Abstract 4135307: Integrating genomics and proteomics to identify causal proteins and biologic pathways for incident atrial fibrillation in chronic kidney disease

Introduction/ Background: Individuals with chronic kidney disease (CKD) are at an increased risk for developing atrial fibrillation (AF). Research Objective: By integrating genomics and proteomics, we sought to identify proteins and biologic pathways causally linked to the development of AF in the CKD population. Methods / Approach: We measured 4638 unique plasma proteins using SomaScan v.4.0 in participants (ppts) with CKD and no prior AF from 2 cohorts: Chronic Renal Insufficiency Cohort (CRIC, n=2654) and Atherosclerosis Risk in Communities Cohort (ARIC, n=1326). Associations of individual proteins with incident AF were analyzed using Cox regression after adjustment for demographics, comorbidities, and kidney function. Among proteins independently associated with incident AF in both cohorts, we tested for causality using two-sample Mendelian Randomization (MR). Previously published genome wide association studies (GWAS) were used to identify both protein quantitative loci (cis-pQTL) and summary statistics for incident AF. We then used Ingenuity Pathway Analysis to compare proteins and pathways associated with both incident AF and an increase in left atrial (LA) size across serial echocardiograms in CRIC. Results / Data: Over the 5-year analytic period, incident AF occurred in 150 ppts from CRIC and 140 ppts from ARIC. Eight proteins were independently associated with AF in both cohorts: NT-proBNP, SVEP1, TAGLN, TFF3, WAP4, MMP-12, CILP2 and NELL-1. Of these, 3 were significant in MR analysis (Figure 1): CILP2 and MMP-12 maintain structural integrity of the extracellular matrix in the heart and modulate the fibrotic response; NELL-1 is responsible for cell signaling in kidney disease and cardiovascular development. In addition, leading biologic pathways implicated in both development of AF and increase in LA size included systemic fibrosis (p=1.7x10 -4 for AF and 2.3 x10 -4 for LA); regulation of insulin-like growth factor (p=2.3 x10 -4 for AF and p=4.3 x10 -7 for LA) and extracellular matrix degradation (p=5.5 x10 -4 for AF and p=4.2 x10 -4 for LA). Conclusions: Trans-omics analyses identified 3 proteins causally associated with developing AF in the CKD population. Also, several pathways involved with cardiac remodeling and fibrosis are common to the development of AF and LA remodeling.