rs2077647

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.

Population-based case-control study of 1,304 prostate cancer cases and 1,266 controls examining 73 SNPs in five estrogen pathway genes (ESR1, ESR2, CYP19A1, CYP1A1, CYP1B1). Only CYP1B1 rs1056836 (Val158Met) retained significance after multiple comparisons adjustment (OR=1.22, 95% CI 1.02-1.46, p=0.004). ESR1, CYP1A1, and CYP1B1 variants showed nominal associations with prostate cancer risk, and ESR2/CYP19A1 variants associated with tumor aggressiveness, though these did not persist after correction.

A case-control study of 114 Japanese postmenopausal women with osteoporosis and 171 controls found that minor alleles of ESR1 SNPs rs2077647 (exon 1) and rs2234693 (intron 1) were significantly associated with increased osteoporosis risk (OR 2.48-3.27). The haplotype CC at these risk SNPs showed strong association with osteoporosis (OR = 3.15, 95% CI = 1.83-5.41). Notably, moderate alcohol consumption showed a protective gene-environment interaction, reducing the genetic risk by approximately 80% (OR = 0.22, 95% CI = 0.05-0.83).

This study identified rs2144025, an intronic SNP in ESR1 (estrogen receptor alpha), associated with brain ESR1 mRNA isoform expression and psychiatric behavioral traits. The variant showed large allelic expression imbalance (p=1.6E-6) in prefrontal cortex brain samples from bipolar disorder and schizophrenia subjects. In four large GWAS cohorts, rs2144025 was significantly associated with hypomanic episodes in bipolar females (p=0.0004, additive model), psychiatric comorbidity in ADHD (p=2.4E-5, dominant), psychological diagnoses in girls (p=0.0009), and grandiose delusions in schizophrenia (p=0.0004, dominant).

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.

A comprehensive candidate gene study evaluating 150 SNPs across 476 kb of the ESR1 gene (estrogen receptor alpha) in 577 African American cases with type 2 diabetes and end-stage renal disease (T2DM-ESRD) versus 596 controls. After multiple testing correction, three SNPs remained significant: rs11964281 (promoter, adjusted P=0.0289), rs1569788 (intron 4, adjusted P=0.0278), and rs9340969 (intron 4, adjusted P=0.0467). A novel region in intron 4-intron 6 showed clustering of 23 associated SNPs, suggesting this region may contain functionally relevant polymorphisms for T2DM/diabetic nephropathy susceptibility.

This study identified rs2144025 (C>T) in ESR1 intron4 as a regulatory variant associated with brain ESR1 mRNA isoform expression imbalance in psychiatric patients. The intronic SNP showed strong association with allelic mRNA ratios (p=1.6e-6) and was significantly associated with behavioral traits including hypomanic episodes in female bipolar disorder patients (p=0.0004), comorbid psychological symptoms in ADHD (p=0.00002), psychological diagnoses in female children (p=0.0009), and grandiose delusions in schizophrenia (p=0.0004).

This study examined associations between seven estrogen receptor alpha (ESR1) gene SNPs and femoral neck bone geometry in 1,873 Caucasian subjects from 405 nuclear families. SNP4 (rs1801132) showed within-family association with endocortical diameter (P=0.008) and subperiosteal width (P=0.021), with total associations of P=0.005 and P=0.003 respectively. SNP5 (rs932477) was associated with cortical thickness and buckling ratio (P=0.035 and P=0.041). However, after correction for multiple testing (empirical P<0.011), most associations did not remain significant, and the variants explained only small amounts of phenotypic variation (0.72-1.64%).