4.6e-2
N 898
Preliminary work
European (Spanish)
Loria-Kohen V et al. “Polymorphism in the CLOCK gene may influence the effect of fat intake reduction on weight loss.” Nutrition (burbank, Los Angeles County, Calif.) (2016)
Allele T
OR —
β 0.044
p 8.0e-3
N 179
Candidate gene study
European (Spanish)

Breast cancer

The CLOCK rs3749474 T allele is associated with a modest reduction in breast cancer risk, with the C allele conferring higher risk. A systematic review and meta-analysis of 27 studies (96,756 participants including 38,231 cases) identified rs3749474 as one of 10 clock gene SNPs significantly associated with cancer risk, with the T allele showing OR=0.86 (95% CI 0.76–1.00, p=0.02) for breast cancer based on 1,004 cases and 1,098 controls across two datasets. Evidence was rated intermediate quality (Venice AAA criteria). The 3′-UTR location of the SNP suggests it may influence CLOCK mRNA levels in breast tissue, potentially affecting cell-cycle regulation via circadian clock mechanisms.

Benna C et al. “Genetic variation of clock genes and cancer risk: a field synopsis and meta-analysis.” Oncotarget (2017)
Allele C
OR 0.86
p 2.0e-2
N 2,102
Meta-analysis
multi-ancestry
▶

Research that mentions this SNP (3)

▶
Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer
AssociationN=704Yibing Chen et al.(2019)· Cancer Medicine

This association study examined nine functional SNPs in circadian positive feedback loop genes (CLOCK, BMAL1, NPAS2) in 704 Chinese gastric cancer patients. Three SNPs showed significant associations with overall survival and recurrence-free survival: rs11133399 in CLOCK (HR 1.27-1.29, p=0.007-0.020), rs2279284 in BMAL1 (HR 1.12-1.18, p=0.024-0.048), and rs1044432 in BMAL1 (HR 0.82-0.84, p=0.042-0.047). Functional assays confirmed that the G allele of rs11133399 enhanced CLOCK promoter activity and gene expression.

Traits studied:Gastric cancer prognosisOverall survivalRecurrence-free survival
PubMedDOIMetascience Observatory
▶
Polymorphism in alpha 2A adrenergic receptor gene is associated with sialorrhea in schizophrenia patients on clozapine treatment
AssociationN=237Anssi Solismaa et al.(2014)· Human Psychopharmacology: Clinical and Experimental

This dissertation examined pharmacogenetic associations with clozapine adverse effects in 237 Finnish schizophrenia patients. ADRA2A rs1800544 was associated with clozapine-induced sialorrhea (OR 2.13, 95% CI: 1.17-3.88, p=0.013). Eight HNMT SNPs in complete linkage disequilibrium (r²=1) were associated with sedation. CHRM3 rs685548 and weighted genetic risk scores from HTR4, HTR7, TPH1, CHRM2, ABCB1, and OPRM1 were associated with anticholinergic symptoms.

Traits studied:Anticholinergic symptomsClozapine pharmacokineticsClozapine-induced sialorrheaConstipationSchizophrenia (treatment-related adverse effects)Sedation
PubMedDOIMetascience Observatory
▶
Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer
ReviewFeng Zhou et al.(2012)· Cancer

Handbook of Experimental Pharmacology (Volume 217) providing comprehensive review of circadian clock biology and its role in health and disease. Discusses molecular mechanisms of circadian regulation, circadian control of metabolism, sleep, hormones, and behavior, and applications to pharmacotherapy including cancer chronotherapy. Reviews genetic variants in circadian genes (CLOCK rs1801260 and rs4580704, MTNR1A rs2119882, MTNR1B rs3781637) associated with metabolic traits and disease susceptibility, and circadian clock gene mutations linked to cancer risk and metabolic disorders.

Traits studied:Advanced sleep phase syndromeBreast cancerCancer susceptibilityChronic lymphocytic leukemiaColorectal cancerDelayed sleep phase syndromeFasting glucoseHypertensionInsulin resistanceMetabolic syndromeNon-Hodgkin lymphomaObesityOvarian cancerPolycystic ovary syndromeSleep disordersType 2 diabetes
PubMedDOIMetascience Observatory

Gene information from NCBI Gene. Variant classifications from ClinVar.

Community Wiki

No community notes yet for this variant. Sign in to start one.

Comments

Sign in to join the discussion.

Loading comments…