Full
Outline
To explore the relationship between AH and genetic susceptibility of BC, as well as the potential mediating mechanisms, given that epidemiological investigations have explored the association between autoimmune hyperthyroidism (AH) and the risk of developing breast cancer (BC) while the causality is controversial and the potential mediating pathways remain unclear due to confounding factors.
Two-sample Mendelian randomization (MR) was employed to investigate the causal relationship between AH and BC, with molecularly stratified analyses encompassing all receptor-defined subtypes (ER+BC, ER-BC, luminal A-like, luminal B-like, luminal B/HER2-negative-like, HER2-enriched-like, and TNBC). Additionally, the two-step Mendelian randomization (TSMR) method was used to investigate the mediating role of immune regulatory factors. Statistical inference primarily utilized inverse variance-weighted (IVW) estimators, complemented by pleiotropy-robust sensitivity validation protocols. Heterogeneity was evaluated using Cochran’s Q test. Pleiotropy was detected by combining the MR-Egger intercept term and the MR-PRESSO method to ensure the robustness and reliability of the research results.
Genetically predicted AH was causally associated with luminal B-like BC (OR=0.940, 95% CI: 0.900-0.983, P=6.05×10-3), whereas AH was not observed to be causally associated with other subtypes of overall BC. The cathepsin Z (CTSZ) was determined to be a mediator of the association between AH and luminal B-like BC, with a mediation ratio of 11.494% (95% CI: 2.124%-43.623%).
This study suggests that AH increases the expression of CTSZ and thus reduces the genetic susceptibility to luminal B-like BC, and understanding this mechanism provides new insights for the development of BC prevention strategies and interventions.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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