RESUMEN

Protein tyrosine phosphatases (PTPs) regulate T cell receptor (TCR) signalling and thus have a role in T cell differentiation. Here we tested whether the autoimmune predisposing gene PTPN22 encoding for a PTP that inhibits TCR signalling affects the generation of forkhead box protein 3 (FoxP3)(+) T regulatory (Treg ) cells and T helper type 1 (Th1) cells. Murine CD4(+) T cells isolated from Ptpn22 knock-out (Ptpn22(KO) ) mice cultured in Treg cell polarizing conditions showed increased sensitivity to TCR activation compared to wild-type (WT) cells, and subsequently reduced FoxP3 expression at optimal-to-high levels of activation. However, at lower levels of TCR activation, Ptpn22(KO) CD4(+) T cells showed enhanced expression of FoxP3. Similar experiments in humans revealed that at optimal levels of TCR activation PTPN22 knock-down by specific oligonucleotides compromises the differentiation of naive CD4(+) T cells into Treg cells. Notably, in vivo Treg cell conversion experiments in mice showed delayed kinetic but overall increased frequency and number of Treg cells in the absence of Ptpn22. In contrast, the in vitro and in vivo generation of Th1 cells was comparable between WT and Ptpn22(KO) mice, thus suggesting PTPN22 as a FoxP3-specific regulating factor. Together, these results propose PTPN22 as a key factor in setting the proper threshold for FoxP3(+) Treg cell differentiation.

Asunto(s)

RESUMEN

Recent investigations suggest that Adenosine Deaminase (ADA) could play a role in susceptibility to rheumatoid arthritis (RA). The purpose of our study is to investigate the possible role of genetic variability of ADA in the susceptibility to RA. We studied three intragenic ADA polymorphisms, ADA1, ADA2 and ADA6, in a sample of 91 subjects with RA and in 246 healthy subjects from the same Caucasian population and compared genotype and pairwise haplotype distributions between cases and controls. No statistically significant differences between RA and controls are observed for ADA genotypes. A border line difference for ADA1-ADA2 haplotype distribution is observed due to a decreased proportion of ADA1 *2/ADA2 *2 haplotype in RA compared to controls. Our data indicate a border line effect of ADA gene polymorphism on susceptibility to RA that need to be confirmed in other clinical settings.

Asunto(s)

RESUMEN

BACKGROUND: Adenosine deaminase is a polymorphic enzyme that has an important role in immune functions and in the regulation of intracellular and extracellular concentrations of adenosine and adenosine receptor activity. AIM: To search for possible association of type 1 diabetes mellitus (DM1) with three loci haplotypes (ADA1, ADA2, ADA6) of the adenosine deaminase gene. PATIENTS: One hundred and eighty-nine consecutive children with DM1 from Sassari, Sardinia, and a control sample of 239 children from the same area were studied. METHODS: ADA loci genotypes were determined by DNA analysis. RESULTS: Compared to controls, diabetic boys show a decrease of the 2(2)/6(1) haplotype while diabetic girls show an increase of the same haplotype. This association was replicated in an independent sample from Continental Italy. CONCLUSIONS: The 2(2)/6(1) haplotype may exert a protective action in males but may increase susceptibility to DM1 in females: OR = 0.398, 95% CI 0.16-0.96 for males, and OR = 2.31, 95% CI 1.32-4.06 for females.

Asunto(s)

RESUMEN

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is the third major locus affecting risk of type I diabetes (T1D), after HLA-DR/DQ and INS. The most associated single-nucleotide polymorphism (SNP), rs2476601, has a C->T variant and results in an arginine (R) to tryptophan (W) amino acid change at position 620. To assess whether this, or other specific variants, are responsible for T1D risk, the Type I Diabetes Genetics Consortium analyzed 28 PTPN22 SNPs in 2295 affected sib-pair (ASP) families. Transmission Disequilibrium Test analyses of haplotypes revealed that all three haplotypes with a T allele at rs2476601 were overtransmitted to affected children, and two of these three haplotypes showed statistically significant overtransmission (P=0.003 to P=5.9E-12). Another haplotype had decreased transmission to affected children (P=3.5E-05). All haplotypes containing the rs2476601 T allele were identical for all SNPs across PTPN22 and only varied at centromeric SNPs. When considering rs2476601 'C' founder chromosomes, a second haplotype (AGGGGC) centromeric of PTPN22 in the C1orf178 region was associated with protection from T1D (odds ratio=0.81, P=0.0005). This novel finding requires replication in independent populations. We conclude the major association of PTPN22 with T1D is likely due to the recognized non-synonymous SNP rs2476601 (R620W).

