Genetic variability within Adenosine Deaminase gene and uterine leiomyomas.

OBJECTIVE: The recent observation of an association of colon cancer with two polymorphic sites within the Adenosine Deaminase (ADA) gene suggests an involvement of these polymorphisms in the development of solid tumors. This prompted us to search for a similar association in uterine leiomyomas. STUDY DESIGN: We have studied 181 women admitted to the hospital for leiomyomas requiring surgical intervention and 248 women of comparable age without clinical signs of leiomyomas. All women were from the White population of Rome and gave verbal consent to participate in the study. The genotypes of three polymorphic sites (ADA1, ADA2, ADA6) of ADA gene were determined by DNA analysis. RESULTS: A higher proportion of ADA2*1/*1 genotype and of carriers of the ADA6*1 allele was observed in women with leiomyomas as compared to controls. This parallels the association found in colon cancer. CONCLUSIONS: This pattern is identical to that previously observed in colon cancer making the possibility of mere sample chance artifact unlikely and supporting the hypothesis that genetic polymorphisms within the ADA gene could be involved in the susceptibility to solid tumors. Genetic variability within the ADA gene may influence adenosine concentration and in turn the immune response by lymphocytes in solid tumors. On the other hand ADA molecules acting as ecto-enzyme may be involved in the transduction of signals in the cell surface with important effects on tumor development.

The effect of ACP1, ADA6 and PTPN22 genetic polymorphisms on the association between p53 codon 72 polymorphism and endometriosis.

PURPOSE: Association between p53 codon 72 and endometriosis has been observed in populations of East Asia but not in those of European descent. Genetic polymorphisms could interact with p53 codon 72 influencing its association with endometriosis, thus explaining these differences among populations. METHODS: 130 women hospitalized for endometriosis and a sample of 250 women without endometriosis have been studied. All women were from the White population of Rome. ACP1, PTPN22, ADA6 and p53 codon 72 genotypes were determined by DNA analysis. Statistical analysis was performed by SPSS package. Three-way contingency table analyses were performed by a log linear model according to Sokal and Rohlf. RESULTS: There is an epistatic interaction among ADA6, p53 codon 72 and endometriosis resulting in a positive association between carriers of *Pro allele of p53 codon 72 and endometriosis in women carrying the ADA6 *1 allele. PTPN22 and ACP1 show an additive effect with p53 codon 72 concerning their effect on endometriosis. The strength of association between p53 codon 72 and endometriosis is positively correlated with the number of the three factors considered. CONCLUSION: ADA6, PTPN22 and ACP1 are involved in immune reactions: since endometriosis has an autoimmune component, a cooperative interaction among these genetic systems appears biological plausible. The present result could contribute to explain the differences observed among populations concerning the association between p53 codon 72 and endometriosis.

Allergy and Uterine Leiomyomas: Cooperative Interaction with ACP1 Genetic Polymorphism.

BACKGROUND: The possible association between allergy and neoplastic disorders has been the subject of many investigations but no general relationship has been determined. Little attention, however, has been paid to the possible role of allergy in the clinical manifestations of these diseases. In this study, the role of allergy in the susceptibility to uterine leiomyomas and in their growth was investigated. Interaction with ACP1 , a genetic polymorphism associated with the growth of leiomyomas, has been also considered. METHODS: Two hundred and three White woman from the population of Rome hospitalized for symptomatic leiomyomas requiring surgical intervention have been studied. One hundred thirty eight healthy women have been considered as controls. Allergy has been evaluated by prick test. T-test for equality of means, analysis of variance and linear correlation analysis has been performed. The level of statistical significance was set at 0.05. RESULTS: The frequency of allergic manifestations in women with leiomyomas does not differ from healthy women. The dimension of leiomyomas is lower in allergic than in non allergic women (p=0.004). The ACP1 *B/*B genotype and allergy cooperate in lowering the dimension of leiomyomas; the proportion of woman with small leiomyomas (<10 percentile) is much higher in allergic women carrying the *B/*B genotype as compared to other women (p<0.001). About 8% of variance of leiomyomas dimension is attributable to the joint effect of ACP1 and allergy. CONCLUSION: Allergic women with high concentration of ACP1 f isoform (*B/*B genotype) are protected from excessive leyomioma growth. If confirmed in other clinical settings, our observation may have practical importance in identifying women at risk of more severe clinical manifestations.

PTPN22 and uterine leiomyomas.

