Integrating Genomics and Proteomics to Identify Causal Proteins and Biologic Pathways for Incident Atrial Fibrillation in CKD

BACKGROUND: Chronic kidney disease (CKD) is strongly associated with atrial fibrillation. Understanding the biological pathways for this association and creating predictive models has been challenging. Left atrial enlargement is a substrate for atrial fibrillation but any overlap between biomarkers of atrial fibrillation and left atrial enlargement in individuals with CKD is unknown. METHODS: We evaluated 4,590 plasma proteins with SomaScan in two cohorts of adults with CKD: the Chronic Renal Insufficiency Cohort (CRIC, n=2,654) and the Atherosclerosis Risk in Communities Cohort (ARIC, n=1,326). Using Mendelian randomization, we identified proteins along the causal pathway to atrial fibrillation. We also identified proteins and corresponding pathways associated with larger echocardiographic left atrial size, a recognized substrate for atrial fibrillation. Lastly, we developed and validated a multi-protein risk score for incident atrial fibrillation in the CKD population. RESULTS: Over five years, incident atrial fibrillation occurred among 150 individuals in CRIC and 140 in ARIC. We identified three proteins causally linked to incident atrial fibrillation: neural epidermal growth factor like (NEL)-like protein 1 (NELL1), cartilage intermediate layer protein 2 (CILP2), and matrix metallopeptidase 12 (MMP12). Pathway analysis revealed an overlap in 8 of the top 10 canonical pathways for incident atrial fibrillation and left atrial enlargement. A risk model for incident atrial fibrillation comprised of proteins had annualized AUCs over 5 years ranging from 0.65 to 0.76, a performance similar to the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE AF) clinical risk score. CONCLUSIONS: This study identified causal proteins and biological mechanisms underlying incident atrial fibrillation in CKD. A proteomic risk score for incident atrial fibrillation in CKD performed similarly to CHARGE-AF.