Asunto(s)

RESUMEN

Mycobacterium tuberculosis, the causal agent of pulmonary tuberculosis (TB), remains a major health problem throughout the world causing high mortality in humans. Previous studies showed that several genes may play crucial roles in susceptibility to TB. The PTPN22 gene encodes the lymphoid tyrosine phosphatase that has an important regulatory effect on T- and B-cell activation in immune response. The purpose of this study was to investigate the role of two functional missense single nucleotide polymorphisms (SNPs) of the PTPN22 gene region (R620W and R263Q) in the susceptibility to TB in the Moroccan population. A case-control association study was performed including 123 pulmonary TB patients and 155 healthy controls. All subjects were genotyped by TaqMan SNP genotyping assays. Regarding the PTPN22 R620W (C1858T) SNP, we observed a statistically significant difference in the distribution of the PTPN22 1885T allele between pulmonary TB patients and healthy controls (0.41% vs 3.2%, P = 0.01, odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.01-0.93). With respect to the PTPN22 R263Q (G788A), we observed an increase of 788A allele frequencies in TB patients compared with those in healthy controls (3.65% vs 0.65%, P = 0.01, OR = 5.85, 95% CI = 1.17-39.55). These results suggest that PTPN22 gene variants may affect susceptibility to TB in the Moroccan population.

Asunto(s)

RESUMEN

OBJECTIVES: Assuming an immune component in the pathogenesis of atherosclerosis, we have investigated a possible association between coronary artery disease (CAD) and the acid phosphatase locus 1 (ACP1) genetic polymorphism, which has previously been found to be associated with immune disorders. METHODS: 226 subjects admitted to the hospital for CAD, 358 consecutive newborn infants, 279 adult subjects with type 2 diabetes without CAD and 137 adults without diabetes and without CAD from the Caucasian population of Rome were studied. The ACP1 genotype was determined by DNA analysis. Statistical analyses were performed using the SPSS package. RESULTS: CAD females showed an excess of ACP1 *A/*C and *B/*C genotypes and a deficiency of ACP1 *B/*B genotype compared to controls, while CAD males did not show significant differences. Among diabetic women the proportion of *C allele carriers was much greater in those with CAD than in those without CAD. This difference was much less evident in nondiabetic women. CONCLUSION: ACP1 may be involved in susceptibility to CAD. Since ACP1 has been found to be associated with immunological diseases, our observation reinforces the notion of an immune component in the pathogenesis of atherosclerosis.

Asunto(s)

RESUMEN

The missense PTPN22 C1858T polymorphism recently emerged as an important population-independent risk factor for type 1 diabetes (T1D) and other autoimmune diseases. The PTPN22 gene encodes the lymphoid tyrosine phosphatase (LYP), a negative regulator of signal transduction through the T-cell receptor. Although the frequency of the polymorphism is variable among different ethnic groups, the association between PTPN22 *T1858 and T1D has been replicated in several populations. Here, we contribute the first replication of the association between PTPN22 and T1D in populations from continental Italy, carried out in two independent samples of T1D patients (N = 216 and 82) and controls (N = 271 and 89). Our data also suggest that T1D carriers of the *T1858 allele could be at increased risk for other comorbid autoimmune disorders.

Asunto(s)

RESUMEN

BACKGROUND: Previous studies have shown a negative association between ACP1 *B/*C genotype and total IgE level. ACP1 (acid phosphatase locus 1) is a polymorphic phosphotyrosine phosphatase that interacts with IL4-RA and is involved in T cell receptor signaling. METHODS: In the present paper, we have studied the relationship between *B/*C genotype which shows high ACP1 activity and skin testing in 300 adult subjects referred for allergic manifestations. ACP1 genotypes were determined by DNA analysis. RESULTS: There is a significant negative correlation between the intensity of skin test reaction and *B/*C genotype (p = 0.01). The proportion of *B/*C genotype is lower in allergic subjects with intense skin reaction than in allergic subjects with moderate skin reaction and in healthy controls. CONCLUSIONS: This new observation confirms by a different approach the relationship between ACP1 polymorphism and allergic manifestations, suggesting that high ACP1 activity protects against these manifestations.

