TBX2 Is a CKD-MBD Causal Gene by Regulating Calcium Homeostasis and Inflammation

Background: Chronic kidney disease–mineral and bone disorder (CKD-MBD) is a syndrome characterized by biochemical mineral abnormalities, bone fragility, and vascular calcification, leading to increased morbidity and mortality. Genome-wide association studies (GWAS) have identified numerous loci associated with kidney diseases. However, the causal variants, genes, cell types, and disease mechanisms remain largely unknown. Methods: We integrated GWAS, human kidney expression of quantitative trait analysis using Bayesian colocations, and summary-based Mendelian randomization studies to identify likely causal genes for CKD-MBD. We used single-cell RNA data to pinpoint causal cell types. Additionally, we generated TBX2 knockdown (KD) mice to study mechanism. Results: We prioritized TBX2 (T-Box Transcription Factor 2) as a CKD-MBD risk gene. Human kidney single-cell epigenetic and immunostaining studies indicated kidney connecting tubular cells and vascular smooth muscle cells (VSMCs) as key disease-causing cell types. TBX2-KD mice exhibited increased urinary calcium excretion at baseline and showed heightened susceptibility to kidney injury in a chronic kidney disease model. These mice also demonstrated elevated tissue calcification, leading to activation of crystal-induced NLRP3 inflammasome pathways and increased inflammation. Conclusion: In summary, our GWAS identified TBX2 as a risk gene for CKD-MBD. We showed that TBX2 regulates tissue calcification and crystal-induced inflammation, thereby influencing CKD-MBD risk and uncovering a novel mechanism for CKD-MBD development.