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

Abstract

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.