Multisite Chronic Pain and the Risk of Breast Cancer and Its Subtypes: A Mendelian Randomization Study

Wanyu Li,1,2 Jintao Liu,3 Teng Wang,2,3 Yudong Hou,3,4 Jianheng Bao,2,3 Yanyan Song,1,2 Longbi Liu,2,3 Shuke Ge,3 Yaohua Shang,5 Rongdi Wang,1 Min Zhang,1 Meng Xu1 1Department of Colorectal Surgery, Dalian University of Technology Affiliated Central Hospital (Dalian Central Hospital), Dalian, Liaoning Province, 116033, People’s Republic of China; 2Graduate School, Dalian Medical University, Dalian, Liaoning Province, 116041, People’s Republic of China; 3Department of Thyroid Surgery, Central Hospital Affiliated to Dalian University of Technology, Dalian, Liaoning Province, 116033, People’s Republic of China; 4Graduate School, China Medical University, Shenyang, Liaoning Province, 110122, People’s Republic of China; 5The First Department of Hand and Foot Surgery, Central Hospital Affiliated to Dalian University of Technology, Dalian, Liaoning Province, 116033, People’s Republic of ChinaCorrespondence: Meng Xu, Email [email protected]: Chronic pain (CP) is widespread and a major cause of disability. However, its genetic and environmental risk factors, as well as its relationship with breast cancer (BC), remain unclear. The study is the first to apply Mendelian randomization (MR) to explore the causal relationship between CP and BC.Methods: Two-sample MR and multivariable MR (MVMR) were performed using genome-wide association study (GWAS) data. Univariable MR assessed the effect of CP on BC, while MVMR adjusted for body mass index (BMI). The inverse variance-weighted method was used as the primary method.Results: Univariable MR found a strong genetic link between stomach/abdominal pain and overall BC risk (OR 3.411, 95% CI 1.029– 11.313, P=0.045). Neck/shoulder pain was associated with Luminal_A breast cancer risk (OR 1.999, 95% CI 1.263– 3.163, P=0.003). Multivariable MR, adjusting for BMI, confirmed these findings for stomach/abdominal pain to overall BC (OR 4.39, 95% CI 1.48– 13.06, P=0.008) and neck/shoulder pain to Luminal_A BC (OR 2.46, 95% CI 1.24– 4.87, P=0.010). No associations were found for other pain types (headache, hip pain, back pain, knee pain, facial pain) with BC subtypes.Conclusion: Genetic evidence in this study suggests a causal link between stomach/abdominal pain and overall BC, and between neck/shoulder pain and Luminal-A BC risk in Europeans. Determining the cause of this discrepancy might shed light on the complicated link between breast cancer etiology and chronic pain genetics, emphasizing the need for further investigations and potential clinical applications to enhance breast cancer prevention and management.Keywords: Mendelian randomization, chronic pain, breast cancer, BMI, confounder