Approved Research

Identification of causal relationship and interactions between genetic and environmental risk factors related to chronic kidney disease

Lay summary

Chronic kidney disease (CKD) is a major health problem with an increasing prevalence of over 10% worldwide. CKD has been recognized as a heterogeneous clinical entity with different etiologies and clinical courses influenced by multiple risk factors. Conventional risk factors of CKD are mainly based on moderate to low-to moderate-grade evidence. Many current approaches to prevent CKD such as lifestyle modification have not been demonstrated in randomized controlled trials. Although previous GWAS genetic studies have identified numerous loci related to kidney function, these loci could account for only small part of overall heritability and gene-environment interactions in CKD have not been well evaluated. Large-scale biobank data and newly developed genetic research methods could provide an opportunity to verify the role of numerous environmental factors in relation to CKD. Therefore, we aim to identify gene-environment interactions and causal association of known or novel risk factors (or their biomarkers) related to kidney outcomes using a wide range of phenotypic and genetic data in UK biobank. We will investigate the causal relationships between known and novel risk factors and kidney function or chronic kidney disease outcomes using Mendelian randomization. In this study, polygenic risk score analysis for CKD and gene-environment (G x E) interaction analysis will be performed to assess the contribution of environmental factors to kidney outcomes. We will also investigate rare variants with presumed larger effect size and their interaction with environmental exposures using whole exome sequencing or whole genome sequencing data of UK biobank. We expect to complete this study in the next 3 years. This study will contribute to deeper understanding of genetic and environmental risk factors of CKD and establish better evidence of preventive strategies for kidney function decline. Our findings could explain the heterogeneous and complex phenotypic traits of CKD with multiple environmental, genetic risk components, and their interactions, which improve risk stratification and personalized treatment for individuals at a risk of CKD.