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Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta.

ABSTRACT: Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of CoA. Previous studies have shown a rare MYH6 variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster (PCDHA delCNVs) are significantly associated with CoA and BAV. Here, analysis of a non-Icelandic white CHD cohort (n = 166) recovered rare MYH6 variants in 10.9% of CoA and 32.7% of BAV/CoA patients, yielding odds ratios of 18.6 (p = 2.5 × 10^-7) and 20.5 (p = 7.4 × 10^-5) for the respective association of MYH6 variants with CoA and BAV/CoA. In combination with the PCHDA delCNVs, they accounted for a third of CoA cases. Gene expression datasets for the human and mouse embryonic heart showed that both genes are predominantly expressed in the atria, not the ventricle. Moreover, cis-eQTLs analysis showed the PCHDA delCNV is associated with reduced atrial expression of PCHDA10, a gene in the delCNV interval. Together, these findings showed that PCDHA/MYH6 variants account for a substantial fraction of CoA cases. An atrial rather than ventricular hemodynamic model for CoA is indicated, consistent with the known early atrial functional dominance of the human embryonic heart.

SUBMITTER: Zhu W

PROVIDER: S-EPMC9032275 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta.

Zhu Wenjuan W Williams Kylia K Young Cullen C Lin Jiaunn-Huey JH Teekakirikul Polakit P Lo Cecilia W CW

Genes 20220402 4

Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of CoA. Previous studies have shown a rare <i>MYH6</i> variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster (<i>PCDHA</i> delCNVs) are significantly asso ...[more]

PMID: 35456442

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Project description:(1) ObjectiveCoarctation of the aorta (CoA) is a complex congenital heart disease. Research on differential genes in patients with CoA and other groups of aortas and investigating the pathogenesis of aorta coarctation is essential for prevention and diagnosis. (2) Methods: This study was conducted between January 2019 and December 2021. The first step was the analysis of differential genes in four groups of aortic tissues. Group A: 46 cases, coarctation specimen of the CoA group; Group B: 46 cases, anastomotic margin specimen of the CoA group; Group C: 22 cases, aortic specimen of the aortic stenosis group; and Group D: 6 cases, aorta of the necropsy group. Genomic and proteomic differences were compared in aortic specimens from different patient groups in Southwestern China. The second step the CRISPR technology was used to knock out the differential genes in mice. The phenotypes were verified using ultrasound after obtaining homozygous mice. (3) Results: Quantitative polymerase chain reaction indicated that BMP4, Smad4, STRA6, CRABP I, and COX-2 genes were statistically downregulated in group A than in other groups. STRA6 expression was 0.33 ± 0.66 in group A and 1.03 ± 0.20 in group D. The difference between the two groups was statistically significant. Western blotting revealed that BMP4, Smad4, STRA6, and CRABP I had a low expression in group A at the proteomic level. STRA6 protein was 0.13 ± 0.02 in group A and 0.48 ± 0.07 in group D. Group A decreased by 73.7 %, a statistically significant difference. Double-labeled immunofluorescence demonstrated co-expression of BMP4 and STRA6 in the tunica adventitia vasorum of group A. However, BMP4 expression in the tunica adventitia vasorum and endangium of the constricted aorta showed a double-loop sign. Primary filial generation offspring were generated using CRISPR knockout of the STRA6 gene. The first filial generation was mated with the wild-type mice to produce the second filial generation. 72.7 % homozygous mice in the fourth week of the second filial generation were detected using ultrasound, indicating a reduction in aortic diameter. (4) Conclusions: BMP4, STRA6, and COX-2 genes may be associated with CoA in Southwestern Chinese patients. STRA6 knockout, a gene that initiates the retinoic acid pathway, may lead to CoA.

Project description:BackgroundCoarctation of the aorta is a common form of critical congenital heart disease that remains challenging to diagnose prior to clinical deterioration. Despite current screening methods, infants with coarctation may present with life-threatening cardiogenic shock requiring urgent hospitalization and intervention. We sought to improve critical congenital heart disease screening by using a novel pulse oximetry waveform analysis, specifically focused on detection of coarctation of the aorta.Methods and resultsOver a 2-year period, we obtained pulse oximetry waveform data on 18 neonates with coarctation of the aorta and 18 age-matched controls hospitalized in the cardiac intensive care unit at Children's Healthcare of Atlanta. Patients with coarctation were receiving prostaglandin E1 and had a patent ductus arteriosus. By analyzing discrete features in the waveforms, we identified statistically significant differences in the maximum rate of fall between patients with and without coarctation. This was accentuated when comparing the difference between the upper and lower extremities, with the lower extremities having a shallow slope angle when a coarctation was present (p-value 0.001). Postoperatively, there were still differences in the maximum rate of fall between the repaired coarctation patients and controls; however, these differences normalized when compared with the same individual's upper vs. lower extremities. Coarctation patients compared to themselves (preoperatively and postoperatively), demonstrated waveform differences between upper and lower extremities that were significantly reduced after successful surgery (p-value 0.028). This screening algorithm had an accuracy of detection of 72% with 0.61 sensitivity and 0.94 specificity.ConclusionsWe were able to identify specific features in pulse oximetry waveforms that were able to accurately identify patients with coarctation and further demonstrated that these changes normalized after surgical repair. Pulse oximetry screening for congenital heart disease in neonates may thus be improved by including waveform analysis, aiming to identify coarctation of the aorta prior to critical illness. Further large-scale testing is required to validate this screening model among patients in a newborn nursery setting who are low risk for having coarctation.

Dataset Information

Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta.

Publications

Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta.

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