PHACTR1 u kardiovaskularnim bolestima: od studija asocijacije na celokupnom genomu do funkcionalnih studija

Gen za regulator protein fosfataze i aktina 1 (eng. protein phosphatase and actin regulator 1, PHACTR1) je ušao u žižu interesovanja kada je u studijama asocijacije na celokupnom genomu pokazao značajnu povezanost sa različitim fenotipovima kardiovaskularnih bolesti (KVB). Nekoliko validacionih studija je istaklo uticaj varijanti gena PHACTR1 na koronarnu bolest, infarkt miokarda, kalcifikaciju arterija i disekciju cervikalnih arterija. Vodeća varijanta rs9349379 je pokazala protektivan ili štetan efekat na KVB, jasno definišući podelu na bolesti u čijoj osnovi je ateroskleroza i one do kojih dovode drugi procesi. U srpskoj populaciji, analiziran je haplotipski efekat tri varijante gena PHACTR1, rs9349379 A/G, rs2026458 C/T i rs2876300 A/G, na aterosklerozu karotidnih i koronarnih arterija, kao i njihov efekat na transkripciju gena PHACTR1 u karotidnom plaku i mononuklearnim ćelijama periferne krvi. Na ovom polju se vodi dugogodišnja polemika oko toga da li je varijanta rs9349379 povezana sa KVB preko funkcionalnog uticaja na PHACTR1 ili na gen za endotelin 1, EDN1. U funkcionalnim studijama je predloženo nekoliko mehanizama delovanja PHACTR1 na kardiovaskularni sistem imajući u vidu da interaguje sa dva esencijalna ćelijska proteina, protein fosfatazom 1 i G-aktinom. U ovom radu dat je pregled dosadašnjih istraživanja PHACTR1 u KVB.Protein phosphatase and actin regulator 1 (PHACTR1) gene entered the spotlight when it showed a significant association with various phenotypes of cardiovascular diseases (CVD) in genome-wide association studies. Several validation studies have highlighted the impact of PHACTR1 variants on coronary artery disease, myocardial infarction, arterial calcification, and cervical artery dissection. The leading PHACTR1 variant rs9349379 showed a protective or pathogenic effect on CVD, clearly defining the division into atherosclerosis- based diseases and those caused by other processes. In Serbian population, analysis has been conducted on haplotype effect of three PHACTR1 gene variants, rs9349379 A/G, rs2026458 C/T and rs2876300 A/G, on carotid and coronary atherosclerosis, as well as their effect on PHACTR1 mRNA level in carotid plaque tissue and peripheral blood mononuclear cells. However, there is a long-standing controversy about whether the rs9349379 variant is associated with CVD through a functional effect on PHACTR1 or on the endothelin 1 gene, EDN1. Several mechanisms of action of PHACTR1 on the cardiovascular system have been proposed in functional studies, considering that it interacts with two essential cellular proteins, protein phosphatase 1 and G-actin. This paper provides an overview of the up to date research conducted on the PHACTR1 in CVD

PRO12ALA GENE POLYMORPHISM IN THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA AS A RISK FACTOR FOR THE ONSET OF TYPE 2 DIABETES MELLITUS IN THE SERBIAN POPULATION

Abstract- The peroxisome proliferator-activated receptor gamma (PPARγ) is a gene candidate for the onset of type 2 diabetes mellitus (T2DM). We investigated the association of the PPARγ Pro12Ala gene with the onset of T2DM for the first time in the Serbian population. The study population consisted of 197 controls and 163 T2DM patients. The 12Ala allele tended to be more frequent in the group of T2DM patients (0.11) compared to the control subjects (0.09). The results from this study indicate that the PPARγ2 12Ala allele presents a non-significant risk factor for T2DM development in the Serbian population

MMP-1 and -3 haplotype is associated with congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of progressive chronic kidney disease that may lead to end-stage renal disease and renal replacement therapy in childhood. Altered expression or activity of matrix metalloproteinases (MMPs) have been found in CAKUT. The MMP-1, -3, and -8 polymorphisms studied here are located in the gene promoters and alter expression. Our aim was to investigate associations of MMP polymorphisms, solely and in haplotypes, with CAKUT in children. A case-control study with 101 pediatric patients and 281 controls was performed. The MMP-1 (-1607 1G/2G), -3 (5A/6A), and -8 (-799 C/T) genotypes were determined by PCR-restriction fragment length polymorphism. We found statistically significant associations of MMP-3 5A/6A polymorphism (p LT 0.0001) and 1G(-1607)-6A haplotype, with no preferences for MMP-8 -799C or T alleles, with CAKUT (OR = 2.93, 95 % CI 1.43-5.98, adjusted for gender, p = 0.003) and with obstructive uropathies in a subgroup of patients (OR = 4.57, 95 % CI 2.74-7.61, adjusted for gender, p LT 0.0001). MMP-3 genotypes and MMP-3 and -1 haplotypes encompassing either MMP-8 -799C or T alleles were associated with CAKUT and obstructive uropathies in pediatric patients. Still, functional and association studies are needed to elucidate evident roles of MMPs in CAKUT