Yukai Wang Mengmeng Chen Lin Wang Yonggui Wu ^*

• First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China

Background: Both diabetic kidney disease (DKD) and chronic kidney disease (CKD) are more prevalent among individuals with lower levels of education in observational studies. To quantify the mediation effect of recognized cardiometabolic traits, we obtain causal estimates between education and DKD as well as CKD.We assessed the causal effect of education on DKD and CKD, separately estimated the causal effect of 26 cardiometabolic traits on DKD and CKD, and finally calculated the mediating effects and mediating proportions of each using two-step, twosample multivariable Mendelian randomization (MVMR). Furthermore, the genetic association between exposure, mediators, and outcomes was investigated using linkage disequilibrium score (LDSC) regression analysis. Expression quantitative trait loci (eQTL) were retrieved from the Genotype-Tissue Expression Project (GTEx) v8 to serve as genetic instrumental variables. Transcriptome-wide association studies (TWAS), Bayesian colocalization analysis, and Summary-data-based Mendelian Randomization (SMR) analysis were performed to explore underlying susceptibility genes between education, mediators, and kidney diseases.Higher education with a genetically predicted 1-SD (4.2 years) was linked to a 48.64% decreased risk of DKD and a 29.08% decreased risk of CKD. After extensive evaluation of 26 cardiometabolic traits, 7 and 6 causal mediators were identified as mediating the effects of education on DKD and CKD, respectively. The largest mediating factor between education and DKD was BMI, which was followed by WHR, T2D, fasting insulin, SBP, fasting glucose, and DBP. In contrast, candidate mediators in the education-to-CKD pathway included BMI, followed by cigarettes smoked per day, WHR, SBP, T2D, and DBP. MR analysis revealed that 3 TP53INP1 was found to be a shared susceptibility gene for cardiometabolic traits and DKD, while L3MBTL3 was found to be a shared susceptibility gene for cardiometabolic traits and CKD.Our findings provide solid evidence that education has a causally protective effect on the development of DKD and CKD. We additionally reveal significant directions for intervention on cardiometabolic traits that mitigate the negative effects of educational inequities on the onset of DKD and CKD. Our work demonstrates a shared genetic basis between education, cardiometabolic traits, and kidney diseases. Future research aiming at lowering kidney risk may benefit from these findings.