Europace. 2023 Nov 15:euad320. doi: 10.1093/europace/euad320. Online ahead of print.
BACKGROUND AND AIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4,137 serum proteins and incident AF in the prospective population-based AGES/Reykjavik study.
METHODS: The study included 4,765 participants, of whom 1,172 developed AF. Cox proportional hazards regression models were fitted for 4,137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent AUC-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models.
RESULTS: The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both NT-proBNP-dependent (e.g., CHST15, ATP1B1, SVEP1) and independent components (e.g., ASPN, AKR1B, LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. NT-proBNP improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all timepoints.
CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. NT-proBNP is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.