OBJECTIVE: It has been suggested that the development of uterine leiomyomas is positively influenced by an immune system in a chronically inflammatory state and that a lower level of regulating T cell (Treg cells) would play a central role. Since it has been suggested that the W620 variant of protein tyrosine phosphatase non-receptor type 22 (PTPN22) decreases the number of Treg cells, we investigated a possible relationship between PTPN22 polymorphism and uterine leiomyomas. STUDY DESIGN: We studied 203 white women from Rome who were hospitalized for symptomatic leiomyomas requiring surgical intervention. These women were considered in a previous paper regarding the relationship between ACP1 and dimension of leiomyomas. As controls we studied 355 healthy women from the same population with comparable age and without clinical evidence of leiomyomas. All women gave written informed consent to participate to the study. Chi square test of independence and T-test for difference between means were performed by SPSS package. RESULTS: Considering the whole sample, a borderline association between PTPN22 and leiomyomas was observed: the *C/*T genotype is more frequent in cases than in controls. This association is marked and statistically significant in younger women only. The main diameter of tumor is significantly greater in *C/*T than in *C/*C women. This effect is present in younger women only. The *C/*T genotype also shows a higher tendency to intramural localization, but no effect of age is observed upon this association. CONCLUSIONS: The data suggest a positive effect of *C/*T genotype on susceptibility to leiomyomas in younger women. In these women a *C/*T genotype favors the growth of leiomyomas.

Study of factors influencing susceptibility and age at onset of type 1 diabetes: A review of data from Continental Italy and Sardinia.

AIM: To investigate the role of protein tyrosin phosphatase 22 (PTPN22), maternal age at conception and sex on susceptibility and age at onset of type 1 diabetes (T1D) in Continental Italy and Sardinian populations. METHODS: Three hundred seventy six subjects admitted consecutively to the hospital for T1D and 1032 healthy subjects as controls were studied in Continental Italy and 284 subjects admitted consecutively to the hospital for T1D and 5460 healthy newborns were studied in Sardinia. PTPN22 genotype was determined by DNA analysis. Maternal age at conception and age at onset of disease were obtained from clinical records. χ(2) test of independence, student t test for differences between means and odds ratio analysis were carried out by SPSS programs. Three way contingency table analysis was carried out according to Sokal and Rohlf. RESULTS: The pattern of association between PTPN22 and T1D is similar in Continental Italy and Sardinia: the proportion of *T allele carriers is 13.6% in T1D vs 6.7% in controls in Continental Italy while in Sardinia is 7.3% in T1D vs 4.4% in controls. The association between T1D and maternal age at conception is much stronger in Sardinia than in Italy: the proportion of newborn from mother aging more than 32 years is 89.3% in T1D vs 32.7% in consecutive newborn in Sardinia (P < 10(-6)) while in Continental Italy is 32.2% in T1D vs 19.1% in consecutive newborns (P = 0.005). This points to an important role of ethnicity. A slight prevalence of T1D males on T1D females is observed both in Continental Italy and Sardinia. PTPN22 genotype does not exert significant effect on the age at onset neither in Continental Italy nor and Sardinia. Maternal age does not influence significantly age at onset in Italy (8.2 years in T1D infants from mothers aging 32 years or less vs 7.89 years in T1D infants from mothers aging more than 32 years: P = 0.824) while in Sardinia a border line effect is observed (5.75 years in T1D infants from mothers aging 32 years or less vs 7.54 years in T1D infants from mothers aging more than 32 years: P = 0.062). No effect of sex on age at onset is observed in Continental Italy while in Sardinia female show a lower age at onset of T1D as compared to males (8.07 years in males vs 6.3 years in females: P = 0.002). CONCLUSION: The present data confirm the importance of ethnicity on susceptibility and on the age at onset of T1D.

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.

Further observations on associations between the ADA gene and past malaria morbidity in Sardinia.

OBJECTIVES: Adenosine Deaminase (ADA) contributes to the regulation of adenosine concentration and in turn to T cell activation. Genetic variability of ADA activity may have, therefore, an important role in resistance to malaria. Indeed, previous studies in Sardinia have shown a lower frequency of ADA1 *2 allele (associated with low ADA activity) in areas, where malaria was heavily endemic compared to areas where malaria was not endemic. We have now studied the ADA2 locus, another polymorphic site with two alleles ADA2 *1 and ADA2 *2 within the ADA gene. METHODS: In the area of Oristano (where malaria was endemic in the past) 51 consecutive newborns and in the area of Nuoro (where malaria was not as endemic) 48 consecutive newborns were examined. ADA1 and ADA2 genotypes were determined by DNA analysis. RESULTS: The low frequency of the ADA1 *2 allele in the area where malaria was endemic is confirmed. The frequency of the ADA2 *2 allele is higher in Oristano than in Nuoro resulting in a higher frequency of the ADA1 *1/ADA2 *2 haplotype in Oristano as compared to Nuoro. This suggests a selective advantage of this haplotype in a malarial environment. CONCLUSIONS: The ADA gene shows other polymorphic sites further studies on their role in human adaptation to malaria could be rewarding.

p53 Codon 72 Genetic Polymorphism in Asthmatic Children: Evidence of Interaction With Acid Phosphatase Locus 1.

