Elsevier

International Journal of Cardiology

Volume 227, 15 January 2017, Pages 331-334
International Journal of Cardiology

HMGA1 is a novel candidate gene for myocardial infarction susceptibility

https://doi.org/10.1016/j.ijcard.2016.11.088Get rights and content

Abstract

Background

Acute Myocardial infarction (AMI), a leading cause of morbidity and mortality worldwide, is a dreadful acute complication of coronary atherosclerosis. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of developing AMI. The architectural transcription factor high-mobility-group AT-hook 1 (HMGA1) has been involved in atherosclerosis, plaque formation, inflammation, and in the pathogenesis of insulin resistance and T2DM. An association of the HMGA1 rs146052672 variant with T2DM has been recently reported. Thus, our aim was to evaluate whether this variant was also associated with AMI.

Methods and results

In a case–control study from Calabria (Southern Italy), we enrolled 254 consecutive, unrelated, patients with first diagnosis of AMI, and 508 age, sex-matched controls. Genotyping of the rs146052672 was performed using the TaqMan allelic discrimination method. We found that this variant was present in 7.9% of AMI patients and in 3.1% of controls (p = 0.003). Multiple logistic regression confirmed that the rs146052672 was significantly associated with AMI (OR = 2.54; p = 0.002), and this association was independent of classical cardiovascular risk factors such as gender, hypertension, obesity and T2DM (for all, p < 0.05).

Conclusions

Our findings demonstrate that a relationship exists between the HMGA1 rs146052672 variant and AMI, suggesting that defects at the HMGA1 locus may play a pathogenetic role in AMI, in the absence of T2DM and other cardiovascular risk factors.

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).

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    S. De Rosa and E. Chiefari contributed equally to this study.

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