Using Genetics to Assess the Role of Acetate in Ischemic Heart Disease, Diabetes, and Sex-Hormone-Related Cancers: A Mendelian Randomization Study

Background: Acetate, a short-chain fatty acid, has gained attention for its contrasting roles, with evidence suggesting it may offer cardiovascular protection but also promote cancer, particularly those involving sex hormones. However, these influences have been scarcely assessed in epidemiological research. Objective: To investigate the relationship between acetate and ischemic heart disease (IHD), diabetes, and cancers related to sex hormones. Methods: Mendelian randomization (MR) was used to assess potential causal effects, selecting genetic variants without linkage disequilibrium (r(2) < 0.001) and with genome-wide significance for acetate (p < 5 x 10(-8)). These variants were applied to large genome-wide association studies (GWAS) for ischemic heart disease (IHD; up to 154,373 cases), diabetes (109,731 cases), and five sex-hormone-related cancers (breast, colorectal, prostate, ovarian, and endometrial cancers, ranging from 8679 to 122,977 cases). We employed various methods for analysis, including penalized inverse variance weighting (pIVW), inverse variance weighting, weighted mode, and weighted median. Results: This study indicates that acetate may be associated with a lower risk of ischemic heart disease (IHD), with an odds ratio (OR) of 0.62 per standard deviation (SD) increase in acetate and a 95% confidence interval (CI) of 0.39 to 0.98. Additionally, acetate was linked to a higher breast cancer risk, with an OR of 1.26 and a 95% CI ranging from 1.08 to 1.46. This association remained robust across multiple sensitivity analyses. Conclusions: Acetate, along with factors that influence its activity, may serve as possible targets for breast cancer treatment and possibly IHD, offering opportunities for new drug development.