Metabolic Risk Factors, Genetic Risk Score, and Risk of Incident CKD

Background: Multiple modifiable risk factors are associated with chronic kidney disease (CKD). However, the combined effect of metabolic risk and genetic risk on CKD remains unexplored. Methods: This study investigated the association between metabolic risk factors (Obesity, high low-density lipoprotein cholesterol [LDL-C], hypertension, diabetes), genetic risk score and incident CKD, using data from UK Biobank. We used polygenic risk scores (PRS) for hypertension, diabetes, body mass index (BMI), and LDL-C, utilizing PRS data by Genomics PLC as part of UK Biobank project. The primary outcome was the incident CKD. Cox proportional model were used and population attribution fraction (PAF) were analyzed in risk of CKD. Results: This study included 171,955 participants, with a mean age 55.7 years and 86,153 (50.1%) being men. During the 12.8-year follow-up period, 8,641 incident CKD occurred. Prevalent hypertension exhibited the highest PAF at 17.4% (95% CI, 16.1, 18.7). Regarding the total CKD risk, 5.4% (95% CI, 5.0, 6.0) and 9.6% (95% CI, 8.7-10.7) were attributable to prevalent diabetes or obesity, respectively; while high LDL-C did not show significant attribution to CKD risk. Similar to the metabolic risk factors, PRS_hypertension, PRS_diabetes, and PRS_BMI contributed to CKD risk; PAF 14.7 (95% CI, 12.7-16.6), 5.5 (95% CI, 3.3-7.6), and 5.4 (95% CI,.3.4-7.4), respectively. The risk of CKD was more significantly attributable to hypertension in the high PRS_hypertension and PRS_diabetes group. Prevalent diabetes, and obesity were more significantly attributed to the risk of CKD in the highest quintile of PRS_hypertension. Conclusion: In this prospective cohort study, both metabolic risk factors and genetic risk were contributed to the development of CKD, except LDL-C. Notably, in the genetically high-risk subgroup, metabolic risk factors showed a more pronounced and significant contribution to CKD risk.Figure 1. Population attribution fraction of metabolic risk factors and genetic risk score for CKD