rs2234693

Candidate gene association study in Xinjiang women identifying pelvic organ prolapse (POP) susceptibility loci. Among 88 POP cases and 108 controls, ESR1 rs17847075 (OR=2.738, P=0.041) and rs2234693 (OR=2.99, P=0.024), ZFAT rs1036819 (OR=10.286, P=0.036), and protective FBLN5 rs12589592 (OR=0.111, P=0.029) showed significant associations with POP risk.

This comprehensive review synthesizes literature on gestational diabetes mellitus (GDM), demonstrating its complex multifactorial etiology involving genetic factors (SNPs in GCKR, KCNQ1, MTNR1B, TCF7L2), epigenetic modifications (DNA methylation and microRNA expression), and alterations in microbial composition across multiple body sites. While certain SNP variants are associated with GDM phenotypes globally, genetic predisposition alone does not explain disease development; lifestyle factors can modify epigenetic signatures and microbiota composition to modulate risk. Evidence indicates genes, epigenetic alterations, and microbiota can transfer from mother to offspring with long-term health consequences.

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 115 osteoarthritis cases and 117 controls in Mexican mestizo population examined two polymorphisms in the estrogen receptor alpha gene (ER alpha). The study identified three allelic haplotypes (TA, CG, and CA) and found that the CG haplotype was associated with significantly reduced risk of primary knee osteoarthritis when adjusted for age, gender, and BMI (OR = 0.5, 95% CI: 0.3-0.9, P = 0.04), with the protective effect particularly pronounced in males.

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.

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 case-control study of 80 Bulgarian patients with idiopathic scoliosis and 160 healthy controls found statistically significant association between the ESR1 PvuII polymorphism (rs2234693) and scoliosis susceptibility. The PP genotype was associated with 2.37-fold increased risk of IS (p=0.006; 95% CI: 1.27-4.43), and the P allele showed 1.48-fold increased risk (p=0.045; OR: 1.01-2.17). No association was found with the XbaI polymorphism (rs9340799). Certain genotype combinations (XX-Pp and Xx-PP) showed elevated odds ratios for curve severity.

A nested case-control study of 309 postmenopausal osteoporotic women and 293 controls found that the IL6 -634G>C SNP (rs1800796) was associated with osteoporosis (OR 2.51, p=0.0047), independent of smoking or statin use. Additionally, the LRP5 C135242T SNP (rs545382) showed association with osteoporosis specifically in cigarette smokers (OR 2.8, p=0.03), suggesting a gene-environment interaction.

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.

This case-control study of 159 Ukrainian individuals (144 born macrosomic, 27 normosomic) investigates genetic associations with deciduous tooth eruption timing. The study identified associations between RANKL rs9594759 (multiplicative model, increased risk of delayed eruption) and IL10 rs1800896 (overdominant model, increased risk of delayed eruption). CYP19A1 rs2414096 G allele and ESR1 rs9340799 -351 A allele were found as risk factors for fetal macrosomia formation. RANKL and IL10 variants showed multidirectional modifying effects on tooth eruption timing in macrosomic individuals.

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.

A comprehensive review of the genetic basis of aggressive behavior, covering candidate genes in neurotransmitter systems (TPH1, TPH2, SLC6A4, DRD4, COMT, MAOA), hypothalamic-pituitary genes (OXT, OXTR, AVPR1A, AVPR1B), and GWAS findings (LRRTM4 rs11126630 p=5.30×10⁻⁸, CDH13 rs11649622 p=4.19×10⁻⁶, FYN rs2148710 p=2.9×10⁻⁸, DYRK1A). The review concludes that genetic predisposition to aggressive behavior involves multiple genes with small individual effects (1-2% each).

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).

A case-control association study of 88 women with pelvic organ prolapse (POP) and 153 controls examined five estrogen receptor alpha (ESR1) gene polymorphisms. The ESR1 rs2228480 GA genotype was significantly associated with increased POP risk (OR 2.05, 95% CI 1.05-4.02, p=0.036) in multivariable logistic regression, suggesting genetic variations in the estrogen receptor alpha gene may contribute to POP susceptibility.

A candidate gene association study of 6,752 women from the Study of Osteoporotic Fractures examined 31 polymorphisms in 18 candidate osteoporosis genes for associations with fracture risk and bone mineral density. ALOX15_G48924T (rs7220870) T/T genotype was associated with 33% higher hip fracture risk (HR=1.33, 95% CI 1.00-1.77); PRL_T228C (rs7739889) C alleles reduced nonvertebral fracture risk by ~20%; BMP2_A125611G (rs235764) G/G showed 51% higher vertebral fracture risk (OR=1.51, 95% CI 1.03-2.23); and MMP2_C595T (rs243865) T allele carriers had reduced vertebral fracture risk. No significant associations were found with total hip BMD.

This meta-analysis of 18,917 individuals from 8 European centers examined three common ESR1 gene polymorphisms (Xba I rs9340799, Pvu II rs2234693, and TA repeat rs3138774) and their association with bone mineral density (BMD) and fracture risk. While no significant effects on BMD were observed, the Xba I polymorphism showed significant protective associations with fracture risk: women homozygous for the absence of an Xba I site had 19% reduced odds of all fractures (OR 0.81, P=.002) and 35% reduced odds of vertebral fractures (OR 0.65, P=.003), independent of BMD.