Causal Relationship Between Type 2 Diabetes Mellitus and Preeclampsia: A Bidirectional Two-Sample Mendelian Randomized Study

Xuwen Song,1 Yikang Wang,2 Pengsheng Li,3 Yafei Wang,4 Xinghui Wen,4 Qingwen Nie,1 Wanlu An,1 Huan Wang,1 Fang He1 1Department of Obstetrics and Gynecology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 3Department of Obstetrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, Guangdong Province, People’s Republic of China; 4Department of Obstetrics and Gynecology, The Second People’s Hospital of Guiyang, Guiyang, Guizhou Province, People’s Republic of ChinaCorrespondence: Fang He, Department of Obstetrics and Gynecology; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China, Tel +8618922182396, Email [email protected]: Observational epidemiologic investigations into the link between diabetes mellitus and preeclampsia (PE) have been conducted, but genetic evidence is still lacking. We utilized a two-sample Mendelian randomization (MR) analysis to shed light on the potential influence of type 2 diabetes mellitus (T2DM) on PE at the genetic prediction level.Methods: We carried out a two-sample bidirectional MR analysis, utilizing genetic variants associated with T2DM (N=461,920) and PE (N=219,817) from the largest available genome-wide association studies. Using inverse variance weighting (IVW) and five validated approaches—MR-Egger, MR-RAPS, ConMix, weighted median, and weighted mode—we derived a potential causal association between T2DM and PE. The relationship between PE and T2DM was explored using reverse MR analysis.Results: The two-sample MR analysis indicated a causal link between T2DM and PE, with an odds ratio of 1.10 (95% CI, 1.02– 1.18; P=0.01). The weighted mode method yielded an odds ratio of 1.22 (95% CI, 1.06– 1.40; P=0.019), and the weighted median method produced an odds ratio of 1.19 (95% CI, 1.04– 1.36; P=0.022). However, no significant association was detected in the MR-Egger analysis. Heterogeneity was noted in the analysis of T2DM and PE, but no significant horizontal pleiotropy was observed. The results of the reverse MR analysis indicated no significant causal association between PE and T2DM.Conclusion: For the first time, MR analysis showed a positive causal link from T2DM to PE, but not vice versa. The limited number of SNPs in reverse analysis may affect reliability. Future studies should use more instrumental variables to strengthen findings. Further experiments are also needed to explore underlying mechanisms.Keywords: causal effect, type 2 diabetes mellitus, preeclampsia, genome-wide association study