HMGA1 is a novel candidate gene for myocardial infarction susceptibility
Introduction
Coronary Artery Disease (CAD) and Acute Myocardial Infarction (AMI) are the leading cause of morbidity and mortality worldwide [1]. Inflammation plays a pivotal role in the progression of atherosclerosis and in the development of AMI, favoring plaque destabilization and rupture, which is the major pathophysiological determinant of AMI [2], [3]. Type 2 diabetes mellitus (T2DM), which is characterized by hyperinsulinism, insulin resistance and chronic hyperglycemia, is associated with a two- to four-fold increased risk of CAD and AMI [4]. Accordingly, cardiovascular diseases (CVD) are the main cause of death among patients affected by type 2 diabetes [5]. One of the most known mechanisms for this association is the interplay between insulin resistance, inflammation and atherosclerosis [6], [7]. The development of both AMI and diabetes is usually associated to multiple concurrent risk factors, including genetic and environmental elements, such as hypercholesterolemia, hypertension, and smoking [8], [9]. Interestingly, epidemiological studies suggest that grossly 50% of susceptibility to CAD is inherited [9]. Thus, an increasing effort is being devoted to identify the genetic components that contribute to cardiovascular risk, by exploiting also the most recent genome-wide association studies (GWAS) data. However, despite over forty different loci were identified and validated up to date, altogether these explain less than 10% of the global genetic impact on CAD [9].
The architectural transcription factor, high-mobility group A1 (HMGA1), is a non-histone chromatin protein that acts as a dynamic regulator of chromatin structure and gene activation [10]. We previously found that defects in HMGA1 gene and protein expression are associated with insulin resistance and T2DM in both humans and mice [11], [12]. Within this context, a new rare variant, rs146052672, which consists of a C insertion at position − 13 of exon 6 of the HMGA1 gene has been thereafter associated with increased risk of T2DM and metabolic syndrome [13], [14]. On the other hand, by controlling the production of several inflammatory cytokines, chemokines and adhesion molecules [15], HMGA1 plays a critical role in atherosclerosis and the development and progression of atherosclerotic plaques [16], promotes the proliferation of vascular smooth muscle cells and their migration to the neointima [17], [16], and regulates adipose tissue growth and differentiation, as well as cholesterol homeostasis [18], [19]. Notably, cardiac defects have been reported in Hmga1-knockout mice, together with increased vascular susceptibility to injury [20], [21].
Based on these considerations, the aim of the present study was to verify whether an association exists between the HMGA1 gene polymorphism rs146052672 and the development of AMI.
Section snippets
Study population
A total of 254 patients referred to our center for AMI were age- and sex-matched in a 2:1 fashion with 508 control subjects from Calabria (Southern Italy) a region which consists of a population of limited genetic diversity [22]. Study population composition: 100 consecutive patients presenting with AMI, in absence of T2DM; 100 consecutive patients with AMI and T2DM; 56 patients with AMI and impaired fasting glucose (IFG); 508 age- and sex-matched healthy controls. All subjects were recruited
Study population
100 consecutive patients presenting with AMI in the absence of T2DM and 100 consecutive patients with AMI and T2DM were included in this study. During the inclusion period, 54 patients with AMI and IFG were also enrolled and maintained in a parallel subgroup. Patients' characteristics are reported in Table 1. Briefly, AMI patients were mostly males (79%), with 35% presenting a ST-Elevation Myocardial Infarction (STEMI), while the remaining had a Non ST-Elevation Myocardial Infarction (NSTEMI).
Discussion
In the present study, we evaluated the incidence of the HMGA1 rs146052672 variant in a prospective cohort of AMI patients, compared to a matched healthy subjects control group. The relevance of our findings is confirmed by showing that the rs146052672 variant resulted significantly associated with AMI, independently of T2DM or other classic cardiovascular risk factors, thereby providing incremental information over the standard cardiovascular risk profile. Our results herein confirm and extend
Disclosures
None.
Acknowledgment
The present work was partly supported by the Research Grant “NUTRAFAST” (PON01_01226) from the Italian Ministry of Education, University and Research (MIUR).
References (28)
- et al.
Insulin resistance, hyperglycemia, and atherosclerosis
Cell Metab.
(2011) - et al.
Pathogenesis of acute coronary syndromes
J. Am. Coll. Cardiol.
(2013) - et al.
Genes and coronary artery disease: where are we?
J. Am. Coll. Cardiol.
(2012) - et al.
HMGA1 proteins in human atheroscleroticplaques
Pathol. Res. Pract.
(2005) - et al.
HMG chromosomal proteins in development and disease
Trends Cell Biol.
(2007) - et al.
Expression of a truncated Hmga1b gene induces gigantism, lipomatosis and B-cell lymphomas in mice
Eur. J. Cancer
(2011) - et al.
Heart disease and stroke statistics-2016 update: a report from the American Heart Association
Circulation
(2016) - et al.
Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes
Arterioscler. Thromb. Vasc. Biol.
(2015) - et al.
A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis
J. Am. Heart Assoc.
(2015) - et al.
Diabetes and cardiovascular disease
JAMA
(1979)
Population-based estimates of mortality associated with diabetes: use of a death certificate check box in North Dakota
Am. J. Public Health
Role of insulin resistance in endothelial dysfunction
Rev. Endocr. Metab. Disord.
High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function
Prog. Nucleic Acid Res. Mol. Biol.
Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice
Nat. Med.
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S. De Rosa and E. Chiefari contributed equally to this study.