Shared genetic architecture between inflammatory proteins and eGFR difference identifies chronic inflammation risk factors for kidney function impairment

Chronic kidney disease(CKD) is linked to systemic inflammation, yet the shared genetic mechanisms remain unclear. Emerging evidence indicates that the difference between cystatin C- and creatinine-based eGFR serves as an early biological indicator capturing inflammatory, cardiometabolic, and mortality-related risk signals that precede subclinical kidney injury. Using large-scale cohorts (~390,000 UK Biobank; ~36,000 deCODE), we integrated genome-wide association studies across 13 kidney function traits and 839 inflammation-related proteins. Cross-trait genetic analyses and Mendelian randomization highlighted that the eGFR difference is highly heritable and shares genetic components with cardiometabolic signals. Multiple upstream inflammatory proteins, including ALPI, FABP9, INSR, and ABO, showed consistent protein-to-trait effects, corroborated by protein-level associations in 50,000 UK Biobank participants. Proteomic polygenic risk scores improved prediction of eGFR difference by 61% beyond demographic factors, achieved performance comparable to later-life clinical factors. Together, these findings provide the first genome-wide evidence delineating the genetic and inflammatory architecture of the eGFR difference, offering new biological insights for Cardiovascular-Kidney-Metabolic(CKM) risk stratification and transplant monitoring.