Analysis in silico of the single nucleotide polymorphism G–152A in the promoter of the angiotensinogen gene of Indonesian patients with essential hypertension

• Published in: Asian biomedicine Vol. 12; no. 1; pp. 15 - 25
• Main Authors: Susanto, Akhiyan Hadi, Rohman, Mohammad Saifur, Utomo, Didik Huswo, Lukitasari, Mifetika
• Format: Journal Article
• Language: English
• Published: Sciendo 31.12.2018
• Subjects: angiotensinogen; essential hypertension; genetic promoter region; hypoxia-inducible factor 1; molecular docking; simulation; single nucleotide polymorphism
• ISSN: 1875-855X; 1875-855X
• DOI: 10.1515/abm-2018-0027

Abstract Background Single nucleotide polymorphism (SNP) G–152A (rs11568020) in the promoter of the angiotensinogen gene ( AGT ) may modulate its transcription. Translation of mRNA to angiotensinogen induces hypertension during hypoxia. The G allele at position –152 is located within the hypoxia-response element (HRE) transcription factor-binding site for the hypoxia-inducible factor 1 (HIF-1) heterodimer. However, the function of the –152 site in HIF-1 binding is not fully elucidated. Objectives To determine the frequency of SNP G–152A in Indonesian patients with hypertension and the function of this SNP. Methods We determined the frequency of the SNP in 100 patients by direct sequencing, and the influence of SNP G–152A on predicted binding of HIF-1 to the HRE using a docking approach in silico. Results The AGT promoter in our patients had genetic variants –152G and –152A (19:1). Predicted binding indicated that HIF-1 directly contacts the major groove of the G allele, but not the A allele. Scoring according to weighted sum High Ambiguity Driven biomolecular DOCKing showed that the score for the A allele–HIF-1 complex (–47.1 ± 6.9 kcal/mol) was higher than that for the G allele–HIF-1 complex (–94.6 ± 14.1 kcal/mol), indicating more favorable binding of HIF-1 to the G allele. Conclusions SNP G–152A reduces the favorability of binding of HIF-1 to the HRE. The occurrence of this SNP in the AGT promoter of Indonesian patients with essential hypertension suggests that the G allele is a genetic susceptibility factor in hypertension regulated by HIF-1.