Asunto(s)

RESUMEN

OBJECTIVE: Genetic differences in the activity of phosphotyrosine phosphatases between mother and embryo could result in a differential activation of signals induced by growth factors in the two sides of placenta. Previous observations suggest that this may have important effects on intrauterine development and survival. The aim of the present study is to confirm previous observations and show new data. STUDY DESIGN: We have studied 573 mother/newborn pairs, 169 wife/husband couples with repeated spontaneous abortion and 34 fertile wife/husband couples RESULTS: In mother/newborn pairs, the analysis of joint mother/infant ACP1 distribution has shown a deficit of pairs with the mother having low ACP1 S isoform concentration and the infant having high S isoform concentration, and an excess of pairs with the mother having high S isoform concentration and the infant having low S isoform concentration. In RSA couples there is an excess of couples in which the wife has low S isoform concentration and the husband has high S isoform concentration and a deficit of couples in which the wife has high S isoform concentration and the husband has low S isoform concentration. In fertile couples the pattern is reversed. CONCLUSION: The data suggest that when the mother to fetus S isoform concentration ratio is in favour of the mother, the probability of survival of the fetus is greater than in the opposite situation.

Asunto(s)

RESUMEN

PROBLEM: In consideration of the effect of adenosine deaminase (ADA) and ACP1 (a low-molecular-weight protein tyrosine phosphatase) on T-cell receptor activity, we have analysed the joint distribution of these polymorphisms in a sample of women with primary repeated spontaneous abortion (RSA) to search for possible interactive effects on susceptibility to RSA. METHOD OF STUDY: ACP1 and ADA phenotypes were determined in 170 women with primary RSA in 79 healthy consecutive puerperae and in 160 female newborns from the Caucasian population of Rome and in 357 healthy consecutive puerperae from the Caucasian population of Penne. Chi-square test of independence and three way contingency table analysis by a log-linear model were performed. RESULTS: Women with low-ADA activity and high-ACP1 activity show the lowest susceptibility to RSA. Women with high-ADA activity and low-ACP1 activity, on the contrary, show the highest susceptibility to RSA and also the highest incidence of auto antibodies and of A blood group incompatibility. CONCLUSION: The data are in agreement with those expected on the basis of the effects of ACP1 and ADA genetic variability on T-cell receptor activity and suggest a cooperative effect of the two polymorphic systems in the susceptibility/resistance to repeated spontaneous abortion.

Asunto(s)

RESUMEN

BACKGROUND: Data collected by our group in the past years indicate a relationship between ACP1 genetic polymorphism and susceptibility/resistance to immunological diseases. Recent observations suggest that through modulation of ZAP-70 activity, the enzyme may influence T cell activation. In view of the current interest in gender differences in autoimmune diseases we reviewed our data to enlighten possible effects of gender on the relationship between ACP1 and class of immunological disease. METHODS: We studied three samples of subjects with allergic disorders of a total of 299 subjects, 71 subjects with Crohn's disease and 188 children with type 1 diabetes. Three-way contingency tables were analyzed by a log linear model and two-way contingency tables by chi(2) test. RESULTS: There is an association between ACP1 and allergy (Th2 class) that depends on gender: the presence of the ACP1*A allele seems to make females more susceptible to allergic manifestations as compared to males. ACP1 is also associated with Crohn's disease and type 1 diabetes: the relationship between this class (Th1) of immunological diseases and ACP1 depends on gender. The presence of *A allele seems to make females less susceptible to this class of diseases as compared to males. CONCLUSIONS: The ACP1*A allele which is associated with low ACP1 activity appears responsible for a complex relationship involving gender, ACP1 and Th1/Th2 orientation. Low ACP1 activity influencing ZAP-70 activity and in turn T cell activation seems to have opposite effects on Th1/Th2 orientation depending on gender.

