Abstract
BACKGROUND: Blood lipids are implicated in the development of breast cancer (BC), though the genetic connection remains unclear, particularly in African populations. Observational studies on this topic are limited by confounding factors and reverse causation, potentially affecting the reliability of findings. METHODS: We applied univariate and multivariable two-sample Mendelian randomization to assess the causal association between blood lipids (total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides [TG]) and BC. Summary-level data for lipid traits were sourced from the Africa Wits-INDEPTH partnership for Genomic Research (AWI-Gen) (N = 10,603 women). BC data were obtained from the largest genome-wide association study of BC in African women, comprising 18,034 BC cases and 22,104 controls. RESULTS: Our analysis revealed that genetically predicted TG was associated with a decreased BC risk (OR = 0.73, 95% CI = 0.56-0.95, p = 0.018. In contrast, no significant associations were found between TC, HDL, or LDL levels and BC risk: TC (OR = 1.04, 95% CI = 0.93-1.18, p = 0.467), HDL (OR = 1.29, 95% CI = 0.93-1.79, p = 0.121), and LDL (OR = 1.04, 95% CI = 0.90-1.20, p = 0.577). After adjusting for the effects of other lipid traits, the association between TG and BC was attenuated, and no associations were observed for TC, HDL, or LDL. No causal relationship was found between lipid traits and BC subtypes. CONCLUSIONS: This study provides evidence that elevated triglycerides may be associated with a reduced risk of BC, whereas no significant associations were observed for TC, HDL, or LDL. Further research is needed to better understand the underlying mechanisms and potential clinical implications of these findings.