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

KEY POINTS: Using proteomics and Mendelian randomization, we identified causal proteins for the development of atrial fibrillation in patients with CKD. Immunologic function, cell growth, and neural development were common biologic pathways underlying atrial fibrillation and left atrial enlargement. Machine learning led to a nine-protein risk model that had a similar predictive performance for incident atrial fibrillation as clinical risk scores. BACKGROUND: CKD is strongly associated with atrial fibrillation. Understanding the biologic pathways for this association and creating predictive models have been challenging. Left atrial enlargement is a substrate for atrial fibrillation, but any overlap between biomarkers of atrial fibrillation and left atrial enlargement in patients with CKD is unknown. METHODS: We evaluated 4590 plasma proteins with SomaScan in two cohorts of adult patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC; n =2654) and the Atherosclerosis Risk in Communities cohort (ARIC; n =1326). 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. Finally, we developed and validated a multiprotein risk score for incident atrial fibrillation in the CKD population. RESULTS: Over 5 years, incident atrial fibrillation occurred among 150 patients in the CRIC and 140 in the ARIC cohort. We identified three proteins causally linked to incident atrial fibrillation: neural EGF like‑like protein 1, cartilage intermediate layer protein 2, and matrix metallopeptidase 12. Pathway analysis revealed an overlap in eight of the top ten canonical pathways for incident atrial fibrillation and left atrial enlargement. A risk model for incident atrial fibrillation composed of proteins had annualized areas under the receiver-operating characteristic curve over 5 years ranging from 0.65 to 0.76, a performance similar to the Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation (CHARGE-AF) clinical risk score. CONCLUSIONS: This study identified causal proteins and biologic mechanisms underlying incident atrial fibrillation in CKD. A proteomic risk score for incident atrial fibrillation in CKD performed similarly to the CHARGE-AF clinical risk score.