EXPLORING THE CAUSAL LINK BETWEEN SLEEP DURATION AND BREAST CANCER: A MENDELIAN RANDOMIZATION STUDY

Background: Previous observational studies reported that sleep traits were associated with breast tumors. However, the causal relationship between sleep duration and breast tumors is not clear. Methods: We performed a two-sample bi-directional Mendelian Randomization (MR) analysis with publicly available Genome-Wide Association Studies (GWAS) summary statistics to detect the causal relationship between genetically predicted sleep duration and the risk of breast tumors, including breast cancer (Estrogen Receptor (ER)+/ER-, Human Epidermal Growth Factor Receptor (HER)2+/HER2-), benign breast tumors and carcinoma in situ of the breast. The Inverse Variance Weighting (IVW) method was used as the gold standard for MR results and MR Egger regression, weighted median, weighted mode and simple mode methods were taken as auxiliary analyses. We also conducted sensitivity analyses, including tests for heterogeneity, horizontal pleiotropy and leave-one-out analysis, to evaluate the validity of the detected causal relationships. An additional reverse direction MR analysis was further performed to examine the causal effect of breast tumors on sleep duration. Design and methods: The study included 311 women aged 20 years to 38 years, who have had at least one pregnancy end in miscarriage and 225 women in the control group. The study of the genotypes of the selected genetic variants was carried out by real-time Polymerase Chain Reaction (PCR) with melting curve analysis. Results: Suggestive evidence for the causal effect of genetically predicted sleep duration on breast cancer was identified (Odds Ratio (OR) =1.328, 95% Confidence Interval (CI): 1.013–1.741, p=0.04). When distinguished by molecular phenotype, we found a causal association trend between sleep duration and ER+ and ER- breast cancer (ER+ breast cancer p=0.051, ER- breast cancer p=0.077). We did not detect a causal effect of sleep duration on benign breast tumors (OR=1.002, 95% CI: 0.999–1.005, p=0.242) or carcinoma in situ of the breast (OR=1.090, 95% CI: 0.403–2.947, p=0.08). Reverse MR analysis did not indicate that having breast cancer could affect sleep duration (OR = 1.002, 95%CI: 0.995– 1.010, p = 0.494). Conclusion: The results of this study identified a causative effect of genetically predicted sleep duration on breast cancer, suggesting that ensuring appropriate sleep duration and avoiding excessive sleep might be helpful for preventing breast cancer.