Association of the angiotensinogen gene polymorphism with atherosclerosis and its risk traits in the Saudi population

Abstract

BackgroundAngiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals.MethodsLinkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System.ResultsSix variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ2 = 7.02; p = 0.0081) and another GGCGGAGT (χ2 = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2 = 5.66; p = 0.017) and ATTGAGAC (χ2 = 5.93; p = 0.015), obesity with GGCGGAGT (χ2 = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ2 = 6.68; p = 0.010) and GGTGGGAT (χ2 = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD.ConclusionThese results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.

Polymorphism in miR-31 and miR-584 binding site in the angiotensinogen gene differentially influences body fat distribution in both sexes

“…As AGT-increasing ?11525 C/A (rs7079) A allele (Mopidevi et al 2013) is only present in combination with the major allele of the three eQTL, the effects on AGT secretion are apparently contradictory and rs7079 CC homozygotic genotype responding to miR-31 and miR-584 binding thus compensate the overproduction of AGT caused by promoter variant. This LD can also explain the findings of Al-Najai et al where the C allele (G in antiparallel strain) and CC genotype were associated with a higher risk of hypertension (Al-Najai et al 2013). …”

“…The only study so far evaluating the effect of miRNA binding site ?11525 C/A (rs7079) on BMI was performed by Al-Najai et al In accordance with our results, no association with BMI was found; however, the polymorphism was associated with hypertension and coronary artery disease. ?11525 C/A (rs7079) was also found to be in LD with other polymorphisms in the AGT gene (Al-Najai et al 2013). Other studies focused on other polymorphisms of the AGT gene that are in LD with rs7079 (International HapMap Consortium 2003), with similar results.…”

The C4280A (rs5705) gene polymorphism of the renin (REN) gene is associated with risk of developing coronary artery disease, but not with restenosis after coronary stenting

“…On the other hand, the angiotensinogen is a key Experimental and Molecular Pathology 99 (2015) 128-132 component of RAS, it is cleaved by renin to produce angiotensin I. AGT gene presents five important single nucleotide polymorphisms (SNPs), three in the promoter region [− 6 ANG (rs5051), − 217 GNA (rs5049) and − 532 CNT (rs5046)] and two in the exon 2 [C4072T (rs699) and C3889T (rs4762)]. These SNPs have been associated with risk of developing hypertension, acute myocardial infarction, vascular disease, coronary artery disease, atherosclerosis, and coronary artery bypass graft in several populations (Inoue et al, 1997;Karayannis et al, 2010;Ragia et al, 2010;Mehri et al, 2011;Dzielinska et al, 2011;Abd El-Aziz et al, 2012;Al-Najai et al, 2013;Brugts et al, 2011). On the other hand, the REN gen presents two relevant SNPs, one in the intron 4 [G5795T (rs5707)] and one in the exon 2 [C4280A (rs5705)].…”

Risk given byAGTpolymorphisms in inducing susceptibility to essential hypertension among isolated populations from a remote region of China: A case-control study among the isolated populations

“…The T-allele of rs3789679 was found to be significantly associated with the increased risk of atherosclerosis and obesity involved with hypertension among the Saudi population. 58 The haplotype rs5051A, rs3789679C, rs2004776A, rs4762C, rs3789670G, rs2493132G, rs2478523C, rs7079C was found to be associated with the risk of myocardial infarction among the Europeans. 118 Our present study among both Hani and Yi populations showed no association of these two polymorphisms with EH.…”