RWOP1 Genetic risk factors associated with the multimorbid development of chronic kidney disease by cardiovascular disease patients

Background Many cardiovascular diseases are associated with chronic kidney disease (CKD) and their burden as comorbidities is high. There is a pressing need to understand the molecular mechanisms by which cardiovascular diseases drive the development of CKD in multimorbidity. Methods and Results We performed an analysis of the risk of CKD onset across the full spectrum of cardiovascular disease phenotypes using UK Biobank primary and secondary care data (N = 129,824). We identified 17,347 cases of new onset CKD stage 3–5 within patients with pre-existing type 2 diabetes (T2D) (N = 13,409) and without diabetes (N = 116,415). We identified 8 cardiovascular disease phenotypes significantly associated with CKD onset including heart failure, atrial fibrillation, myocardial infarction, hypertension, ischaemic heart disease, peripheral vascular disease, hypotension, and angina pectoris. We performed a genome-wide association study (GWAS) to identify genetic variants enriched within identified high-risk CKD cardiovascular disease backgrounds and found 9 novel significant (p < 5 x 10⁻⁸) genetic loci associated with CKD in varying cardiovascular disease backgrounds. We used epigenomic databases and kidney eQTL data to link identified lead SNPs to likely target genes and found 1 novel CKD-associated gene in a background of hypertension with a clear SNP-to-gene assignment. We corroborated the identified gene-CKD association using single-cell RNA-seq kidney data and found the novel CKD-associated gene to have a highly specific cell-type expression within kidney podocytes. Conclusions We identified 9 novel CKD-associated loci that were enriched within high-risk-CKD, cardiovascular disease backgrounds. We identified a novel CKD-associated gene against a background of hypertension and found this gene to be highly enriched in podocytes in kidneys. This work has identified novel genetic and molecular factors associated with high-risk cardiovascular to CKD trajectories.