Several lines of evidence are implicating an increased persistence of apoptotic cells in patients with asthma. This is largely due to a combination of inhibition, or defects in the apoptotic process and/or impaired apoptotic cell removal mechanisms. Among apoptosis-inducing genes, an important role is played by p53. In the present study, we have investigated the possible relationship between p53 codon 72 polymorphism and asthma and the interaction with ACP1, a genetic polymorphism involved in the susceptibility to allergic asthma. We studied 125 asthmatic children and 123 healthy subjects from the Caucasian population of Central Italy. p53 codon 72 and ACP1 polymorphisms were evaluated using a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method. There is a statistically significant association between p53 codon 72 polymorphism and allergic asthma: Arg/Arg genotype is more represented in asthmatic patients than in controls (P=0.018). This association, however, is present in subjects with low ACP1 activity A/A and A/B only (P=0.023). The proportion of children with A/A and A/B genotype carrying Arg/Arg genotype is significantly high in asthmatic children than in controls (OR=1.941; 95% C.I. 1.042-3.628). Our finding could have important clinical implications since the subjects with A/A and A/B genotypes of ACP1 carrying Arg/Arg genotype are more susceptible to allergic asthma than Pro/Pro genotype.

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.

Acid phosphatase locus 1 genetic polymorphism and cancer grading.

BACKGROUND: Currently, there is a surge of interest on the possible relationship between cancer and acid phosphatase locus 1 (ACP(1)), an enzyme involved in the modulation of growth factors and cellular metabolism. As far as the authors know, the possible relationship between ACP(1) genetic variability and cancer grading has not yet been considered. In this article, the authors have studied the relationship between ACP(1) genotype and grade in colon and endometrium cancers. METHODS: Seventy-one patients with colon cancer and 71 patients with endometrium cancer were studied. ACP(1) genotype was determined by DNA analysis. Three-way contingency table analysis was carried out according to Sokal and Rohlf. Other statistical analyses were performed using SPSS programs. RESULTS: There is a significant association between ACP(1) and cancer grade mainly due to ACP(1) genotypes carrying the *C allele that are much less represented in patients with low grade when compared with those with high grade. In both cancers, the concentration of S isoform is significantly lower in low grade than in high grade. The relationship between ACP(1) and grade is the same in the 2 cancers. CONCLUSIONS: Assuming the presence of diverse classes of cancer, the role of ACP(1) in the modulation of growth factors and cellular metabolism could have significant effects in less aggressive forms but not in more aggressive ones.

Effect of ADA1 mother-fetus and wife-husband phenotypic differences on the ratio birth weight/placental weight in fertile women and on reproductive success in couples with RSA.

OBJECTIVES: To study the effect Adenosine Deaminase locus 1 (ADA(1)) mother-fetus and wife-husband phenotypic differences on the ratio Birth Weight/Placental Weight (BW/PW) in fertile women and on reproductive success in couples with repeated spontaneous abortion (RSA). METHODS: 209 couples with primary RSA and a consecutive series of 379 healthy puerperae with their newborn infants from the White Caucasian population of central Italy were studied. In primary RSA women reproductive success was indicated by the presence of at least one live-born infant within 5 years of follow up. Two way contingency tables were analyzed by chi-square. RESULTS: The proportion of primary RSA couples with at least a live-born infant shows the highest value in couples mother ADA(1)1/father carrier of ADA(1)*2 allele (55.2%) and the lowest value in reciprocal couples mother carrier of ADA(1)*2 allele /father ADA(1)1 (18.7%) (O.R. = 5.33; P = 0.023). The highest ratio BW/PW is observed in the class mother ADA(1)1/newborn carrier of ADA(1)*2 allele while the lowest ratio is observed in the reciprocal class mother carrier of ADA(1)*2 allele/ newborn ADA(1)1. CONCLUSIONS: Differences between mother and fetus in ADA(1) phenotype may influence the ratio BW/PW in healthy women and reproductive success in RSA women.

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.

