Title:The 9p21 Locus and its Potential Role in Atherosclerosis Susceptibility; Molecular Mechanisms and Clinical Implications
Volume: 22
Issue: 37
Author(s): Amir Tajbakhsh, Mohammad Sadegh Khorrami, Seyed Mahdi Hassanian, Malihe Aghasizade, Alireza Pasdar, Mina Maftouh, Ehsan Tabatabai, Seyed Mohammad Reza Parizadeh, Mostafa Fazeli, Gordon A. Ferns, Majid Ghayour-Mobarhan and Amir Avan
Affiliation:
Keywords:
Coronary artery disease, risk stratification, biomarkers, 9p21 locus.
Abstract: 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.