Meta-analysis reveals differential gene expression in tetralogy of Fallot versus controls

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY Birth Defects Research Pub Date : 2023-12-25 DOI:10.1002/bdr2.2293

Sarah Mae Voskamp, Maya Alexis Hammonds, Thomas M. Knapp, Ashley L. Pekmezian, Dexter Hadley, Jennifer S. Nelson

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Abstract

Objectives

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect in the United States. We aimed to identify genetic variations associated with TOF using meta-analysis of publicly available digital samples to spotlight targets for prevention, screening, and treatment strategies.

Methods

We used the Search Tag Analyze Resource for Gene Expression Omnibus (STARGEO) platform to identify 39 TOF and 19 non-TOF right ventricle tissue samples from microarray data and identified upregulated and downregulated genes. Associated gene expression data were analyzed using ingenuity pathway analysis and restricted to genes with a statistically significant (p < .05) difference and an absolute experimental log ratio >0.1 between disease and control samples.

Results

Our analysis identified 220 genes whose expression profiles were significantly altered in TOF vs. non-TOF samples. The most striking differences identified in gene expression included genes FBXO32, PTGES, MYL12a, and NR2F2. Some top associated canonical pathways included adrenergic signaling, estrogen receptor signaling, and the role of NFAT in cardiac hypertrophy. In general, genes involved in adaptive, defensive, and reparative cardiovascular responses showed altered expression in TOF vs. non-TOF samples.

Conclusions

We introduced the interpretation of open “big data” using the STARGEO platform to define robust genomic signatures of congenital heart disease pathology of TOF. Overall, our meta-analysis results indicated increased metabolism, inflammation, and altered gene expression in TOF patients. Estrogen receptor signaling and the role of NFAT in cardiac hypertrophy represent unique pathways upregulated in TOF patients and are potential targets for future pharmacologic treatments.

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元分析显示法洛氏四联症与对照组的基因表达存在差异。

目标：法洛氏四联症（TOF）是美国最常见的紫绀型先天性心脏缺陷。我们旨在利用对公开数字样本的荟萃分析确定与 TOF 相关的遗传变异，从而发现预防、筛查和治疗策略的目标：我们使用基因表达总库搜索标签分析资源（STARGEO）平台从微阵列数据中识别了39个TOF和19个非TOF右心室组织样本，并确定了上调和下调基因。相关基因表达数据采用巧妙通路分析法进行分析，并仅限于疾病样本与对照样本之间具有统计学意义（P 0.1）的基因：结果：我们的分析确定了 220 个基因，这些基因在 TOF 与非 TOF 样本中的表达谱发生了显著变化。最明显的基因表达差异包括 FBXO32、PTGES、MYL12a 和 NR2F2。一些最重要的相关典型通路包括肾上腺素能信号传导、雌激素受体信号传导以及 NFAT 在心脏肥大中的作用。总的来说，参与适应性、防御性和修复性心血管反应的基因在TOF样本与非TOF样本中的表达发生了改变：我们利用 STARGEO 平台对开放的 "大数据 "进行了解读，从而确定了 TOF 先天性心脏病病理的强大基因组特征。总体而言，我们的荟萃分析结果表明，TOF患者的代谢、炎症和基因表达均发生了改变。雌激素受体信号转导和NFAT在心脏肥大中的作用代表了TOF患者体内上调的独特通路，是未来药物治疗的潜在靶点。

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来源期刊

Birth Defects Research Medicine-Embryology

CiteScore

3.60

自引率

9.50%

发文量

153

期刊介绍： The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks. Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.