Common genetic variants improve risk stratification after atrial switch operation for transposition of the great arteries

Abstract

Abstract Background Current clinical risk scores are able to predict late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but a large heterogeneity in clinical course remains. Purpose To study whether common genetic factors are predictive of outcome and provide added value to an existing clinical risk score in TGA-AtrSO patients. Methods This multicenter study examined the association of genome-wide single-nucleotide polymorphisms (SNPs) in TGA-AtrSO patients with a combined clinical endpoint: time to symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Furthermore, we evaluated whether a polygenic risk score (PRS) constructed of independent single-nucleotide polymorphisms (SNPs) with a p<1x10–5 could be of added value to a recently published clinical risk score (included clinical factors: age >30 years, prior ventricular arrhythmia, age >1 year at repair, ≥moderate right ventricular dysfunction, severe tricuspid regurgitation, and ≥mild left ventricular dysfunction). Results We followed 133 patients (age at inclusion 28 [IQR 24–35] years, 59% male) for 13 [IQR 8–16] years. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one locus that reached genome-wide significance (p<1x10–8) and 18 loci marked by 20 SNPs that reached the suggestive threshold (p<1x10–5). The constructed PRS remained an independent predictor after correction for the clinical score (HR=1.21/point increase [95% CI 1.13–1.29], p=3x10–10). While the clinical risk score indicated intermediate (5–20%) 5-year risk of events in 52 patients (39%), the combined risk score (clinical score + PRS) reclassified 35 patients to low (<5%) and 6 to high (>20%) risk. Observed 5-year event-free survival based on the combined score remained 100% for low-risk patients, compared to 23% and 64% in intermediate and high-risk patients, respectively. This resulted in improved risk stratification with the combined risk score vs the clinical risk score alone (p=2x10–16, C-statistic 0.95 vs 0.85). Conclusions Genetic factors explain some of the variation in clinical course of TGA-AtrSO patients and improve risk stratification. In the heterogeneous group of patients with a clinical score indicating intermediate risk, the combined model could classify 67% of patients more accurately to <5% or >20% risk. These data argue for more research into the impact of genetics on clinical outcome in adult congenital heart disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Figure 1. Risk stratification of predicted 5-year risk of events based on the clinical model versus the combined model (clinical risk score + polygenic risk score).