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Probing the epigenetic signatures in subjects with coronary artery disease

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Abstract

Depletion of S-adenosyl methionine and 5-methyltetrahydrofolate; and elevation of total plasma homocysteine were documented in CAD patients, which might modulate the gene-specific methylation status and alter their expression. In this study, we have aimed to delineate CAD-specific epigenetic signatures by investigating the methylation and expression of 11 candidate genes i.e. ABCG1, LIPC, PLTP, IL-6, TNF-α, CDKN2A, CDKN2B, F2RL3, FGF2, P66 and TGFBR3. The methylation-specific PCR and qRT-PCR were used to assess the methylation status and the expression of candidate genes, respectively. CAD patients showed the upregulation of IL-6, TNF-α, CDKN2A, CDKN2B, F2RL3, FGF2, P66, and TGFBR3. Hypomethylation of CDKN2A loci was shown to increase risk for CAD by 1.79-folds (95% CI 1.22–2.63). Classification and regression tree (CART) model of gene expression showed increased risk for CAD with F2RL3 > 3.4-fold, while demonstrating risk reduction with F2RL3 < 3.4-fold and IL-6 < 7.7-folds. This CAD prediction model showed the excellent sensitivity (0.98, 95% CI 0.88–1.00), specificity (0.91, 95% CI 0.86–0.92), positive predictive value (0.82, 95% CI 0.75–0.84), and negative predictive value (0.99, 95% CI 0.94–1.00) with an overall accuracy of 92.8% (95% CI 87.0–94.1%). Folate and B12 deficiencies were observed in CAD cases, which were shown to contribute to hypomethylation and upregulation of the prime candidate genes i.e. CDKN2A and F2RL3. Early onset diabetes was associated with IL-6 and TNF-α hypomethylation and upregulation of CDKN2A. The expression of F2RL3 and IL-6 (or) hypomethylation status at CDKN2A locus are potential biomarkers in CAD risk prediction. Early epigenetic imprints of CAD were observed in early onset diabetes. Folate and B12 deficiencies are the contributing factors to these changes in CAD-specific epigenetic signatures.

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Funding

Bobbala Indumathi has received the Research Fellowship (Senior Research Fellow) from the Indian Council of Medical Research (ICMR), Government of India, New Delhi.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India

    Bobbala Indumathi & Vijay Kumar Kutala

  2. Department of Cardiology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India

    Sai Satish Oruganti

  3. Sandor Speciality Diagnostics Pvt Ltd, Hyderabad, India

    Shaik Mohammad Naushad

Authors
  1. Bobbala Indumathi
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  2. Sai Satish Oruganti
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  3. Shaik Mohammad Naushad
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  4. Vijay Kumar Kutala
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Corresponding author

Correspondence to Vijay Kumar Kutala.

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Conflict of interest

BI has received Fellowship from Indian Council of Medical Research, Government of India, New Delhi. The other authors SSO, SMN, VKK declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Research Committee of Nizam’s Institute of Medical Sciences, Hyderabad, India and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Institutional Ethics Committee has approved the study (Approval Number EC/NIMS/1578/2015). Informed consent was obtained from all the study participants.

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Indumathi, B., Oruganti, S.S., Naushad, S.M. et al. Probing the epigenetic signatures in subjects with coronary artery disease. Mol Biol Rep 47, 6693–6703 (2020). https://doi.org/10.1007/s11033-020-05723-w

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  • DOI: https://doi.org/10.1007/s11033-020-05723-w

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