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.

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.

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.

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.

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.

Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue.

A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. PTPN22 encodes the lymphoid tyrosine phosphatase (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling through the T cell receptor. The C1858T single nucleotide polymorphism results in the LYP-R620W variation within the LYP-Csk interaction motif. LYP-W620 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively interacts with its substrate Lck in a Csk-dependent manner. T cell receptor-induced phosphorylation of LYP by Lck on an inhibitory tyrosine residue releases tonic inhibition of signaling by LYP. The R620W variation disrupts the interaction between Lck and LYP, leading to reduced phosphorylation of LYP, which ultimately contributes to gain-of-function inhibition of T cell signaling.

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.

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.

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.

Is there an association between uterine leiomyomas and acid phosphatase locus 1 polymorphism?

OBJECTIVE: Platelet derived growth factor (PDGF) is involved in the development of leiomyomas. The low-molecular-weight phosphoprotein-tyrosine-phosphatase (LMWPTP), controlled by the highly polymorphic acid phosphatase locus 1 (ACP1), is able to dephosphorylate the PDGF receptor. Therefore, we searched for a possible association between ACP1 and leiomyomas. STUDY DESIGN: We studied 172 women hospitalized for symptomatic leiomyomas requiring surgical intervention and 164 healthy women without clinical evidence of leiomyomas from the same white population. The chi(2) test of independence, Pearson correlation, analysis of variance, and post hoc test for difference between means were performed. RESULTS: The distribution of ACP1 genotypes among patients does not differ significantly from that of healthy women. However, leiomyoma size was negatively correlated with ACP1 F isoform concentrations. Leiomyoma size was smaller among carriers of the *B/*B genotype, which has the highest concentration of the F isoform, than among carriers of *A/*A, *C/*B, and *C/*C genotypes, which have the lowest concentration of the F isoform. CONCLUSION: High ACP1 F isoform concentration, through dephosphorylation of the PDGF receptor, may negatively regulate cell proliferation and growth of leiomyomas.

Type 1 diabetes: evidence of interaction between ACP1 and ADA1 gene polymorphisms.

BACKGROUND: ACP1 (acid phosphatase locus 1, a cytosolic low-molecular-weight phosphotyrosin phosphatase) and ADA1 (adenosine deaminase locus 1) are two polymorphic systems involved in immune reactions. Observed interactions at the biochemical and clinical levels between the two systems prompted this investigation of a possible interaction concerning susceptibility to type 1 diabetes. MATERIAL/METHODS: Two hundred eighty-seven children admitted consecutively to the hospital for type 1 diabetes and 727 healthy newborn infants were studied. All were from the Caucasian Italian population living in the central area of Italy. ACP1 and ADA1 genotypes were determined by DNA analysis. RESULTS: In the type 1 diabetics the distribution of ACP1 genotypes was dependent on the ADA1 genotypes, showing an excess of the low-activity *A/*A and *A/*B genotypes in the ADA1*2 carriers compared with the ADA1*1/*1 subjects (OR: 2.200, 95%CI: 1.133-4.298). Such an association was not present in the healthy newborn infants. CONCLUSIONS: This investigation based on the biological effects of ACP1 and ADA1 on the immune system and on the known biochemical interaction between the two systems showed a significant interaction between the two system concerning susceptibility to type 1 diabetes. The low-activity ACP1 genotypes *A/*A and *A/*B carrying the low-activity ADA1*2 allele were more common in type 1 diabetic than in healthy newborns (OR: 1.699 95%CI: 1.066-2.702).

Lack of association between MTHFR C677T and MTHFR A1298C genetic polymorphisms and mental retardation.

Findings suggest that there is no association between MTHFR C677T and MTHFR A1298C and mental retardation in the studied Italian population and that these polymorphisms are not contributing to the aetiology of mental retardation.

Association of adenosine deaminase polymorphism with mild mental retardation.

