Placental DNA methylation changes for the detection of tetralogy of Fallot

Ray Bahado-Singh, Sangeetha Vishweswaraiah, Nitish Kumar Mishra, Chittibabu Guda, Uppala Radhakrishna
Ultrasound in Obstetrics & Gynecology 2019 April 12

OBJECTIVES: To determine whether the methylation level of cytosine nucleotides in placental DNA can be used to predict Tetralogy of Fallot (TOF) and provide insights into its mechanism of development.

METHODS: The Illumina HumanMethylation450 BeadChips assay was used to measure cytosine ('CpG' or 'cg') methylation (i.e. the addition 'methyl group') levels at loci throughout the placental genome. Area under the ROC curve (AUC) and 95% CI was calculated for TOF detection for CpG loci with significant methylation changes in TOF. False Discovery Rate (FDR) p-value <0.05 was considered significant. Ingenuity Pathway Analysis (IPA) (QIAGEN) was used to identify gene pathways that were significantly overexpressed and thus altered in TOF compared to controls.

RESULTS: We used 8 cases of isolated TOF and 10 unaffected newborn placentas. We found a total of 166 significantly differentially methylated CpG loci: TOF versus controls, in 166 separate genes. These biomarkers demonstrated from fair up to excellent individual predictive accuracy for TOF detection, with AUC ROC ≥ 0.75 (FDR p-value <0.001). The following CpG loci [gene] had high predictive accuracy: cg05273049 [ARHGAP22]: AUC (95% CI) = 1.0 (1.0, 1.0), cg02540011 [CDK5]: AUC (95% CI) = 0.96 (0.87, 1.0), cg08404201 [TRIM27] AUC (95% CI) = 0.95 (0.84, 1.0), cg00687252 [IER3]: AUC (95% CI) = 0.95 (0.84, 1.0). Pathway Analysis revealed over-representation (dysregulation) of gene pathways involved in normal cardiac development. Examples include: Cardiomyocyte Differentiation via BMP Receptors, Cardiac Hypertrophy Signaling, Role of NFAT in Cardiac Hypertrophy. Cardiac hypertrophy is an important feature of TOF.

CONCLUSION: Placental cytosine methylation yielded accurate markers for TOF detection and provided mechanistic information on TOF development. Our work appears to confirm a central role of epigenetic changes and of the placenta in the development of TOF. This article is protected by copyright. All rights reserved.

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