Gene‐by‐gene interactions associated with the risk of conotruncal heart defects

Lyu, Chao; Webber, Daniel; MacLeod, Stewart L.; Hobbs, Charlotte A.; Li, Ming

doi:10.1002/mgg3.1010

Cited by 5 publications

(4 citation statements)

References 82 publications

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“…Previous studies have also investigated the role of DNMT SNPs in relation to the risk of CHDs. Lyu et al discovered that a SNP pair, including rs11892646 located in the DNMT3A gene and rs56219526 located in the MTRR gene, was associated with a risk of developing a conotruncal heart defect [147]. Further, a study in southeastern Iran found that the AG (heterozygous) genotype at rs6999593 in DNMT1 was strongly correlated with the susceptibility to and severity of congenital heart diseases, notably ventricular septal defects and TOF, suggesting its potential as a biomarker of disease [148].…”

Section: Dnmts In Congenital Heart Defects and Paediatric Cvdmentioning

confidence: 99%

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases

Emon,

Al-Qazazi,

Rauh

et al. 2023

Cells

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DNA methylation is an epigenetic mechanism that regulates gene expression without altering gene sequences in health and disease. DNA methyltransferases (DNMTs) are enzymes responsible for DNA methylation, and their dysregulation is both a pathogenic mechanism of disease and a therapeutic target. DNMTs change gene expression by methylating CpG islands within exonic and intergenic DNA regions, which typically reduces gene transcription. Initially, mutations in the DNMT genes and pathologic DNMT protein expression were found to cause hematologic diseases, like myeloproliferative disease and acute myeloid leukemia, but recently they have been shown to promote cardiovascular diseases, including coronary artery disease and pulmonary hypertension. We reviewed the regulation and functions of DNMTs, with an emphasis on somatic mutations in DNMT3A, a common cause of clonal hematopoiesis of indeterminant potential (CHIP) that may also be involved in the development of pulmonary arterial hypertension (PAH). Accumulation of somatic mutations in DNMT3A and other CHIP genes in hematopoietic cells and cardiovascular tissues creates an inflammatory environment that promotes cardiopulmonary diseases, even in the absence of hematologic disease. This review summarized the current understanding of the roles of DNMTs in maintenance and de novo methylation that contribute to the pathogenesis of cardiovascular diseases, including PAH.

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Section: Dnmts In Congenital Heart Defects and Paediatric Cvdmentioning

confidence: 99%

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases

Emon,

Al-Qazazi,

Rauh

et al. 2023

Cells

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“…A better understanding of the genes and pathways influencing progenitor cell behavior would improve our understanding of CTD etiology. A few studies have directly interrogated epistasis in the folate metabolism pathway as a risk factor for CTD [ 30 ], however to our knowledge, no CTD studies have performed a more comprehensive analysis of interaction across many genetic variants, genes, or pathways.…”

Section: Introductionmentioning

confidence: 99%

Gene-Interaction-Sensitive enrichment analysis in congenital heart disease

et al. 2022

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Background Gene set enrichment analysis (GSEA) uses gene-level univariate associations to identify gene set-phenotype associations for hypothesis generation and interpretation. We propose that GSEA can be adapted to incorporate SNP and gene-level interactions. To this end, gene scores are derived by Relief-based feature importance algorithms that efficiently detect both univariate and interaction effects (MultiSURF) or exclusively interaction effects (MultiSURF*). We compare these interaction-sensitive GSEA approaches to traditional χ2 rankings in simulated genome-wide array data, and in a target and replication cohort of congenital heart disease patients with conotruncal defects (CTDs). Results In the simulation study and for both CTD datasets, both Relief-based approaches to GSEA captured more relevant and significant gene ontology terms compared to the univariate GSEA. Key terms and themes of interest include cell adhesion, migration, and signaling. A leading edge analysis highlighted semaphorins and their receptors, the Slit-Robo pathway, and other genes with roles in the secondary heart field and outflow tract development. Conclusions Our results indicate that interaction-sensitive approaches to enrichment analysis can improve upon traditional univariate GSEA. This approach replicated univariate findings and identified additional and more robust support for the role of the secondary heart field and cardiac neural crest cell migration in the development of CTDs.

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“…Congenital heart defects comprise some of the most common, serious, and clinically important groups/types of birth defects [ 1 , 2 , 3 ]. These defects consist of a heterogenous group of structural heart malformations (i.e., conotruncal heart defects that affect the cardiac outflow tract) that are thought to have at least some shared genetic basis [ 4 , 5 , 6 , 7 ]. Some conotruncal heart defects involve a deviation from the normal position of the origin of the aorta and pulmonary trunk, in which case the great vessels are said to be transposed.…”

Section: Introductionmentioning

confidence: 99%

“…In general, both common and rare inherited variants are thought to play a role in conotruncal defects [ 7 , 13 , 14 ]. However, prior genome-wide association studies (GWAS) of conotruncal heart defects, both among cases with and without 22q11.2DS, have had somewhat limited success in identifying significant associations.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States

Oluwafemi

Musfee

Mitchell

et al. 2021

Genes

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Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.

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Gene‐by‐gene interactions associated with the risk of conotruncal heart defects

Cited by 5 publications

References 82 publications

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases

Gene-Interaction-Sensitive enrichment analysis in congenital heart disease

Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States

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