INTERNATIONAL JOURNAL OF CARDIOLOGY AND CARDIOVASCULAR MEDICINE (ISSN:2517-570X)

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.

ACP₁ ; ADA₁; CAD; Age at onset 

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].

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.

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.

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.

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.

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. 

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 

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