Abstract
BackgroundInconsistent findings from observational studies have reported that C-reactive protein (CRP) is likely associated with risk of prostate cancer. Because conventional observational studies are susceptible to confounding and reverse causality, it remains unclear whether there is a causal relationship of CRP with risk of prostate cancer.MethodsIn this study, we applied a two-sample Mendelian randomization (MR) approach to evaluate the potential causal association of circulating CRP levels with prostate cancer risk. Instrumental variables (IVs) and corresponding genetic association estimates for circulating CRP levels were obtained from a meta-analysis of genome-wide association studies (GWASs) including 204,402 participants of European descent. The genetic association estimates of these IVs with prostate cancer were obtained from a GWAS meta-analysis including 79,148 cases and 61,106 controls of European ancestry. The inverse-variance weighted (IVW) method was used as primary MR analyses, whereas in sensitivity analyses, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used to assess the presence of pleiotropy. Odd ratio (OR) and 95% CI were calculated.ResultsOverall, 58 single-nucleotide polymorphisms were used as instruments for circulating CRP levels. MR analysis suggested that genetically determined CRP levels were not associated with prostate cancer risk (OR 1.06, 95% CI 0.96 to 1.16) using the IVW method. Sensitivity analyses using alternative MR methods produced similar results (OR 1.00, 95% CI 0.93 to 1.08 for the weighted-median method; OR 1.02, 95% CI 0.95 to 1.08 for MR-PRESSO test). MR-Egger regression did not suggest evidence of directional pleiotropy (P = 0.25).ConclusionOur study found that genetically predicted circulating CRP levels were not associated with prostate cancer risk, suggesting that CRP is unlikely to be a causal factor in the development of prostate cancer.
Highlights
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer death in men worldwide, with estimations of almost 1.3 million new cases and approximately 359,000 deaths in 2018 [1]
Detailed information about the 58 SNPs used as IVs for circulating levels of C-reactive protein (CRP) and their association estimates with prostate cancer risk is listed in Supplementary Table 2
MR analysis indicated that genetically predicted one-unit increase in the log-transformed circulating CRP levels were not associated with prostate cancer risk [odd ratio (OR) 1.06, 95% CI 0.96 to 1.16, and P = 0.24] using the inverse-variance weighted (IVW) method based on a random-effects model (Figure 2)
Summary
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer death in men worldwide, with estimations of almost 1.3 million new cases and approximately 359,000 deaths in 2018 [1]. Because circulating C-reactive protein (CRP) is an important biomarker for low-grade chronic inflammation, the association of this biomarker with the incidence of prostate cancer has been investigated in several observational epidemiological studies. Because conventional observational studies are susceptible to potential bias such as unmeasured confounders and reverse causality, it remains unclear whether the association of CRP with prostate cancer risk is causal or not. Inconsistent findings from observational studies have reported that C-reactive protein (CRP) is likely associated with risk of prostate cancer. Because conventional observational studies are susceptible to confounding and reverse causality, it remains unclear whether there is a causal relationship of CRP with risk of prostate cancer
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