Genetic association of lipids and lipid-lowering drug target genes with breast cancer.

Abstract

Background: Although several preclinical and epidemiological studies have shown that blood lipids and lipid-lowering drugs can reduce the risk of breast cancer, this finding remains controversial. This study aimed to explore the causal relationship between dyslipidemia,lipid-lowering drugs, and breast cancer. We also aimed to evaluate the potential impact of lipid-lowering drug targets on breast cancer.

Method: Data of 431 lipid- and lipid-related phenotypes were obtained from genome-wide association study (GWAS), and mendelian randomization (MR) analyses were performed using two independent breast cancer datasets as endpoints. Genetic variants associated with genes encoding lipid-lowering drug targets were extracted from the Global Lipid Genetics Consortium. Expression quantitative trait loci data in relevant tissues were used to further validate lipid-lowering drug targets that reached significance and combined with bioinformatics approaches for molecular expression and prognostic exploration. Further mediation analyses were performed to explore potential mediators.

Result: In two independent datasets, phosphatidylcholine (18:1_0:0 levels) was associated with breast cancer risk (discovery: odds ratio (OR) = 1.255 [95% confidence interval (CI) 1.120-1.406]; p = 8.936 × 10^-5, replication: OR = 1.016 [95% CI, 1.003-1.030]; p = 0.017), HMG- CoA reductase (HMGCR) inhibition was genetically modeled and associated with a reduced risk of breast cancer (discovery: OR = 0.833 [95% CI 0.752-0.923], p = 5.12 × 10^-4; replication: OR = 0.975 [95% CI 0.960-0.990], p = 1.65 × 10^-3). There was a significant MR correlation between HMGCR expression in whole blood and breast cancer (OR = 1.11 [95% 1.01-1.22] p = 0.04). Bioinformatics analysis revealed that HMGCR expression higher in breast cancer tissues than in normal tissues, along with poor overall survival and relapse-free survival, and was associated with multiple immune cell infiltration. Finally, the mediation analysis showed that HMGCR inhibitors affected breast cancer through different immune cell phenotypes and C-reactive protein levels.

Conclusion: In this study, we found for the first time that phosphatidylcholine (18:1_0:0) levels are associated with breast cancer risk. We found that HMGCR inhibitors are associated with a reduced risk of breast cancer, and part of their action may be through pathways other than lipid-lowering, including modulation of immune function and reduction of inflammation represented by C-reactive protein levels.