Plasma metabolites as mediators in inflammation-related proteins - benign prostatic hyperplasia risk: insights from Mendelian randomization

Benign prostatic hyperplasia (BPH) is a chronic disease that pretends to occur in elderly men. Inflammatory and metabolic factors play a key role in the pathogenesis and progression of BPH. The extent to which effects of 91 inflammation-related proteins on BPH are mediated by 1400 plasma metabolites is unclear. In our study we examined the effects of these traits using genetic evidence. We used two-sample Mendelian randomization ( two-sample MR) and Multivariable MR (MVMR) to determine:there is a genetic causal relationship between Interleukin-2 levels (IL-2)and BPH,N6,N6-dimethyllysine levels play a mediation role:higher IL-2 was associated with higher risk of BPH(β = 0.071, OR:1.074,95%CI[1.002–1.152], p  = 0.045 and lower levels of N6,N6-dimethyllysine levels (β1=-0.127 p  = 0.02).The N6,N6-dimethyllysine levels (β2=-0.039, p  = 0.008) was negatively genetic associated with the risk of BPH.The mediation effect was 0.005,95% confidence interval(CI) [0.0004,0.012],odds-ratio (OR) :1.005,95%CI[1.000,1.012].Then,we analyzed the phenotypic co-localization of the two pairs : IL-2—BPH and N6,N6-dimethyllysine levels—BPH, which showed that IL-2 and BPH co-locate the SNP of rs145516501 on the NO. 13 chromosome. N6,N6-dimethyllysine levels, and BPH are co-located to the SNP of rs4917820 on the NO. 10 chromosome.The mediation proportion is 7.04%.The study suggested that N6,N6-dimethyllysine levels appear to mediate the causal effect of IL-2 on BPH.