The CEBPβ-XOR Axis and Genetic Risk for Metabolic Dysfunction–Associated Kidney Disease

Introduction and Objective: Metabolic dysfunction-associated kidney diseases (MDAKDs) are kidney diseases associated with metabolic abnormalities, and genetics is known to contribute to disease progression. We recently uncovered Xor promoter variants associated with risk for progressive DKD in mice indicating a causal role for impaired XOR regulation. Here, we examined whether variants in XOR promoter influences susceptibility to MDAKDs. Methods: We assessed the phenotype correlations of XOR promoter orthologue variants and examine their gene-level relevance to human MDAKD. We performed phenome-wide association studies (PheWAS) on human XOR promoter variants using the All of Us Program (AoU) whole genome sequencing dataset (n = 414,830). We generated ancestry-specific cohorts by stratifying European, African, and Admixed American. Next, we constructed the phenotypes based on ICD-10 codes mapped to phecodeX and performed association testing across phenotypes in the ancestry groups. All analyses were corrected for age, sex and the first 10 genetic principal components. A fixed-effect multi-ancestry meta-analysis was performed using the phenotypes observed in at least 2 ancestry groups. We also utilized PheWAS summary statistics of XOR promoter variants from the Million Veteran Program (MVP, n = 635,969). Results: Kidney-related and endocrine/metabolism disorder associations were identified in both ancestry-specific and multi-ancestry meta-analysis at P<0.05. Importantly, we determined 8 XOR promoter variants in predicted transcription factor binding sites for CEBPß in both datasets using CHIP-seq experiments from ReMap2022. These XOR variants displayed associations with atherosclerosis, cystic kidney disease, metabolic syndrome, nephrotic syndrome, type 1 diabetes with renal manifestations, glomerular diseases, gout and proteinuria. Conclusion: Xor promoter variants display associations with multiple metabolic, kidney disorders, which guide us to further explore human XOR variants and risk for MDAKD. Disclosure: M. Kars: None. U.S. Ekperikpe: None. Y. Itan: None. I.S. Daehn: None. Funding: National Institutes of Health (R01DK139395)