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.