Common genetic variants contribute to risk of transposition of the great arteries

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus

High burden of drug therapy in adult congenital heart disease : Polypharmacy as marker of morbidity and mortality

AIMS: To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD. METHODS AND RESULTS: Data of 14 138 ACHD patients from the CONCOR registry [35 (24-48) years, 49% male] and age- and sex-matched referents (1:10 ratio) were extracted from the Dutch Dispensed Drug Register for the years 2006-14. Adult congenital heart disease patients had more cardiovascular and non-cardiovascular drugs than referents (median 3 vs. 1, P < 0.001). Polypharmacy, defined as ≥5 dispensed drug types yearly, was present in 30% of ACHD and 15% of referents {odds ratio [OR] = 2.47 [95% confidence interval (CI) 2.39-2.54]}. Polypharmacy was independently associated with female sex [OR = 1.92 (95% CI 1.88-1.96)], older age [for men: OR = 2.3/10 years (95% CI 2.2-2.4) and for women: OR = 1.6/10 years (95% CI 1.5-1.6); Pinteraction < 0.001], and ACHD severity [mild: OR = 2.51 (95% CI 2.40-2.61), moderate: OR = 3.22 (95% CI 3.06-3.40), severe: OR = 4.87 (95% CI 4.41-5.38)]. Cluster analysis identified three subgroups with distinct medication patterns; a low medication use group (8-year cumulative survival: 98%), and a cardiovascular and comorbidity group with lower survival (92% and 95%, respectively). Cox regression revealed a strong association between polypharmacy and mortality [hazard ratio (HR) = 3.94 (95% CI 3.22-4.81)], corrected for age, sex, and defect severity. Polypharmacy also increased the risk of hospitalization for adverse drug events [HR = 4.58 (95% CI 2.04-10.29)]. CONCLUSION: Both cardiovascular and non-cardiovascular medication use is high in ACHD with twice as much polypharmacy compared with the matched general population. Patients with polypharmacy had a four-fold increased risk of mortality and adverse drug events. Recognition of distinct medication patterns can help identify patients at highest risk. Drug regimens need repeating evaluation to assess the appropriateness of all prescriptions. More high-quality studies are needed to improve ACHD care with more evidence-based pharmacotherapy