Effect of genetic factors on the association between coronary artery disease and PTPN22 polymorphism.

PTPN22 has been previously found associated with coronary artery disease (CAD). In the present note we have studied the effect of p53 codon 72, acid phosphatse locus 1 (ACP1) and adenosine deaminase (ADA) genetic polymorphism on the strength of association between PTPN22 and CAD. We have studied 133 non diabetic subjects with CAD, 122 non diabetic cardiovascular patients without CAD and 269 healthy blood donors. Informed written consent was obtained from all subjects and the study was approved by the Ethical Committee. A high significant association between PTPN22 and CAD is observed in carriers of *A allele of ACP1 with a higher proportion of *T allele carriers in non diabetic subjects with CAD as compared to controls and to non diabetic subjects with cardiovascular disease without CAD. A similar pattern is observed in carriers of *Pro allele of p53 codon 72 with a higher proportion of *T allele carriers in non diabetic subjects with CAD as compared to other groups. A highly significant association between PTPN22 and CAD is observed in carriers of ADA2 *2 allele with higher proportion of *T allele carriers in non diabetic subjects with CAD as compared to other group. There is a high significant correlation between the number of factors that contributes to increase the strength of association between PTPN22 *T and CAD and the proportion of *T carriers in CAD. ACP1, p53 codon 72 and ADA are involved in immune reaction and give an important additive contribution to the strength of association between PTPN22 and CAD. This study stresses the importance of the simultaneous analysis of multiple genes functionally related to a specific disease: the approach may give important hints to understand multifactorial disorders.

Coronary artery disease. A study of three polymorphic sites of adenosine deaminase gene.

OBJECTIVES: The role of adenosine as a cardioprotective agent is well known and recent experimental studies suggest that impairment of adenosine-related signal transduction contributes to the pathophysiology of chronic heart failure. The recent observation of an association between ADA, genetic polymorphism and coronary artery disease (CAD) prompted us to study the possible relevance of three intragenic polymorphic sites of the ADA gene (ADA1, ADA2 and ADA6). METHODS AND RESULTS: 136 non-diabetic patients with coronary artery disease and 246 healthy blood donors from the white Italian population of Central Italy and 129 non-diabetic patients with CAD and 204 newborns from the white Polish population were studied. ADA1, ADA2 and ADA6 genotypes were determined by DNA analysis. In males, the proportion of ADA1 *2 (P = 0.0001) and ADA2 *2 (P = 0.005) alleles is lower in CAD than in controls. In males, the haplotype distribution of the pairs ADA1-ADA2, ADA1-ADA6 and ADA2-ADA6 shows statistically significant differences between coronary artery disease and controls. CONCLUSIONS: The present study suggests a complex association between ADA gene and coronary artery diseases. Besides the control of adenosine concentration due to deamination of adenosine, also other functions of the ADA gene could have a role in the susceptibility and/ or clinical course of coronary artery disease.

ACP1 Genetic Polymorphism and Coronary Artery Disease: Evidence of Effects on Clinical Parameters of Cardiac Function.

BACKGROUND: Kinases and phosphatases have an important role in the susceptibility and clinical variability of cardiac diseases. We have recently reported an association between a phosphoprotein phosphatase controlled by Acid Phosphatase locus 1 (ACP1), and Coronary artery disease (CAD) suggesting an effect on the susceptibility to this disease. In the present note we have investigated a possible role of ACP1 in the variability of clinical parameters of cardiac function. METHODS: We have studied 345 subjects admitted to Valmontone Hospital for cardiovascular diseases: 202 subjects with CAD and 143 without CAD, 53 subjects admitted to Cardiac Surgery Division of Tor Vergata University were also considered. RESULTS: In diabetic patients with CAD there is a significant negative association between Left ventricular ejection fraction (LVEF) and ACP1 S isoform concentration. Genotypes with high S isoform concentration show a lower value of LVEF as compared to genotypes with low S isoform concentration. We have also found a significant positive association between cNYHA class and ACP1 S isoform. After surgical intervention, in subjects with high S isoform concentration the decrease of LVEF is more marked as compared to subjects with low S isoform concentration. Overall these observations indicate that high S isoform activity has negative effects on cardiac function. The observation in patients undergoing cardiac surgery confirms the negative association between high S isoform activity and LVEF. CONCLUSIONS: The present study suggests that ACP1 influences both susceptibility to CAD and clinical manifestations of the disease.

p53 codon 72 polymorphism and coronary artery disease: evidence of interaction with ACP1.

