Causal Analysis of Platelet Indices and Breast Cancer, Including Estrogen Receptor-Specific Subtypes: A Mendelian Randomization Study

Yuhao Zhu,1 Jundong Wu1,2 1Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, People’s Republic of China; 2Shantou Key Laboratory of Precision Diagnosis and Treatment in Women’s Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, People’s Republic of ChinaCorrespondence: Jundong Wu, Breast Center, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, Guangdong, 515041, People’s Republic of China, Tel +86-13829663428, Email [email protected]: Changes in platelet indices are associated with breast cancer. But the causal relationship between them remains unclear.Methods: Genetic variation data of platelet indices, including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT), were collected as instrumental variables (IVs). We assessed their impact on the risk of overall breast cancer and its estrogen receptor (ER)+ and ER- subtypes through Mendelian randomization (MR) analysis, including IVs selection, multiple corrections, causality assessment, and sensitivity analysis. Additionally, the findings were validated using an independent dataset and extended the validation to East Asian populations.Results: Our results found that PCT was significantly associated with an increased risk of overall breast cancer (OR, 1.0693 [95% CI, 1.0281– 1.1121]; P = 0.0008) and its ER+ subtype (OR, 1.0691 [95% CI, 1.0233– 1.1169]; P = 0.0028), while they were suggestive evidence of a causal relationship after excluding the outliers determined by MR-PRESSO test. After removing the outliers, the suggestive evidence of a causal relationship between PLT and the increased risk of overall breast cancer (OR, 1.0351 [95% CI, 1.0003– 1.0711]; P = 0.0483) disappeared, whereas MPV was suggestively associated with an increased risk of overall breast cancer (P = 0.0291). PDW was suggestively associated with a lower risk of overall breast cancer (OR, 0.9597 [95% CI, 0.9236– 0.9971]; P = 0.035) and ER+ (OR, 0.9528 [95% CI, 0.9118– 0.9957]; P = 0.0315), ER- (OR, 0.9199 [95% CI, 0.8644– 0.979]; P = 0.0085) subtypes, whose outlier-corrected results were consistent with raw causal estimates. These findings were replicated in an independent dataset but did not generalize to the East Asian population.Conclusion: This study reveals suggestive evidence of a causal relationship between platelet indices, specifically PCT, MPV, and PDW, and the risk of breast cancer and its subtypes. Keywords: Mendelian randomization, platelet indices, breast cancer, subtypes, causal relationship