Educational attainment, body mass index, and smoking as mediators in kidney disease risk: a two-step Mendelian randomization study

Educational attainment (EA) has been linked to various health outcomes, including kidney disease (KD). However, the underlying mechanisms remain unclear. This study aims to assess the causal relationship between EA and KD and quantify the mediation effects of modifiable risk factors using a Mendelian randomization (MR) approach. We performed a two-sample MR analysis utilizing summary statistics from large-scale European genome-wide association studies (GWAS). EA (NGWAS = 766,345) was used as the exposure, and KD (Ncase/Ncontrol= 5,951/212,871) was the outcome. A two-step MR method was applied to identify and quantify the mediation effects of 24 candidate risk factors. Each additional 4.2 years of genetically predicted EA was associated with a 32% reduced risk of KD (odds ratio [OR] 0.68; 95% confidence interval [CI] 0.56, 0.83). Among the 24 candidate risk factors, body mass index (BMI) mediated 21.8% of this protective effect, while smoking heaviness mediated 18.7%. This study provides robust evidence that EA exerts a protective effect against KD, partially mediated by BMI and smoking. These findings highlight the potential for targeted public health interventions aimed at mitigating obesity and smoking-related risks to reduce KD incidence, particularly among individuals with lower educational attainment.