BACKGROUND: Common biological features between cancer and atherosclerosis suggest possible association of p53 with atherosclerotic diseases, but data on such a relationship are controversial, suggesting interactions with other variables. Acid phosphatase locus 1 (ACPACP1) is a polymorphic gene that controls the synthesis of an enzyme involved in important metabolic functions. Since ACPACP1 is associated with coronary artery disease (CAD), we searched for possible interactions between this enzyme and p53 codon 72 polymorphism with regard to their effects on susceptibility to CAD. MATERIAL/METHODS: The study included 381 patients admitted to the hospital for cardiovascular disease (232 patients with CAD and 149 with other cardiovascular problems) and 97 healthy newborns. RESULTS: The proportion of subjects carrying the *Pro allele of p53 codon 72 and the high activity *B*C genotype of ACPACP1 is higher in CAD (10.3%) than in non-CAD patients (2.0%) and in healthy newborns (6.2%). CONCLUSIONS: The data suggest an interaction between p53 codon 72 and ACPACP1 wherein a positive effect of the p53 *Pro allele on susceptibility to CAD occurs, but only in the presence of the ACPACP1 genotype characterized by high enzymatic activity.

p53 codon 72 polymorphism and coronary artery disease: evidence of association with left ventricular ejection fraction.

INTRODUCTION: Recently, there has been a surge of interest on the possible relationship between p53 polymorphism and coronary atherosclerosis. The authors have investigated the possible association of p53 codon 72 polymorphism with left ventricular ejection fraction (LVEF) in subjects with and without coronary artery disease (CAD). METHODS: The authors have studied 198 subjects admitted consecutively to Valmontone Hospital for CAD and 129 subjects admitted for cardiovascular diseases without CAD. Fifty-nine subjects admitted for CAD to Division of Cardiac Surgery of Tor Vergata University were also studied. All subjects were from the white population. The p53 polymorphism was evaluated using the restriction fragment length polymorphism polymerase chain reaction. RESULTS: p53 codon 72 polymorphism is a significant independent predictor of LVEF in subjects with CAD but not in subjects with cardiovascular disease without CAD. In subjects with CAD, LVEF is significantly lower in subjects carrying the *Pro variant than in *Arg/*Arg subjects. This effect is more evident in subjects with a positive history of infarction. CONCLUSIONS: Our study points to a significant relationship of p53 codon 72 polymorphism with cardiac function in subjects with CAD.

Isolated left ventricular noncompaction in a case of sotos syndrome: a casual or causal link?

A 16-year-old boy affected by Sotos syndrome was referred to our clinic for cardiac evaluation in order to play noncompetitive sport. Physical examination was negative for major cardiac abnormalities and rest electrocardiogram detected only minor repolarization anomalies. Transthoracic echocardiography showed left ventricular wall thickening and apical trabeculations with deep intertrabecular recesses, fulfilling criteria for isolated left ventricular noncompaction (ILVNC). Some sporadic forms of ILVNC are reported to be caused by a mutation on CSX gene, mapping on chromosome 5q35. To our knowledge, this is the first report of a patient affected simultaneously by Sotos syndrome and ILVNC.

A Case of Isolated Left Ventricular Noncompaction with Basal ECG-Tracing Strongly Suggestive for Type-2 Brugada Syndrome.

Isolated left ventricular noncompaction (ILVNC) is a cardiomyopathy caused by intrauterine arrest of compaction of the myocardial fibres and meshwork, an important process in myocardial development. ILVNC is clinically accompanied by depressed ventricular function, arrhythmias, and systemic embolization. We reported a case of ILVNC with basal ECG-tracing strongly suggestive for type-2 Brugada syndrome (BrS). Up to now, this is the first report investigating the association between ILVNC and this particular ECG pattern.

