Associations of genetically determined circulating proteins with breast cancer risk or survival

Abstract

Abstract Background There are few large-scale studies that focus on the associations between circulating proteins and breast cancer (BC) risk or survival. This study aimed to evaluate the potential circulating proteins associated with BC risk or survival using the Mendelian randomization (MR) method. Methods We collected the protein quantitative trait locus (pQTL) data of 4,907 circulating proteins from the DeCODE study (n = 35,559) as exposures. We gathered the genome wide association study (GWAS) data of BC from BCAC (OncoArray, n = 138,508) and BCAC (iCOGS, n = 76,167). The FinnGen study (n = 224,737) as the outcomes. The BC survival data was obtained from BCAC (OncoArray, n = 91,686). We used two sample MR framework to assess the associations between genetically predictive proteins and BC risk. Besides strict quality control, sensitivity tests and false discovery rate (FDR) or bonferroni correction, we further performed meta-analysis to ensure the robustness of the results. Results Four proteins—SIA4B (OR = 0.58, 95% CI (confidence interval): 0.51–0.64), CDH1 (OR = 0.83, 95% CI: 0.77–0.89), ALPI (OR = 0.91, 95% CI: 0.90–0.93) and CCDC134 (OR = 0.84, 95% CI: 0.80–0.88) are associated with reduced BC risk. 57 circulating proteins passed the sensitivity test and causally associated with BC survival. Conclusions Genetically predicted four circulating proteins (SIA4B, CDH1, ALPI and, CCDC134) are associated with reduced BC risk. 57 proteins are associated with BC survival. Our analyses from genetics and MR provide insights into the causes of BC and add evidence for reducing the risk of BC.