A Mendelian randomization study of insulin therapy for type 1 diabetes increasing the potential risk of ovarian cancer

Background Type 1 diabetes (T1D) has been associated with a higher risk of Ovarian cancer (OC), albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between T1D and OC may contribute to improved primary prevention of OC. We aimed to investigate the putative causal role of T1D on OC, and to identify the potentially mediatory effects of the usage of insulin product underlying this relationship.

We performed a two-sample Mendelian randomization (MR) analysis using genetic variants associated with T1D and OC from genome-wide association studies. Then, a multivariable MR analysis was conducted to investigate whether T1DM has an independent effect on OC after adjusting for potential confounders. Finally, the mediating role of insulin product was subsequently explored using mediation analysis via two-step MR.

the MR estimated based on IVW method indicated a causal association between genetically determined T1D and Ovarian cancer (OC) (OR: 1.0006, 95% CI 1.0001–1.0011; P = 0.0164). After adjusting for body mass index, Smoking, physical activity, age at menopause and age at menarche, respectively, we found that a causal relationship between T1DM and OC was still statistically significant (OR>1, P <0.05). The two-step MR analysis revealed that insulin product acted as a mediating moderator between the T1D and OC (mediated proportion, 1.07%).

Our findings suggest that T1D may confer a risk effect to OC, mediated in part by therapeutic insulin product. Therefore, precise dosage of insulin product or an alternative to insulin in T1D patients have a profound significance in terms of the prevention of OC. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study research was funded by The National Natural Science Foundation of China (Grant No. 82273479 to LZ) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: JiLin University Ethics Committees I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript All data produced are available online atGWAS summary data.