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The deleterious impact of a non-synonymous SNP on protein structure and function is apparent in hypertension

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Abstract

Essential hypertension (EH) is a significant health issue around the globe. The indifferent therapy regimen suggests varied physiological functions due to the lifestyle and genetic presentations of an individual. The endothelial nitric oxide synthase (NOS3) gene is a crucial vascular system marker in EH that contributes significantly to the phenotype. Hence, the present study aimed to employ the candidate gene approach and investigate the association between NOS3 single nucleotide polymorphism (SNP) E298D (G894T/rs1799983) by applying several in silico tools and validation through human samples screening. We corroborated computational findings through a case-control study comprising 294 controls and 299 patients; the 894T allele emerged significantly as the risk allele (odds ratio=2.07; P=6.38E−05). The in silico analyses highlighted the significance of E298D on the native structure and function of NOS3. The dynamics simulation study revealed that the variant type 298D caused structural destabilization of the protein to alter its function. Plasma nitrite levels were reduced in patients (P=0.0002), and the same correlated with the 894T allele. Furthermore, correlations were apparent between clinical, genotype, and routine biochemical parameters. To conclude, the study demonstrated a perceptible association between the SNP E298D and NOS3 protein structure stability that appears to have a bearing on the enzyme’s function with a deleterious role in EH.

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Acknowledgements

The volunteers of the study to consent to be part of it, the staff at GB Pant Institute of Post Graduate Medical Education and Research, New Delhi, and Director CSIR-Institute of Genomics & Integrative Biology, Delhi for cooperation.

Funding

This work was supported by ICMR, India, grant no. 5/4/1-6/14-NCD-II and GAP0119-EMS to QP.

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Author notes

  1. Rajat Subhra Das

    Present address: All India Institute of Medical Sciences, Raebareli, Uttar Pradesh, 229405, India

Authors and Affiliations

  1. Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, 110007, India

    Kavita Sharma, Kanipakam Hema, Naveen Kumar Bhatraju, Ritushree Kukreti & M. A. Qadar Pasha

  2. Department of Biotechnology, Jamia Millia Islamia, New Delhi, 110025, India

    Kavita Sharma & Mansoor Ali Syed

  3. Agartala Government Medical College, Kunjaban, Agartala, Tripura, India

    Rajat Subhra Das

  4. GB Pant Institute of Post Graduate Medical Education and Research, New Delhi, India

    Mohit Dayal Gupta

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  1. Kavita Sharma
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Contributions

KS contributed to extensive investigations that included in silico human subjects, data analyses, and interpretations, writing and correcting the manuscript. KH contributed to the in silico work and writing and corrections. NKB contributed to representing the data and corrections in the manuscript. RK and RSD contributed to sample collections, sample coding, data analysis, and manuscript writing. MDG handled the subjects and blood sample collection at the hospital, coded the samples, analyzed the data, and contributed to writing the manuscript. MAS and QP conceived, designed, and supervised the project, analyzed the data, and associated with writing and correcting the manuscript.

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Correspondence to Mansoor Ali Syed or M. A. Qadar Pasha.

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Sharma, K., Hema, K., Bhatraju, N.K. et al. The deleterious impact of a non-synonymous SNP on protein structure and function is apparent in hypertension. J Mol Model 28, 14 (2022). https://doi.org/10.1007/s00894-021-04997-6

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