Abstract 16768: Common Autosomal Variants Modify the Penetrance of Left-sided Cardiac Lesions in Turner Syndrome
Background: Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Left-sided congenital cardiac lesions (LSL), primarily bicuspid aortic valve (BAV), coarctation and thoracic aortic aneurysms leading to aortic dissections (TAAD), are 30-50 times more frequent in TS than in the general population. We hypothesized that common autosomal variants may interact with the reduced dosage of sex chromosome genes to cause the increased prevalence of LSL in TS.
Methods: 450 patients with a clinical diagnosis of TS (mean age 28±16 years, 65% 45,X karyotype, 43% BAV, 18% coarctation, 36% ascending aortic dilation > 20 mm/m2) were genotyped on Illumina Omni-Express arrays. After exclusions for non-European ancestry or incomplete data, genome-wide associations of single SNPs with LSL were evaluated using logistic regression with two principal components and imputed against 1000 Genomes Phase 3 data using SHAPEIT and IMPUTE2. METAL was used for meta-analysis of five different cohorts (Harvard, Mayo Clinic, Second University of Naples, National Institutes of Health, National Registry of Genetically Triggered Aneurysms and Cardiovascular Conditions).
Results: Eleven genotyped SNPs in a 70 Kb haplotype block centered on the HMGXB4 gene in 22q12.3 were consistently associated with BAV and/or coarctation in all cohorts (166 cases, 203 controls, min P=1.1x10-6, OR=2.3 (95% CI, 1.6-3.2), lambda=1.02). Seven SNPs in the MFN1 gene in 3q26.33 were associated with ascending aortic dilation (min P=4.3.x10-7, OR=2.8 (95% CI, 1.8-4.2). The proteins encoded by HMGXB4 and MFN1 regulate myocardin and Notch1, which have been implicated in TAAD and BAV. No X or pseudoautosomal SNPs were significantly associated with LSL.
Conclusions: Pending replication in independent cohorts, our results indicate that autosomal variants affecting cardiac developmental genes may serve as genetic modifiers of LSL in TS.
- Congenital heart disease
- Aortic valve
- Genome-wide association studies (GWAS)
- Aortic coarctation
- Thoracic Aorta
Author Disclosures: S. Prakash: None. A. Lin: None. L. Perrone: None. G. Limongelli: None. H. Michelena: None. S. Lemaire: None. S. Body: None. D. Milewicz: Research Grant; Significant; NIH, Bugher Fund, John Ritter Foundation. Consultant/Advisory Board; Significant; Marfan Foundation, John Ritter Foundation, Genetic Aortic Disease Association.
- © 2016 by American Heart Association, Inc.