On May 1, 2023, Dr Zhan along with Dr Na from The University of Hong Kong, Dr Ruan from Shanghai Jiao Tong University School of Medicine, and Dr Wang from Miami University were awarded the AUA Best Poster on “Causal effects of modifiable behaviors on prostate cancer in Europeans and East Asians: a comprehensive Mendelian randomization study” at the 2023 AUA Annual Meeting in Chicago.

Since the global incidence of prostate cancer (PCa) has been continually growing in recent years, healthy lifestyle, an affordable and practicable measure, has come to the fore for cancer prevention.¹ However, the causal effect of lifestyle factors on PCa has not been established. Even common lifestyle behaviors including tobacco smoking, alcohol drinking, fruit and vegetable consumption, and physical activity are disputable on prostate tumorigenesis, as reported by the World Cancer Research Fund Continuous Update Project.² In addition, given the genetic differences amid interethnic populations,³ the lifestyle-PCa relationship can be racially diverse in different regions. Therefore, in this study, we performed a multivariable Mendelian randomization (MR) analysis to reveal the causal inference between 7 lifestyle phenotypes and PCa risks in the European and East Asian populations.

The present study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology using MR guidelines.⁴ The conceptual framework and the 3 MR assumptions of the current study were as follows: (1) instrumental variables (single nucleotide polymorphisms [SNPs]) were truly associated with the lifestyle factors; (2) SNPs were unrelated to the confounders on the lifestyle-PCa nexus; and (3) SNPs affected PCa only via lifestyle factors. The instrumental variables (SNPs) of these behavioral traits (tobacco smoking, alcohol drinking, fruit intake, vegetable intake, physical activity, sexual initiation, and sleep behavior) were obtained from the genome-wide association study (GWAS) catalogue (www.ebi.ac.uk/gwas) and the MR-Base repository of full GWAS association statistics (www.mrbase.org).⁵ Summary GWAS data on the PCa trait in Europeans were obtained from the Prostate Cancer Association Group to Investigate Cancer-associated Alterations in the Genome and Genetic Associations and Mechanisms in Oncology/Elucidating Loci Involved in Prostate Cancer Susceptibility consortia,⁶ whereas the data in East Asians were acquired from the Chinese Consortium for Prostate Cancer Genetics.^7,8 A 2-sample multivariable MR analysis was applied to evaluate the effect of multiple lifestyle phenotypes with shared genetic predictors on the risk of PCa.⁹ All P values were 2-sided and were considered statistically significant when less than .05. The aforementioned analyses were performed using R 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria).

Details of genetic information were shown in Figure 1. For the European sample, the number of SNPs ranged from 3 to 169, and the proportion of variance explained by SNPs varied from 0.01% to 2.44%. The F statistics for most traits were higher than 10, suggesting no potential weak instrument bias. For the East Asian sample, the number of SNPs ranged from 3 to 19, and the proportion of variance explained by SNPs varied from 0.36% to 7.56%. The F statistics indicated a potential weak instrument bias. In the MR analysis, we found that tobacco smoking was identified to cause PCa in Europeans (odds ratio [OR]=1.95, 95% confidence interval [CI]: 1.09-3.50, P = .027). Alcohol drinking (OR=1.05, 95% CI: 1.01-1.09, P = .011) and delayed sexual initiation (OR=1.04, 95% CI: 1.00-1.08, P = .029) were identified to be risk factors whereas vegetable consumption (OR=0.92, 95% CI: 0.88-0.96, P = .001) to be a protective factor of PCa in East Asians (Figure 2).

Figure 1. Details of the genetic variants in the present Mendelian randomization study. EAS indicates East Asian; EUR, European; SNP, single nucleotide polymorphisms.

Figure 2. Causal effects of lifestyle factors on prostate cancer in Europeans and East Asians. * indicates P < .05; **, P < .01; CI, confidence interval; OR, odds ratio.

To the best of our knowledge, this is the first study to apply a multivariable MR approach to systematically determine the causal effects of a series of lifestyle behaviors on prostate cancer in 2 different populations. This study suggests 4 kinds of lifestyle factors relevant to prostate tumorigenesis and sheds light on the importance of healthy lifestyles for cancer prevention. In addition, risk effects of the same lifestyles are discrepant across ancestries. This finding indicates that priority of behavior interventions should be implemented accordingly in different population settings.

Acknowledgments

The full text of this research is published in Biology,¹⁰ and has been permitted for dissemination.