| Title: | Causal Link Between Obstructive Uropathy, Estradiol, and Risk of Breast Cancer: Insights From Observational Evidence and Genetic Association Analyses |
| Journal: | Medicine Advances |
| Published: | 11 Mar 2026 |
| DOI: | https://doi.org/10.1002/med4.70048 |
| URL: | http://dx.doi.org/10.1002/med4.70048 |
Publication 17406
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Abstract
ABSTRACT Background Estradiol, the key endogenous estrogen, reduces the risk of urinary obstruction by smooth muscle relaxation but also increases susceptibility to breast cancer (BC). However, whether estradiol serves as a mechanistic mediator linking urinary tract obstruction and BC remains unclear. This study aimed to determine if there is an association between urinary tract obstruction and the risk of BC and to assess the potential mediating role of systemic estradiol. Methods A case-control study and survival analysis of Cox regression were conducted using clinical data from the United Kingdom Biobank (UKB) (502,129 participants). To explore genetic causality, we performed a two-sample Mendelian randomization (MR) study leveraging extensive genomic data. For obstructive uropathy, we relied on female-only summary statistics sourced from the UKB (520 cases, 193,654 controls), while BC data, categorized by estrogen receptor status, HER2 status, and triple-negative subtypes, were sourced from the open genome-wide association studies database. We identified single-nucleotide polymorphisms with strong links to obstructive uropathy as instrumental variables. Inverse variance-weighted analysis, backed by robustness checks such as Cochran's Q test and MR-Egger regression, were used to ensure reliable results. Results The UKB research revealed a marked correlation between urinary obstruction and the risk of BC ( χ 2 = 576.25, p < 0.001), with particularly robust findings for obstruction caused by kidney stones ( χ 2 = 271.42, p < 0.001) and notable significance for urinary calculi overall ( χ 2 = 9.97, p = 0.041). Survival analysis showed that calculus-related urinary obstruction was an independent protective factor against incident BC (hazard ratio = 0.61, 95% confidence interval: 0.38-0.98, p = 0.041) after adjusting for confounders. The mean estradiol level was significantly lower in women with urinary obstruction than in controls (245.05 [IQR: 200.80-404.60] pmol/L vs. 313.55 [IQR: 216.10-535.50] pmol/L). The MR study found no evidence of a genetic causal association between obstructive uropathy and overall BC (inverse variance-weighted β = −0.60, p = 0.923). A nominally significant association was observed with ER-positive BC in the training set ( β = −7.62, p = 0.038), but failed to replicate in the validation set ( p > 0.05). Given the significant heterogeneity ( Q = 58.01, p = 1.44 × 10 −5 ) and low exposure heritability explained by single-nucleotide polymorphisms [h 2 SNP] = 0.0282, standard error = 0.0015), this finding likely represents a false positive rather than a true causal effect. No pleiotropy or heterogeneity was detected in other analyses (all p > 0.05). Conclusions These observational data suggest that urinary obstruction protects against BC and that estradiol may play a mediating role. However, this association does not appear to be caused by a relationship at the genetic level, highlighting the need to explore alternative biological pathways. </p>
8 Authors
- Hailu Wang
- Yingying Dai
- Wenhai Pan
- Kaiyuan Mao
- Zhiyi Zhang
- Yan Zhang
- Yifan Chen
- Yiyin Zhang
1 Application
| Application ID | Title |
|---|---|
| 89885 | Genetics of complex diseases, comorbidities, and the disease risk prediction |
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