Investigating the causal association among 25(OH)D , 25(OH)D3 , C3-epi- 25(OH)D3 and the risk of oropharyngeal cancer using Mendelian randomization

Abstract

Abstract Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites ,25 hydroxyvitamin D and the epimeric form (C3-epi-25(OH)D3) with the health outcomes and cancer1,2, but little is known about the causal direction of the associations in oropharyngeal cancer (OPC). We aimed to evaluate the causal effect of 25-hydroxyvitamin D (25(OH)D) metabolites ,25 hydroxyvitamin D concentration and the epimeric form (C3-epi-25(OH)D3) on the risk of OPC using Mendelian randomization (MR). Methods: Genetic variants robustly associated with 25(OH)D , 25(OH)D3 and C3-epi-25(OH)D3 were used to perform MR analyses with summary data on 291 OPC cases, obtained from European, North America and South America. We performed two-sample MR analyses using an inverse variance weighted (IVW) as the primary approach, while using 5 additional methods (e.g., MR-Egger, weighted median(WM) and Cochran’s Q) as sensitivity analysis to detect and adjust for pleiotropy. Results: In MR, we found that evidence for a lower causal effect of 25(OH)D3 on risk of OPC in a European population (Weighted Median(WM) OR = 0.47, 95% CI = 0.24-0.91, P = 0.03). Although the IVW showed that it was significant, further leave-one-out results indicated that the negative results were unstable, and the results became positive after rs9304669 was excluded (OR = 0.51, 0.28-0.91, P = 0.02). The remaining results were negative. The results of sensitivity analysis were stable, and indicated that it was no heterogeneity and pleiotropy. Conclusions: Our study found obvious associations of 25(OH)D , 25(OH)D3 and C3-epi-25(OH)D3 with OPC risk.