Functional polymorphisms of GSTA1 and GSTO2 genes associated with asthma in Italian children.

BACKGROUND: Asthma is an airway disorder characterized by bronchial inflammation. An imbalance between the oxidative forces and the antioxidant defense systems has been implicated in the pathogenesis of asthma. Glutathione S-transferases (GSTs) play an important role in cellular protection against inflammation. Several studies have investigated the genetic variability of GSTM1, GSTP1 and GSTT1 enzymes in asthma development with conflicting results. Moreover, in our previous independent case-control study on GSTs and asthma, we have found that GSTA1 and GSTO2 gene polymorphisms are associated with asthma. The aim of the present study is to analyze if some functional polymorphisms of GSTA1, GSTM1, GSTP1, GSTO2 and GSTT1 are associated with asthma in pediatric patients from Chieti (Italy). METHODS: In this study, we performed an association study on 127 asthmatic children and 126 controls. We screened single nucleotide polymorphisms at GSTA1, GSTO2 and GSTP1 loci. The effects of GSTM1 and GSTT1 null genotype were also investigated. RESULTS: The GSTA1*-69T and GSTO2*D142 variants are associated with the significant increased risk of asthma development in our study population, while GSTM1, GSTP1 and GSTT1 genotype distributions were nearly equal between the control group and asthmatics. CONCLUSIONS: Confirming our previous study, these findings suggest that the GSTA1 and the GSTO2 are asthma susceptible genes involved in increasing the risk of asthma development in the Italian population.

Genotypes of p53 codon 72 correlate with age at onset of type 1 diabetes in a sex-specific manner.

In type 1 diabetes mellitus (T1D) p53 pathways are up-regulated and there is an increased susceptibility to apoptosis. The hypothesis is that p53 codon 72 polymorphism could be associated with T1D. A total of 286 children with T1D and a control sample of 730 subjects were studied. p53 codon 72 polymorphism was analysed by polymerase chain reaction. A large increase of p53 *Arg/*Arg was observed in T1D patients with age at onset < 6 years. A strong linear correlation between *Arg/*Arg genotype and age at onset was observed in females. The involvement of the *Arg/*Arg genotype in apoptosis suggests that during the autoimmune process leading to T1D, genetic factors that favor apoptosis may contribute to the onset of overt disease.

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.

PTPN22 1858C>T (R620W) functional polymorphism and human longevity.

The PTPN22 gene, located on chromosome 1p13, encoding lymphoid protein tyrosine phosphatase (LYP), plays a crucial role in the negative control of T lymphocyte activation. Since the age-related change in T-cell signal transduction may be one of the most important causes of cell-mediated immune response decline with ageing, we performed a population-based association study to test whether the PTPN22 1858C>T (R620W) functional polymorphism affects the ability to survive to old age and to reach even exceptional life expectancy. 892 unrelated healthy individuals (age range 8-106 years, 403 males and 489 females) from central Italy were studied. For both gender, the frequency of PTPN22*T1858 carriers does not differ significantly in nona/centenarians and in octogenarians respect to young group. Allele and genotype frequencies of age groups were compared to those reported in previously published studied carried out on control individuals with Italic ancestry (N = 1393), further confirming results obtained from our sample population. Overall, our study suggests that PTPN22*T1858 allele is not negatively selected at oldest ages and we speculate that its increased ability to protect individuals against development of infectious diseases may counteract its deleterious effect on immune system leading to autoimmunity.

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.

Is there a role of ACP1-ADA1 genetic complex in immune reaction? Association with T1D and with past malarial morbidity.

In this article, we confirm the positive association of acid phosphatase locus 1 (ACP1)*A/adenosine deaminase locus 1 (ADA1)*2 gametic type with type 1 diabetes (T1D) previously reported and show a negative correlation between the frequency of this gametic type with past malarial morbidity in Sardinia. One hundred seven adult women with T1D and 385 healthy adult women from the Caucasian population of Central Italy have been studied. Data on 1384 children from the central area of Sardinia have also been reexamined. T1D subjects show a highly significant increase of ACP1*A/ADA1*2 gametic type compared with healthy subjects from the same population (P = 0.003). The frequency of ACP1*A/ADA1*2 gametic type is decreasing with increasing past malarial morbidity. Because ADA1*2 allele decreases the activity of *A allele and since low ACP1 activity decreases Zeta-chain-associated protein kinase with molecular weight 70 kDa (Zap70) activity resulting in weak T-cell receptor signalling an epistatic interaction involving ADA1, ACP1 and Zap70 seems a likely mechanism for the associations observed.