Ansari, J Liver: Dis Transplant 2012, 1:1 http://dx.doi.org/10.4172/2325-9612.1000e101
Journal of Liver: Disease & Transplantation
Editorial
a SciTechnol journal
Defining Single Nucleotide Polymorphic (SNP) Variants Role of Human Angiotensinogen in Liver Fibrosis Rais A. Ansari1* 1
College of Pharmacy, Nova Southeastern University, Florida, USA
The sequencing of human genome has lead to define the variations among individuals, which is quite astonishing. With the advent of single nucleotide variants among genes, that is believed to be present in every 1.0 kb in human genome, determining the effects of these variants on biological process has been a daunting task. Utilizing the modern molecular biological techniques, the role(s) of the SNPs in promoter elements has been defined in several genes. However, the SNPs, which are part of the coding sequences of genes, have been difficult to define. Models to define the messenger RNA stability (Mfold analysis) have been developed. However, such a correlation in terms of end product as protein is still confusing. A number of attempts have been made to decipher the gene function of individual SNP variant, what is referred as “allelic expression variant” of haplotype as compared to wild type. In this context it is noteworthy that allelic variants have found to possess different activities. Angiotensinogen gene is the precursor of several biologically active peptides. The octapeptide (angiotensin II, [Ang II]) is implicated in liver fibrosis that can be caused by many agents, including alcohol. Not all chronic alcoholics proceed to fibrosis, pointing towards individual variations. Blocking the action of Ang II has been shown to inhibit the progression of fibrosis, both in animal models and in several human studies. However, not been able to control the level of Ang II but blocking its action results in the production of other peptides like Ang 1-7 and Ang IV, thus further complicating the matter. Ang II is also a vasopressor molecule whose
activity is increased in hypertensive individuals. To control Ang II action, a wise approach should be to control the precursor level itself. Regulation of gene(s) from SNP can result into different activity of a gene product. Human angiotensinogen carries several SNPs of which, M235T (235T) remains in linkage disequilibrium with -6A/G (-6A) and has been observed among hypertensives, suggestive of higher level as demonstrated by Jeunemaitre. In addition, several other SNPs -217A (-217A/G), -793A (-793 A/G), -1074T (-1074T/G) and also SNPs in distal promoter have been linked to hypertension and higher AGT activity. Knowing the role of these regulatory SNPs might define the human susceptibility to liver fibrosis among chronic alcoholics. In order to define the roles of these SNPs requires developing models to address the problem. One method is to follow the expression of a gene from variant promoter in a transgenic model. Several transgenic studies have been performed on the role of haplotype mediated AGT regulation. Initial study [1,2] indicated no change in expression of human angiotensinogen in transgenic mice. However, in recent past, two studies [3,4] described increased expression from aforementioned SNPs of hAGT. These studies relate to the role of angiotensinogen in blood pressure regulation. These studies did not investigate the role of angiotensinogen expression from SNPs for liver fibrosis. There is an urgent need to develop transgenic animal models to study the role of SNP of hAGT in liver fibrogenesis. References 1. Grobe JL, Dickson ME, Park S, Davis DR, Born EJ, et al. (2010) Cardiovascular consequences of genetic variation at -6/235 in human angiotensinogen using “humanized” gene-targeted mice. Hypertension 56: 981-987. 2. Cvetkovic B, Keen HL, Zhang X, Davis D, Yang B, et al. (2002) Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse. Physiol Genomics 11: 253-262. 3. Jain S, Tillinger A, Mopidevi B, Pandey VG, Chauhan CK, et al. (2010) Transgenic mice with -6A haplotype of the human angiotensinogen gene have increased blood pressure compared with -6G haplotype. J Biol Chem 285: 41172-41186. 4. Jain S, Vinukonda G, Fiering SN, Kumar A (2008) A haplotype of human angiotensinogen gene containing -217A increases blood pressure in transgenic mice compared with -217G. Am J Physiol Regul Integr Comp Physiol 295: R1849-1857.
*Corresponding author: Rais A Ansari, Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Terry Building, Rm 1344, Nova Southeastern University, 3200 S University Drive, Fort Lauderdale, FL 33328, USA, Tel (954)-262-1344; E-mail:
[email protected] Received: June 07, 2012 Accepted: June 08, 2012 Published: June 10, 2012
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