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

Abstract

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. 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. 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. 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.