Associations Between Liver Diseases and Breast Cancer: Evidence From NHANES and Two-Sample Mendelian Randomization Analyses

Abstract

Background: Accumulating evidence indicates that liver-related disorders may be associated with breast cancer susceptibility; however, whether this association reflects a causal relationship remains uncertain. Objectives: This study aimed to examine differences in the prevalence of liver diseases between individuals with and without a prior diagnosis of breast cancer and to investigate potential genetic associations through genetic epidemiological analyses. Methods: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), collected between August 2021 and August 2023, were analyzed to compare baseline characteristics and the prevalence of liver diseases between individuals with a history of breast cancer and cancer-free controls. Subsequent analyses incorporated genome-wide association study (GWAS) summary data for liver-related traits and breast cancer retrieved from the IEU OpenGWAS resource. Two-way Mendelian randomization (MR) analyses were conducted to examine their genetic associations. Heterogeneity and pleiotropy were assessed using standard MR sensitivity analyses, including Cochran Q statistics, MR-Egger regression, MR-PRESSO, and leave-one-out procedures. Results: Compared with the cancer-free control group, individuals with a history of breast cancer were older, and all were female. Notably, the prevalence of self-reported fatty liver disease was significantly higher among participants with a history of breast cancer than among controls (13.0% vs. 2.9%). Subsequent MR analyses indicated that genetically predicted liver diseases showed heterogeneous associations with breast cancer risk across different analytical methods. Among these conditions, nonalcoholic fatty liver disease (NAFLD) showed the most pronounced association in the inverse variance weighted (IVW) analysis (odds ratio = 2.2789; 95% confidence interval = 1.2851 - 4.0413). Reverse MR analyses did not indicate significant associations between genetically predicted breast cancer liability and the risk of the 4 liver diseases. Conclusions: Taken together, our findings suggest that liver diseases, particularly NAFLD, may share a potential genetic relationship with breast cancer. These results warrant further investigation in well-designed prospective and mechanistic studies to clarify the underlying biological pathways. A better understanding of these associations may ultimately contribute to improved strategies for early prevention and risk assessment in breast cancer.