rs1800440
mixedMag 4.0This is a variant in the CYP1B1 gene that changes a asparagine to an serine.
Key Literature Trait Associations
Endometrial Cancer Risk
CYP1B1 is the primary extrahepatic enzyme catalysing 4-hydroxylation of 17beta-oestradiol, generating the genotoxic catechol oestrogen 4-OHE2 which can form depurinating DNA adducts. The rs1800440 C allele (p.Asn453Ser, CYP1B1*4) encodes a protein with a half-life of only 1.6 h versus 4.8 h for the Asn453 wild-type, resulting in ~2-fold lower cellular CYP1B1 protein levels. A meta-analysis found the Ser453 (C) allele significantly reduced endometrial cancer risk (pooled OR=0.82). Women homozygous for the common T allele (Asn453) have higher CYP1B1 activity and consequently greater endometrial cancer susceptibility.
Oestrogen Metabolism / CYP1B1 Enzyme Activity
The rs1800440 missense variant (p.Asn453Ser) in exon 3 of CYP1B1 directly affects post-translational stability of the enzyme via the ubiquitin-proteasome pathway. The Ser453 variant (C allele, CYP1B1*4) is degraded approximately 3 times faster than the Asn453 wild-type, leading to ~2-fold lower intracellular CYP1B1 protein and proportionally reduced 4-hydroxylation of oestradiol. Individuals homozygous for the T allele (Asn453) generate more genotoxic oestrogen metabolites in hormonally active tissues.
Frontal fibrosing alopecia
rs1800440 emerged as the lead signal at the 2p22.2 CYP1B1 locus in a GWAS of frontal fibrosing alopecia (FFA), a scarring hair loss condition predominantly affecting postmenopausal women. The study (1,044 cases, 4,145 controls) identified rs1800440 with posterior probability 0.98 as the putative causal missense variant, suggesting that the Asn453 (T allele) enzyme's higher estrogenic metabolite production may contribute to FFA pathophysiology. This is a biologically compelling finding given CYP1B1's role in estrogen metabolism and the strong female predominance of FFA.
Basal cell carcinoma
The rs1800440-T allele (Asn453, frequency ~82%) is associated with increased basal cell carcinoma (BCC) risk in multiple large GWAS. A 2024 multi-ancestry meta-analysis (50,531 BCC cases, 762,234 controls) identified rs1800440 among 122 BCC-associated loci. A 2019 GWAS (47,742 cases, 634,413 controls) also identified the CYP1B1 locus at genome-wide significance. Effect sizes are modest (OR ~1.08, p ~3×10⁻¹³ to 8×10⁻⁶²), consistent with a common variant contributing to polygenic susceptibility via pigmentation or DNA repair pathways in skin.
Cutaneous melanoma
The rs1800440-T allele is associated with increased cutaneous melanoma risk in large European GWAS. A 2020 genome-wide meta-analysis (36,760 melanoma cases, 375,188 controls) identified the CYP1B1 locus at genome-wide significance (p~3×10⁻¹¹, beta ~0.12). The association likely reflects CYP1B1's role in skin pigmentation pathways and UV-induced genotoxic estrogen metabolism rather than a direct melanocyte function. Effect sizes are modest, consistent with a polygenic risk architecture.
▶GWAS Catalog Trait Associations (10)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (10)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
not specified; Glaucoma 3A; not provided; Congenital glaucoma; Anterior segment dysgenesis 6; Glaucoma 3A;Anterior segment dysgenesis 6;Glaucoma 3, primary infantile, B; CYP1B1-related glaucoma with or without anterior segment dysgenesis
View on ClinVar →▶Research that mentions this SNP (4)
▶Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2)AssociationN=327Nadine Al‐Naamani et al.(2021)· Hepatology
A multicenter case-control study of 37 portopulmonary hypertension (POPH) patients and 290 liver disease controls found that the risk allele rs7175922 in the aromatase gene (CYP19A1) was significantly associated with increased POPH risk (OR 2.36, 95% CI 1.12-4.91, p = 0.02) and higher circulating estradiol levels. Other genetic variants in ESR1 and CYP1B1 were not significantly associated with POPH, but altered estrogen metabolism markers including higher plasma 16α-hydroxyestradiol and lower dehydroepiandrosterone-sulfate were associated with disease.
▶Genetic polymorphism of ESR1 rs2881766 increases breast cancer risk in Korean womenAssociationN=1,220Byung Ho Son et al.(2015)· Journal of Cancer Research and Clinical Oncology
A case-control study of 830 Korean breast cancer patients and 390 controls evaluating associations between genetic polymorphisms in estrogen receptor genes (ESR1, ESR2) and estrogen-metabolizing enzyme genes (CYP1A1, CYP1B1, COMT) with breast cancer risk. ESR1 rs2881766 (OR=1.40, p=0.02), rs2077647 (OR=1.37, p=0.02), rs926778 (OR=1.56, p≤0.01), and rs2273206 (OR=1.40, p=0.01) increased breast cancer risk, while rs3798377 (OR=0.76, p=0.05) decreased risk in overall patients. Associations varied substantially by age group and tumor subtype, with rs2881766 consistently increasing risk across all age groups except luminal B subtype.
▶Variation in PAH‐related DNA adduct levels among non‐smokers: The role of multiple genetic polymorphisms and nucleotide excision repair phenotypeAssociationN=111Arash Etemadi et al.(2013)· International Journal of Cancer
This study examined PAH-related DNA adduct levels in 111 female never-smokers from Iran, evaluating 21 SNPs in 14 xenobiotic metabolism genes and 12 SNPs in 8 DNA repair genes. DNA adduct levels were significantly lower with NAT2 slow alleles (β=-0.24, p=0.01) and ERCC5 non-risk genotype (β=0.16, p=0.04), but higher with MPO risk alleles (β=0.21, p=0.01). The combination of phase I genes and measured NER capacity explained 17% more variation in adduct levels than environmental exposure alone (r²=0.24 vs 0.07), demonstrating the importance of genetic polymorphisms in PAH metabolism and DNA repair capacity.
▶An exploratory case‐only analysis of gene‐hazardous air pollutant interactions and the risk of childhood medulloblastomaAssociationN=98Lupo PJ et al.(2012)· Pediatric Blood & Cancer
A case-only study of 98 children with medulloblastoma/PNET examining gene-environment interactions between chlorinated solvent exposure and detoxification/DNA repair genotypes. Found 11 significant interactions; after multiple comparison correction, only the interaction between high trichloroethylene exposure and OGG1 rs293795 remained significant (OR = 9.24, 95% CI: 2.24-38.24). Two additional borderline significant interactions identified: OGG1 rs159150 with trichloroethylene (OR = 6.50) and NAT1 rs13253389 with vinyl chloride (OR = 0.05, protective).
Gene information from NCBI Gene. Variant classifications from ClinVar.
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