The interaction of ACP1, ADA1, diabetes and gender in coronary artery disease.

INTRODUCTION: Previous separate studies have shown associations of coronary artery disease (CAD) with acid phosphatase locus 1 (ACP1) and adenosine deaminase locus 1 (ADA1) genetic polymorphisms. Because it is known that the 2 systems interact and have important immunologic and metabolic functions, these 2 genes were both examined in the same sets of subjects. METHOD: Two-hundred forty subjects with CAD, 156 subjects with cardiovascular diseases without CAD, 279 subjects with Non Insulin Dependent Diabetes Mellitus (NIDDM) without CAD and 771 consecutive healthy newborn infants have been studied. RESULTS: The association of ACP1 and ADA1 with CAD depends on sex and diabetes. In particular, the association between ADA1 and CAD is present in nondiabetic subjects only, and it is dependent on sex (males), whereas the association of CAD with ACP1 is present in diabetic subjects only, and it is dependent on sex (females). CONCLUSIONS: The fact that the association of ACP1 with CAD is evident only in diabetic subjects, whereas the association of ADA1 with CAD is evident only in nondiabetic subjects suggests an heterogeneity in the pathogenetic mechanisms leading to CAD. In addition, the association with sex that could be based on hormonal differences is in favor of heterogenity.

Longitudinal changes of adiponectin, carbohydrate and lipid metabolism in pregnant women at high risk for gestational diabetes.

To evaluate, in pregnant women at high risk for gestational diabetes (GDM), the longitudinal changes of adiponectin, carbohydrate and lipid metabolism, and to assess their independent value as risk factors for the development of GDM. Fifty women at beginning of pregnancy were studied. Adiponectin, insulin sensitivity (homeostasis model assessment, HOMA) and lipid panel were measured at 1st, 2nd and 3rd trimesters of pregnancy. Twelve patients developed GDM. In both groups, GDM and normal glucose tolerance (NGT), adiponectin decreased from 1st to 2nd and 3rd trimesters by about 5 and 20% (GDM, p < 0.05), and of about 17 and 25% in NGT (p < 0.05), respectively. Values observed in NGT were similar to those of GDM (F = 9.401; p = 0.238). The Cox regression model identified as the strongest independent risk factor for GDM HOMA over 1.24 (RR = 14.12) at 1st trimester, fasting glycaemia over 87 mg/dl (RR = 42.68) triglycerides over 158 mg/dl (RR = 5.87) and body mass index (BMI) over 27 kg/m(2) (RR = 4.38) at 2nd trimester. Adiponectin in high-risk women is characterised by a constant reduction throughout gestation, irrespective of the development of GDM. HOMA, fasting glycaemia, triglycerides and BMI, but not adiponectin are independent predictors of GDM.

Birth weight and coronary artery disease. The effect of gender and diabetes.

BACKGROUND: The developmental origin theory of coronary heart disease proposes that undernutrition in utero permanently changes body functions and metabolism leading to an increased risk of coronary artery diseases (CAD) in adult life. Some studies support this theory but others suggest that birth weight (BW) is not a major risk factor for cardiovascular diseases. Gender differences concerning the association between BW and risk factors for CAD have been reported in some studies but not in others.In this paper we have analyzed the effect of gender and diabetes on the relationship between BW and CAD in the White population of Rome. MATERIAL AND METHODS: 226 subjects admitted to the Hospital for non fatal CAD from the White population of Rome were studied. 395 consecutive newborn infants studied in the same population in the years 1968-1972 were considered for comparison. RESULTS: Among subjects with CAD, reliable information on BW was obtained in 127 subjects. The distribution of BW in CAD depends on gender (p=0.009). In females with CAD there is a tendency toward low BW, while in males with CAD there is a tendency toward high BW. These associations are very marked in non-diabetic subjects with CAD (p=.001), while no significant association is observed in diabetic subjects (p=0.557). CONCLUSION: Our data confirm the association between BW and CAD and suggest that the association depends on gender and is influenced by diabetes.