International Journal of Cardiology and Cardiovascular Medicine

ISSN 2517-570X

ACP1 and ADA1 Genetic Polymorphisms and Coronary Artery Disease. Effects on Age at Onset of Clinical Manifestations

Gloria-Bottini Fulvia1, Banci M2, Saccucci P1, Neri A1, Magrini A1, Bottini E1

1Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy

2Deaprtement of Cardiology, Valmontone Hospital, Valmontone, Rome, Italy

Corresponding author

Fulvia Gloria-Bottini, MD
Department of Biomedicine and Prevention
University of Tor Vergata
Via Montpellier, Rome, Italy
Tel: +39 06 30889514
E-mail: gloria@med.uniroma2.it

  • Received Date: October 26, 2017
  • Accepted Date: November 12, 2017
  • Published Date: January 12, 2018

DOI:   10.31021/ijccm.20181105

Article Type:  Research Article

Manuscript ID:   IJCCM-1-105

Publisher:   Boffin Access Limited.

Volume:   1.1

Journal Type:   Open Access

Copyright:   © 2018 Gloria-Bottini F, et al.
Creative Commons Attribution 4.0


Citation

Gloria-Bottini F, Banci M, Saccucci P, Neri A, Magrini A, et al. (2018) ACP1 and ADA1 genetic polymorphisms and Coronary Artery Disease. Effects on age at onset of clinical manifestations. Int J Cardiol Cardiovasc Med 1:105

Abstract

Previous studies have shown an association of Coronary Artery Disease (CAD) with Acid Phosphatase locus 1 (ACP1) and Adenosine Deaminase locus 1 (ADA1) genetic polymorphisms. Both systems are involved in immune reactions and several studies point to a significant autoimmune component in the pathogenesis of CAD. In the present note we have investigated the role of the two polymorphisms on age of onset of the disease.

Hundred and thirty patients admitted to Valmontone Hospital for the first episode of CAD have been studied. Informed consent was obtained by the patients to participate in the study that was approved by the Sanitary Direction of the Hospital.

In patients at the first episode of CAD, ACP1 genotype was determined in 130 subjects and ADA1 genotype in 126 subjects by DNA analysis. SPSS programs performed statistical analyses.

The age at onset of CAD is lower in subjects with low ACP1 activity genotypes and in those with low ADA1 activity genotypes. The association is stronger in females than in males. The effects of the two systems appears additive with a lower age of onset in subjects carrying the two factors associated with lower age at onset and a higher age in subjects with no factor. The pattern is stronger in females than in males.

Gender differences in autoimmunity are well documented: women with low ACP1 activity and/or ADA1 genotype seem to have a high risk of early clinical manifestations as compared to women carrying genotypes with high activity. These differences support the hypothesis of significant autoimmune component in the pathogenesis of CAD.

Keywords

ACP1; ADA1; CAD; Age at onset

Introduction

Previous studies have shown an association of Coronary Artery Disease (CAD) with Acid Phosphatase locus 1 (ACP1) [1] and with Adenosine Deaminase (ADA1) [2,3]. The present analysis suggests an effect of these genetic systems on the age at onset of clinical manifestations of the disease.

ACP1 gene is located on chromosome 2 and encodes the Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP). The gene shows three co dominant alleles *A, *B and *C: the corresponding 6 genotypes show an activity increasing in the order *A/*A<*A/*B<*B/*B≤ *A/*C<*B/*C<*C/*C. The enzyme has several functions: (i) as flavin mononucleotide phosphatase catalyzes the conversion of flavin mononucleotide to riboflavin contributing to the regulation of flavo-enzymes activity and energy metabolism; (ii) dephosphorylating insulin receptor and band 3 protein modulates the glycolytic rate; (iii) dephosphorylating a negative regulatory Tyr-292 of ZAP-70, ACP1

strengthens T cell receptor signaling [4,5].

Several studies point to a significant link between atherosclerosis and the genetics of autoimmunity. ACP1 has been found associated with several immune diseases including Coronary Artery Disease (CAD) suggesting an important relationship between this polymorphism and CAD possibly through the relationship of ACP1 with ZAP70.

