Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial

Abstract

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R² = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: -0.62; -1.03, -0.02; p = 0.004), pyruvate (β: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (β: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: -0.65; -1.04, -0.26; p = 0.001 and β: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

Keywords: Mendelian randomisation; dietary intervention; green tea; lycopene; prostate cancer.

Figure 1

Analysis steps for investigating the effects of lycopene and green tea on serum metabolome of men at risk of prostate cancer, and the causal role of altered metabolic traits on prostate cancer risk. We conducted 2 analyses. In stage one, relationships between metabolic measures and lycopene or green tea randomisation arms were tested using an intention‐to‐treat analyses. In stage two, we used GWAS summary statistics from Kettunen et al to identify genetic variants that could be used as instrumental variables for the effects of metabolites on prostate cancer risk. Data on the association of these genetic variants with prostate cancer risk were obtained from the PRACTICAL consortium (44,825 prostate cancer cases and 27,904 controls of European ancestry). Data on the association of genetic variants with metabolite levels and with prostate cancer risk were combined to estimate the influence of metabolites on prostate cancer risk. ITT, intention‐to treat; IV, instrumental variable.

Figure 2

Flow of ProDiet participants through the study.Adapted from the main ProDiet study (Lane, AJ., unpublished), with thanks.

Figure 3

(a) Comparison of overall effects on serum metabolic traits between lycopene intervention arms vs. placebo models. Estimates of the standard deviation (SD) difference in metabolic trait concentration between lycopene dietary advice and placebo arms at follow‐up (x‐axis) plotted against the SD difference in metabolic trait concentration in the lycopene supplement arm vs. placebo (y‐axis). (b) Comparison of overall effects on serum metabolic traits between green tea intervention arms vs. placebo models. Corresponding results for green tea. Each dot on plots A and B represents an individual metabolic trait. A linear fit of the overall correspondence summarises the similarity in magnitude between diet and supplement associations (solid lines). A slope of 1 with an intercept of 0 (dashed lines), with all dots sitting on that line (R ² = 1), would indicate that diet and supplement estimates had the same magnitude and direction. Corresponding results for green tea. (c) SD follow−up metabolic trait concentration difference between lycopene diet or supplement vs. placebo. (d) SD follow−up metabolic trait concentration difference between green tea diet (drink) or supplement vs. placebo. Circles indicate β‐regression coefficients for the dietary intervention arms. Squares indicate β‐regression coefficients for the supplement arms. Closed symbols denote values that reached the threshold for multiple testing (p ≤ 0.004). Association magnitudes are in units of 1‐SD metabolic measure concentration. Horizontal bars represent 95% confidence intervals. Abbreviations: C, cholesterol; HDL, high‐density lipoprotein; IDL, intermediate‐density lipoprotein; LDL, low‐density lipoprotein; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; VLDL, very‐low‐density lipoprotein.