TY - JOUR
T1 - The 9p21 locus and its potential role in atherosclerosis susceptibility; molecular mechanisms and clinical implications
AU - Tajbakhsh, Amir
AU - Khorrami, Mohammad Sadegh
AU - Hassanian, Seyed Mahdi
AU - Aghasizade, Malihe
AU - Pasdar, Alireza
AU - Maftouh, Mina
AU - Tabatabai, Ehsan
AU - Parizadeh, Seyed Mohammad Reza
AU - Fazeli, Mostafa
AU - Ferns, Gordon A.
AU - Ghayour-Mobarhan, Majid
AU - Avan, Amir
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Cardiovascular disease (CVD) is the leading cause of global mortality. Although extensive efforts have been made to identify valid biomarkers for CVD risk, relatively few are of proven clinical utility. It is recognized that genetic factors play a major role in determining the susceptibility to CVD. Recent genome-wide-association-studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CVD. Several genetic-polymorphisms have been identified in this region that are highly associated with CVD, and these are clustered around the gene loci for CDKN2B (coding for p15ink4b), CDKN2A (coding for p16ink4a and p14ARF) and the 3′ end of CDKN2BAS, which has been termed antisense noncoding RNA in the INK4 locus (ANRIL). Targeted deletion of the 9p21 locus reduces the cardiac expression of CDKN2A/B and is the most frequent mechanism for methylthioadenosine phosphorylase inactivation, leading to a less stable plaque phenotype in the artery. Further investigations will be essential to explore the clinical utility of emerging-markers in larger and multicenter setting in order to establish their values for risk stratification or prediction a chance of future CVD events. The aim of the current review was to provide an overview of the possible molecular mechanisms by which the chromosome 9p21 locus may confer CVD risk, and the consequential clinical implications with particular emphasis on preclinical/clinical trials on genetic changes of this locus and CVD risk.
AB - Cardiovascular disease (CVD) is the leading cause of global mortality. Although extensive efforts have been made to identify valid biomarkers for CVD risk, relatively few are of proven clinical utility. It is recognized that genetic factors play a major role in determining the susceptibility to CVD. Recent genome-wide-association-studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CVD. Several genetic-polymorphisms have been identified in this region that are highly associated with CVD, and these are clustered around the gene loci for CDKN2B (coding for p15ink4b), CDKN2A (coding for p16ink4a and p14ARF) and the 3′ end of CDKN2BAS, which has been termed antisense noncoding RNA in the INK4 locus (ANRIL). Targeted deletion of the 9p21 locus reduces the cardiac expression of CDKN2A/B and is the most frequent mechanism for methylthioadenosine phosphorylase inactivation, leading to a less stable plaque phenotype in the artery. Further investigations will be essential to explore the clinical utility of emerging-markers in larger and multicenter setting in order to establish their values for risk stratification or prediction a chance of future CVD events. The aim of the current review was to provide an overview of the possible molecular mechanisms by which the chromosome 9p21 locus may confer CVD risk, and the consequential clinical implications with particular emphasis on preclinical/clinical trials on genetic changes of this locus and CVD risk.
KW - 9p21 locus
KW - Biomarkers
KW - Coronary artery disease
KW - Risk stratification
UR - http://www.scopus.com/inward/record.url?scp=85005958987&partnerID=8YFLogxK
U2 - 10.2174/1381612822666160628082453
DO - 10.2174/1381612822666160628082453
M3 - Review article
C2 - 27356775
AN - SCOPUS:85005958987
SN - 1381-6128
VL - 22
SP - 5730
EP - 5737
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
IS - 37
ER -