Haifeng Zhang

Insight into the causality between basal metabolic rate and endometrial and ovarian cancers: Analysis utilizing systematic Mendelian randomization and genetic association data from over 331,000 UK biobank participants

AbstractBackgroundObservational studies have demonstrated that basal metabolic rate (BMR) is associated with the risk of endometrial cancer (EC) and ovarian cancer (OC). However, it is unclear whether these associations reflect a causal relationship.ObjectiveTo reveal the causality between BMR and EC and OC, we performed the first comprehensive two‐sample Mendelian randomization (MR) analyses.MethodsGenetic variants were used as proxies of BMR. GWAS summary statistics of BMR, EC and OC were obtained from the UK Biobank Consortium, Endometrial Cancer Association Consortium and Ovarian Cancer Association Consortium respectively. The inverse variance weighted method was employed as the main approach for MR analysis. A series of sensitivity analyses were implemented to validate the robustness and reliability of the results.ResultsBMR was significantly related to an increased risk of EC (ORSD = 1.49; 95% CI: 1.29–1.72; p‐Value < .001) and OC (ORSD = 1.21; 95% CI: 1.08–1.35; p‐Value < .001). Furthermore, the stratified analysis indicated that BMR was positively associated with endometrioid endometrial cancer (EEC) (ORSD = 1.45; 95% CI, 1.23–1.70; p‐Value < .001), clear cell ovarian cancer(CCOC) (ORSD = 1.89; 95% CI:1.35–2.64; p‐Value < .001) and endometrioid ovarian cancer risk (EOC) (ORSD = 1.45; 95% CI: 1.12–1.88; p‐Value = .005). However, there were no significant associations of BMR with invasive mucinous ovarian cancer (IMOC), high‐grade serous ovarian cancer (HGSOC) and low‐grade serous ovarian cancer (LGSOC). The robustness of the above results was further verified in sensitivity analyses.ConclusionThe MR study provided etiological evidence for the positive association of BMR with the risk of EC, EEC, OC, CCOC and EOC. But this study did not provide enough evidence suggesting the causal associations of BMR with IMOC, HGSOC and LGSOC.

Association between intake of the n-3 polyunsaturated fatty acid docosahexaenoic acid (n-3 PUFA DHA) and reduced risk of ovarian cancer: A systematic Mendelian Randomization study

Whether the intake of docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, is beneficial for ovarian cancer (OC) remains controversial and we hope to disentangle this puzzle using genetic data from large-scale populations in European and Asian. We employed, for the first time, a systematic Mendelian randomization (MR) design to comprehensively evaluate the causal effect of plasma DHA levels, an objective biomarker of DHA intake, on OC risk in European and then verified the extrapolation of the results in the Asian. Data in the analysis included genetic association data obtained from large-scale genome-wide association studies with 13,499 individuals for plasma DHA measurements and 66,450 individuals for OC in the European population, and 1361 individuals for plasma DHA measurements and 61,457 individuals for OC in the Asian population. The causal relationship between DHA and OC was estimated using the inverse-variance weighted approach, together with extensive validation and sensitivity analyses to verify the main results. In the European population, MR evidence suggested a causal relationship between higher plasma DHA levels and lower OC risk (OR, 0.89 for OC per one-SD increment in DHA; 95% CI, 0.83 to 0.96; P = 0.003). Subgroup analysis by histological type of OC indicated that this observed association was stronger among endometrioid ovarian cancer (EOC) (OR, 0.82; 95% CI, 0.69 to 0.96; P = 0.014). A similar causal association of borderline significance was reached in the Asian replication set. The above results were consistently supported by a series of validation and sensitivity analyses. Our study provided robust genetic evidence for a protective association between plasma DHA levels and lower risk of OC, especially EOC, in the European population. These findings may inform prevention strategies and interventions directed towards DHA intake and OC.