The ADA gene is located on chromosome 20 and it is constituted by 12 exons. A number of single nucleotide polymorphisms have been found within the coding and intronic regions of the gene [6]. The SNP (ADA1) corresponding to the presence /absence of a Taq I site (4050-4053 exon 1, C22 G > A, Asp8Asn, rs 73598374) has been found associated with CAD [2,3]. This SNP at exon 1 corresponds to a known functional variant since the G>A transition results in the substitution of asparagine for aspartic acid at codon 8. This mutation is the molecular basis for the biochemical polymorphism at the ADA1 locus described by Spencer et al., with two codominant alleles with activity decreasing in the order ADA1*1>ADA1 *2 [7].

ADA1 catalyzes the irreversible deamination of adenosine to inosine contributing with adenosine kinase to the intra and extracellular concentration of adenosine. Carriers of ADA1*2 allele show a low enzymatic activity as compared to ADA1 *1/*1 genotype. Adenosine has an important role in glucose metabolism and immune functions and is a cardio-protective agent [8,9].

Material and Methods

We have studied 130 patients admitted to Valmontone Hospital for the first episode of Coronary Artery Disease. 55 were females and 75 males. Part of these subjects have been included in previous studies [1,3]. Informed consent was obtained from the patients to participate to the study that was approved by the Sanitary Direction of the Hospital. Clinical data of subjects examined are shown in Table 1.

Parameter % Proportion
Infarction 40.5%
Major Coronary Lesions 83.2%
Bypass 35.2%
Angioplasty 27.1%

Table 1: Clinical data in subjects with CAD.

ACP1 genotype was determined in 130 subjects admitted in the Hospital for the first episode of CAD. ADA1 genotype was determined in 126 subjects at first episode. ACP1 and ADA1 genotypes were determined by DNA analysis as previously described[1,3].

Statistical analyses were carried out by commercial software (SPSS). Eta (η) is a measure of association and eta squared (η2) represents the proportion of variance of dependent variable that is explained by the independent variable.

Results

Table 2 shows the age of subjects admitted to the Hospital for the first episode of CAD in relation to the genotypes of ACP1 and ADA1. The age at onset of clinical manifestations is lower in subjects with low ACP1 activity as compared to other ACP1 genotypes and in carriers of ADA1*2 allele (associated with lower ADA enzymatic activity) as compared to ADA1 *1/*1 genotype. Although the pattern appears similar in males and females, it is stronger in females than in males. For ACP1 eta is 0.308 in females and 0.107 in males. For ADA1 eta is 0.338 in females and 0.047 in males.

Table 2

Table 2:Age at onset of CAD in relation to ACP1 and ADA1 genetic polymorphisms

As shown in Table 3 the effect of the two genotypes in subjects admitted to the Hospital for the first episode of CAD appears additive with a lowest age in subjects carrying the two factors associated with lower age at onset and the highest age in subjects with no factor. Although the pattern is similar in males and females, it is much stronger in females than in males. In females eta is 0.456, eta squared is 0.208 while in males eta is 0.185 and eta squared is 0.034.

Table 3

Table 3: The relationship between age at onset of clinical manifestations of CAD and the number of genetic factors for which an earlier onset of manifestation has been observed.

We have considered in females the effect of the following variables: hypertension, obesity and diabetes. No statistically significant effect of these variables was observed neither on the difference between low activity and medium-high activity ACP1 genotypes nor on the difference between low activity ADA1 genotypes and high activity ADA1 genotype.

Discussion

The present analysis shows a statistically significant positive correlation between ACP1 activity and age at onset of CAD: low activity ACP1 genotypes are associated with early onset of clinical manifestations while high activity genotypes are associated with late onset of manifestations. Such correlation is statistically significant in females but not in males. Since low ACP1 activity is associated in females to early onset and probably to early mortality also, this could result in an apparent relative increase of ACP1 genotypes with high activity in the surviving subjects with CAD. The data also indicate that ADA1*2 allele is associated in females to early onset of clinical manifestations and probably to early mortality. This could result in an apparent relative decrease of subjects carrying this allele in surviving subjects [1,2].

The analysis confirms the involvement of ACP1 and ADA1 in the risk of CAD and suggests an additive effect of the two systems on age at onset of the disease.

Several studies point to a significant autoimmune component in the pathogenesis of atherosclerosis [10,11]: gender differences in autoimmunity are well documented and it has been suggested that in diseases with autoimmune component males and females should be examined separately [12].

The limitation of the study is represented by the relatively low number of subjects examined and by the lack of information on the distribution of ACP1 and ADA1 in subjects not surviving the first episode of CAD.

From the practical point of view the determination of ACP1 and ADA1 genotypes may help to detect subjects with high risk of early manifestations of CAD

References

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