Shaoxue Yang1 *, Jie Song2 *, Hong Yang,2 Wei Liu,2 Yuqing Jiang,2 Xiaohui Sun,2 Ding Ye,2 Songxiao Xu,1 Yingying Mao2 1The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Hangzhou, 310022, People’s Republic of China; 2Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, 310053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingying Mao, Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email myy@zcmu.edu.cn Songxiao Xu, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Hangzhou, 310022, People’s Republic of China, Email xusx1979@126.comObject: Prostate cancer is one of the leading malignancies in men worldwide. Previous observational studies have linked amino acids and transaminase with altered risk of prostate cancer. However, whether these associations were causal remained unclear. Therefore, we conducted a Mendelian randomization (MR) to assess their potential causal associations.Methods: Summary-level data for prostate cancer were obtained from a meta-analysis of genome-wide association studies (GWAS) including 79,148 prostate cancer cases and 61,106 controls of European descent. Instrumental variables (IVs) of amino acids and alanine aminotransferase (ALT) were obtained from a GWAS of 86,507 European individuals and a GWAS of 312,572 participants from the UK Biobank, respectively. MR analyses were performed using inverse-variance-weighted (IVW), likelihood-based, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test and MR-Egger regression.Results: Genetically predicted circulating concentrations of alanine were associated with an increased risk of prostate cancer (odds ratio (OR): 1.16, 95% confidence interval (CI): 1.01– 1.33, P=0.037 by IVW). Consistently, genetically predicted ALT was inversely associated with the risk of prostate cancer (OR: 0.43, 95% CI: 0.27– 0.68, P=3.28× 10− 4 by IVW). MR-Egger regression did not indicate evidence of directional pleiotropy and sensitivity analyses yielded consistent associations.Conclusion: Our study revealed that genetically predicted circulating alanine and ALT levels were associated with an altered risk of prostate cancer, suggesting their potential roles in the development of prostate cancer. Whether targeting alanine, ALT or its downstream effectors are helpful in reducing prostate cancer incidence warrants further investigation.Keywords: alanine, alanine aminotransferase, amino acids, Mendelian randomization, prostate cancer
