Common genetic variants improve risk stratification after atrial switch operation for transposition of the great arteries
Authors: Woudstra O , Skoric-Milosavljevic D , Post M C , Meijboom F J , Jongbloed M R M , Van Dijk A P J , Konings T C , Bezzina C R , Mulder B J M , Bouma B J , Tanck M W T 
Published: October 2021

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&lt;1x10–5 could be of added value to a recently published clinical risk score (included clinical factors: age &gt;30 years, prior ventricular arrhythmia, age &gt;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&lt;1x10–8) and 18 loci marked by 20 SNPs that reached the suggestive threshold (p&lt;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 (&lt;5%) and 6 to high (&gt;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 &lt;5% or &gt;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).