Genetic Causal Relationship and Risk Factors Associated with Type 2 Diabetes and CKD

Background: T2D is the most important risk factor of CKD.T2D-related CKD has family heritability and is heterogeneous.Compared with European and others,T2D patients in Asian are more likely to develop CKD and ESRD.But there is a lack of researchs about the genetic susceptibility of T2D-CKD in different ethnic groups and whether T2D-related genetic factors cause CKD. Methods: We used East Asian-based GWAS of T2D and CKD from BBJ and European-based GWAS of T2D from DIAGRAM and CKD from UKB to explore the genetic causal relationship and risk genes associated with T2D-CKD in different ethnic groups.We performed:(1)LDSC to estimate the genetic correlation;(2)7 Mendelian randomization(MR) or MR-equivalent methods to infer the putative causality;(3)MAGMA and SMR to identify and verify new risk genes;(4)STRING and Reactome to predict the Protein-Protein Interaction and common biological pathways. Results: In both East Asian and European,we all observed significant positive genetic correlation between T2D and CKD(EAS:rg=74.91%; EUR:rg=42.93%).MR also both showed causal effect of T2D on CKD.In East Asian,the OR of IVW is 1.30(P=5.84×10-10).In European,the OR is 1.17(P=1.60×10-10).In contrast,no evidence supports a causal effect of CKD on T2D.Between two populations,Z test showed no significant difference in genetic correlation (P=1.74×10-1).But in MR analysis,the IVW showed that the causality value in East Asian was significantly higher than that in European (P=4.03×10-2).In East Asian,MAGMA and SMR identified 3 new risk geneswhose expression levels were likely involved in the putative causality of T2D on CKD.In European,27 new risk genes were identified.STRING showed that ZSCAN21 in East Asian was structurally similar to ZNF195 in European,and they had gene co-expression and protein interaction.Reactome Pathways showed that they have some common biological pathways.ARC in East Asian and MPP3 in European also had similar findings. Conclusion: In both East Asian and European,we all found the genetic causal effect of T2D on CKD,and the risk of CKD in T2D patients in Asian is higher.3 and 27 new risk genes associated with T2D-CKD were respectively identified in East Asian and European.We found some Protein-Protein Interactions and common biological pathways around some of them. These findings posed new paths on guiding the prevention and early-stage diagnosis of CKD in T2D patients.