The etiology of mild mental retardation remains undefined in about 60% of cases. Even though the causes of mild mental retardation are likely to be heterogeneous, the evidence for genetic involvement is increasing, along with the development of specific diagnostic techniques. To improve our understanding of the genetic basis of mild mental retardation, we explored the role of polymorphisms of adenosine deaminase, an enzyme that is supposed to act as a neuroregulatory protein. To this end, we conducted an association study comparing children with mild mental retardation of unknown origin with two groups of controls: (1) apparently healthy children and (2) children with moderate or severe mental retardation of known etiology. Overall, 338 participants were enrolled in the study. Cases (ie, 80 children) were more likely than controls (ie, 153 healthy children and 105 children with moderate or severe mental retardation) to have the low-activity ADA-Asn 8 (ADA(1) *2) polymorphism (P < .05) and to present the ADA(1) *2/ ADA(2) *1 haplotype. No significant differences were found with respect to adenosine deaminase polymorphisms when comparing the group with moderate or severe mental retardation of known causes and healthy controls. In conclusion, our findings suggest a possible role for a low-activity genotype (ADA-8Asn) (ADA(1) *2) of adenosine deaminase in the pathogenesis of mild mental retardation.

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.

Lack of association between IDE genetic variability and Down's syndrome.

Virtually all patients with Down's syndrome develop Alzheimer disease (AD) during their life; thus, it is extremely important to investigate potential determinants of AD in this population. Previous studies found an association of DS with -48C/T presenilin-1 and with the -850 tumor necrosis factor-alpha, two polymorphisms of genes involved in amyloid beta modulation In this study, we evaluated whether the insulin-degrading enzyme (IDE), a protease involved in the degradation of endogenous brain-derived Abeta peptides, is involved in DS-related AD. To this end, 287 DS patients were compared with 251 apparently healthy controls, in order to assess the association between DS and two single nucleotide polymorphisms located on the introns 14 and 24 of the IDE gene. The comparison of allele and genotype distribution between cases and controls showed no evidence for an association with regard to IDE polymorphism, for both the SNPs (i.e., IDE 185 and IDE 199). In conclusion, the findings of our study suggest that the two IDE polymorphisms considered in the analysis do not appear to play a major role in DS-related AD.

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.

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.

Association between presenilin-1 -48C/T polymorphism and Down's syndrome.

Individuals with Down's syndrome (DS), i.e., trisomy 21, over 40 years of age, are likely to develop neuropathological changes characteristic of Alzheimer's disease (AD). The involvement of chromosome 21 both in DS and AD suggests a shared genetic susceptibility to these disorders, but genetic determinants are still undefined. The -48C/T polymorphism in the PSEN1 promoter is a possible candidate, since it has recently been associated with an increased risk of early onset AD. Based on the assumption that the excess of dementia in DS might be a consequence of a different distribution of the -48C/T polymorphism, we investigated the association between DS and this polymorphism in patients with trisomy 21 and controls. Overall, 260 DS patients and 197 controls were recruited at the Department of Neurosciences, Tor Vergata University of Rome. Cases and controls had similar age and gender distribution. High molecular weight DNA was extracted from whole blood samples collected in EDTANa(2) and -48C/T genotypes were determined. Genotype and allele frequencies were compared between cases and controls. Cases were less likely than controls to have the CC genotype ( P = 0.05). A significant difference for allele distribution between DS cases and controls was found, with DS showing a lower frequency of the allele C compared with the control population (OR: 0.57; 95% CI: 0.35-0.91; P = 0.01). No significant interaction of PSEN1 with age, gender, ApoE and -850 TNF-alpha polymorphisms was found. The association found suggests that the -48C/T polymorphism in the PSN1 gene promoter, which is involved in the modulation of amyloid beta load in human AD, is associated with DS. However, the biological role of this polymorphism in DS-related dementia remains unclear and merits further investigation.

Convulsive disorder and the genetics of signal transduction; a study of a low molecular weight protein tyrosine phosphatase in a pediatric sample.

Recent studies point to an involvement of kinases and phosphatases in ionic channel regulation and in physiopathologic mechanisms leading to convulsive disorders. Acid phosphatase locus 1 (ACP1), also named cytosolic low molecular weight phosphotyrosine phosphatase, is a highly polymorphic phosphatase that is especially abundant in the central nervous system and is known to be involved in several signal transduction pathways. We studied ACP1 in 122 children with idiopathic generalized tonic-clonic seizures, 80 children with febrile convulsions, and 417 controls from the population of Rome. Low activity phenotypes of ACP1 (*A/*A and *A/*B) were found to be over-represented while high activity phenotypes (*C/*C and *B/*C) were under-represented in generalized seizures cases compared to controls (P < 0.005). No significant difference was observed between febrile convulsion cases and controls. These observations suggest a protective role of the high activity ACP1 phenotypes against seizures in children.