Causal relationship between obesity, lifestyle factors and risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study

Abstract

Background: Obesity (waist circumference, body mass index (BMI)) and lifestyle factors (dietary habits, smoking, alcohol drinking, Sedentary behavior) have been associated with risk of benign prostatic hyperplasia (BPH) in observational studies, but whether these associations are causal is unclear.

Methods: We performed a univariable and multivariable Mendelian randomization study to evaluate these associations. Genetic instruments associated with exposures at the genome-wide significance level (P < 5 × 10^-8) were selected from corresponding genome-wide associations studies (n = 216,590 to 1,232,091 individuals). Summary-level data for BPH were obtained from the UK Biobank (14,126 cases and 169,762 non-cases) and FinnGen consortium (13,118 cases and 72,799 non-cases). Results from UK Biobank and FinnGen consortium were combined using fixed-effect meta-analysis.

Results: The combined odds ratios (ORs) of BPH were 1.24 (95% confidence interval (CI), 1.07-1.43, P = 0.0045), 1.08 (95% CI 1.01-1.17, P = 0.0175), 0.94 (95% CI 0.67-1.30, P = 0.6891), 1.29 (95% CI 0.88-1.89, P = 0.1922), 1.23 (95% CI 0.85-1.78, P = 0.2623), and 1.04 (95% CI 0.76-1.42, P = 0.8165) for one standard deviation (SD) increase in waist circumference, BMI, and relative carbohydrate, fat, protein and sugar intake, 1.05 (95% CI 0.92-1.20, P = 0.4581) for one SD increase in prevalence of smoking initiation, 1.10 (95% CI 0.96-1.26, P = 0.1725) and 0.84 (95% CI 0.69-1.02, P = 0.0741) for one SD increase of log-transformed smoking per day and drinks per week, and 1.31 (95% CI 1.08-1.58, P = 0.0051) for one SD increase in sedentary behavior. Genetically predicted waist circumference (OR = 1.26, 95% CI 1.11-1.43, P = 0.0004) and sedentary behavior (OR = 1.14, 95% CI 1.05-1.23, P = 0.0021) were associated with BPH after the adjustment of BMI.

Conclusion: This study supports independent causal roles of high waist circumference, BMI and sedentary behavior in BPH.

Keywords: Benign prostatic hyperplasia (BPH); Causal effect; Lifestyle factors; Mendelian randomization (MR); Obesity.

Fig. 1

Overview and assumptions of the Mendelian randomization study design. Assumption 1: the instrumental variables should be closely related to the risk factor of interest; assumption 2: the instrumental variables should not be associated with potential confounders, and assumption 3: the instrumental variables should affect the risk of outcome only through risk factors and not through other alternative pathways. LD, Linkage disequilibrium; SNP, single nucleotide polymorphisms; BMI, body mass index; IVW, inverse-variance weighted; PRESSO, Pleiotropy Residual Sum and Outlier

Fig. 2

The flow chart of the inclusion and exclusion criterion of candidate SNPs for each exposure-outcome pair. GWAS, genome-wide association studies; BMI, body mass index; LD, Linkage disequilibrium; IVW, inverse-variance weighted; PRESSO, Pleiotropy Residual Sum and Outlier; MR, Mendelian randomization

Fig. 3

Associations of genetically predicted risk factors with benign prostatic hyperplasia using random effect inverse-variance weighted method. IVW, inverse-variance weighted; OR, odds ratio; CI confidence interval; BMI, body mass index; SNP, single nucleotide polymorphism

Fig. 4

Associations of genetically predicted risk factors with benign prostatic hyperplasia using multivariable MR analyses. OR, odds ratio; CI, confidence interval