rs4986938
mixedMag 3.5This is a 3 prime utr variant variant in the ESR2 gene.
Key Literature Trait Associations
Graves' Disease
The ESR2 A1730 allele (rs4986938 T on + strand) is associated with susceptibility to Graves' disease, a sex-biased autoimmune condition. In a Polish cohort of 375 Graves' disease patients and 1,001 controls, the A allele frequency was 38.0% in cases vs. 32.7% in controls (OR=1.26). Under a recessive model, AA1730 homozygotes had OR=1.67. The 3'UTR location suggests the variant may alter ERbeta-mediated regulation of immune tolerance.
Bone Mineral Density (Postmenopausal)
The ESR2 AluI 1730G>A polymorphism (rs4986938; T allele on + strand) in the 3' UTR of oestrogen receptor beta affects mRNA stability and/or microRNA-binding efficiency, potentially altering ERbeta protein levels in bone. Regression analysis showed that the AA1730 homozygous genotype was the strongest genetic predictor of lumbar spine BMD, with 85% of AA1730 carriers having the lowest BMD values. ERbeta has anti-proliferative roles in osteoclast activity; reduced ERbeta expression from the A allele may accelerate bone resorption.
Systemic lupus erythematosus
The A allele of rs4986938 was associated with adult-onset systemic lupus erythematosus (SLE) in a Polish cohort study (OR=1.46, p=0.008, corrected p=0.03). No significant association was found for juvenile-onset SLE in the same study, suggesting an age-specific effect. The finding is consistent mechanistically with the Graves' disease association, as ERβ modulates inflammatory cytokine production and autoimmune tolerance, and the same research group identified both associations. This is a single candidate-gene study and requires replication in larger independent cohorts before clinical relevance can be established.
Breast cancer
The G allele (wild-type) of rs4986938 is associated with modestly higher breast cancer risk, while the A allele appears protective. A systematic review and meta-analysis (Yu et al., 2011; 9 studies, 10,837 cases, 16,021 controls) found that A allele carriers had a 5–6% reduced risk under dominant and co-dominant models (OR=0.944, 95% CI 0.897–0.993). A subsequent 2016 meta-analysis of 33 studies confirmed the A allele's association with decreased breast cancer risk in both Asian and Caucasian populations. Conversely, a large 2019 pan-cancer meta-analysis (23 studies, 24,334 cases, 31,707 controls) found no significant overall cancer association, suggesting the protective signal may be specific to breast cancer and modest in magnitude.
Fibrinogen levels
The AA homozygous genotype of rs4986938 is associated with significantly elevated plasma fibrinogen levels in postmenopausal women. A single Italian cohort study (n=89) found that AA1730 carriers had higher fibrinogen compared to GG+GA genotypes. Elevated fibrinogen is a known cardiovascular risk factor and prothrombotic marker, suggesting a possible mechanism by which this ESR2 variant could influence cardiovascular risk in postmenopausal women. This finding comes from a small single-center study and has not been independently replicated; it should be considered exploratory.
▶ClinVar annotation
▶Research that mentions this SNP (5)
▶Associations of polymorphisms in the genes of FGFR2, FGF1, and RBFOX2 with breast cancer risk by estrogen/progesterone receptor statusAssociationN=2,416Yu‐Ling Cen et al.(2013)· Molecular Carcinogenesis
A hospital-based case-control study in rural and urban India (1,204 cases; 1,212 controls) examined genetic and lifestyle risk factors for breast cancer. Four SNPs in FGFR2 (rs1219648, rs2420946, rs2981575, rs2981582) showed positive associations with breast cancer (ORs 1.32-1.47). Additional SNPs in obesity and metabolic genes (rs374748 in FBN2, rs2922763 in HNF4G, rs2116830 in KCNMA1, rs11121832 in MTHFR, rs16886165 in MAP3K1, rs11594610 in TCF7L2, rs2274459 in MLN) were associated with increased breast cancer risk. Waist-to-hip ratio ≥0.95 showed strong association (OR 3.78; 95% CI 2.92-4.89), and women living first 20 years in rural areas showed protective effect (OR 0.77).
▶Estrogen receptors alpha (rs2234693 and rs9340799), and beta (rs4986938 and rs1256049) genes polymorphism in prostate cancer: Evidence for association with risk and histopathological tumor characteristics in Iranian menMeta-analysisN=69,809Mohammad Reza Safarinejad et al.(2012)· Molecular Carcinogenesis
A meta-analysis of 80 studies (69 publications) with 26,428 cancer cases and 43,381 controls evaluating the ESR1 PvuII rs2234693 T>C polymorphism and cancer susceptibility. Overall, the T allele showed modest decreased cancer risk (OR=0.95, 95% CI=0.91-0.99), with stronger associations for specific cancer types: prostate cancer (TT vs. CC: OR=0.79), leiomyoma (T vs. C: OR=0.82), and hepatocellular carcinoma (TT vs. CC: OR=0.45). The authors conclude that ESR1 PvuII polymorphism has minimal impact on overall cancer susceptibility.
▶Genotypes and Haplotypes of the Estrogen Receptor Genes, but Not the Retinoblastoma-interacting Zinc Finger Protein 1 Gene, Are Associated with OsteoporosisAssociationN=798Harsløf T. et al.(2010)· Calcified Tissue International
Case-control study of 462 osteoporotic patients and 336 controls examining associations between polymorphisms in ESR1, ESR2, and RIZ1 genes and vertebral fractures and bone mineral density (BMD). ESR1 variants XbaI (rs2234693) C allele and PvuII (rs9340799) G allele were associated with decreased vertebral fracture risk in women (P<0.01 and P=0.04 respectively), and the X-P-H haplotype protected against fractures (P=0.04). ESR2 rs1256031 C allele decreased BMD and AluI G allele increased fracture risk; block1haplo2 (rs1256031:T and AluI:A) increased lumbar BMD by 0.04±0.02 g/cm² and decreased fracture risk (P<0.05). RIZ1 Pro704indel showed no significant associations.
▶Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancerAssociationN=4,470Miriam S. Udler et al.(2009)· International Journal of Cancer
This population-based study of 4,470 breast cancer cases from the SEARCH cohort examined associations between germline polymorphisms in 6 steroid hormone metabolism genes (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival after breast cancer diagnosis. A COMT polymorphism (rs4818) showed significant association with survival in a dominant model (HR=0.80, 95% CI: 0.69-0.95, p=0.009), though this was only marginally significant after permutation adjustment (p=0.047). No significant associations were found in the other genes studied.
▶Haplotypes of the estrogen receptor beta gene and breast cancer riskAssociationN=13,550Cox DG et al.(2008)· International Journal of Cancer
This pooled analysis of 5,789 breast cancer cases and 7,761 controls from five prospective cohorts examined associations between estrogen receptor beta (ESR2) gene haplotypes and breast cancer risk. Using haplotype tagging SNPs, the study found that one haplotype (CCAC) was significantly associated with increased breast cancer risk (OR 1.17, 95% CI 1.07-1.28, p=0.0007, corrected p=0.002). No individual SNPs showed independent association, and the haplotype risk was primarily observed in younger women. The results suggest inherited ESR2 variants confer modest increased breast cancer susceptibility in Caucasian women.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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