Asunto(s)

RESUMEN

BACKGROUND: Data from previous study by our group suggest that in smoking women sex ratio of offspring is higher in newborns carrying ACP1C allele than in other ACP1 genotypes, suggesting that differences observed among human population concerning the effect of smoking may depend in part on this genetic factor. OBJECTIVES: In order to further explore this issue we have studied another population and have analysed the relationship between sex ratio and ACP1C gene frequency at population level. METHODS: The analysis includes 719 consecutive births from Central Italy considered in a previous paper and 5510 consecutive births from Sardinia. Data from English and Japanese populations have also been considered in the analysis. RESULTS: Among newborns not carrying ACP1C there is a decrease of SR among the offspring of smoking mothers, while among newborns carrying the ACP1C allele there is an increase of SR among the offspring of smoking mothers relative to non-smoking mothers. Considering Sardinian, Italian, English and Japanese population there is a linear positive relationship between C allele frequency and SR in smoking mothers. CONCLUSIONS: The present observation suggests an interaction between smoking and ACP1 regarding their effects on sex ratio, by which the presence of the ACP1C allele appears to counteract the effect of smoking. This suggests that genetic background may modify the effects of toxic environmental factors on gamete production and functionality and/or on intrauterine survival.

Asunto(s)

Asunto(s)

RESUMEN

We have studied a sample of 120 asthmatic patients and 116 healthy control subjects from the Chinese Han population. Three polymorphic sites: ADA(1), ADA(2), and ADA(6), within the ADA gene have been examined. The proportion of carriers of *2 allele at locus ADA(1) is drastically reduced in asthmatics as compared to controls. There is an epistatic interaction of ADA(2) on the ADA(1) site characterized by a suppressive effect by the *2 allele of ADA(2) on the protective effect exerted by the *2 allele of ADA(1) site on susceptibility to asthma. Our data suggest the presence of some DNA sequences influencing the susceptibility to asthma are located in the area between ADA(1) and ADA(2) sites.

Asunto(s)

RESUMEN

Associations with past malarial morbidity, season of conception, and common diseases such as obesity, type 2 diabetes, and allergy argue against neutrality of the ACP1 genetic polymorphism. Comparison of ACP1 distribution in mothers and their newborns and analysis of the joint wife-husband ACP1 phenotype distribution in couples with repeated spontaneous abortion suggest a negative effect of the ACP1*C allele on early life viability. Analysis of the polymorphism of the ACP1 gene suggests that, unlike the ACP1*A and ACP1*B alleles, the ACP1*C allele is independent of sequences in the 5' flanking region, resulting in an inverted F/S isoform ratio.

Asunto(s)

Asunto(s)

RESUMEN

BACKGROUND: It is likely that besides developmental and environmental factors, genetic factors also play an important role in Th1/Th2 orientation and susceptibility to related disorders. Thus, for each genetic factor involved one would expect an opposite pattern of susceptibility towards Th1- and Th2-associated diseases. METHODS: We report a comparative analysis of the pattern of association of four genetic polymorphisms with bronchial asthma (Th2 disease) and Crohn's disease (CD; Th1 disease). The study population included 291 Roman children with bronchial asthma and 72 adult Romans with CD, and haptoglobin, adenosine deaminase (ADA), acid phosphatase locus 1 (ACP1) and MN phenotypes were determined. RESULTS: Compared with controls from the same population, the pattern of phenotype association observed in bronchial asthma is exactly opposite to that observed in CD. The analysis of pairwise gametic type distribution for ACP1, ADA and MN polymorphisms has shown that the pattern of differences between bronchial asthma and controls is opposite to that observed between CD and controls. CONCLUSIONS: The pattern of differences between bronchial asthma versus CD is compatible with the hypothesis that some of the genetic systems considered contribute to Th1/Th2 orientation.

Asunto(s)

RESUMEN

In 155 asthmatic children we have studied the relationship between prick test positivity and a set of genetic factors previously found to be associated with bronchial asthma. Among these factors, MN system (p = 0.009) and age at onset of symptoms (p = 0.05) are the most important variables separating prick test negative from prick test positive children. MN and age at onset influence independently prick test positivity pointing to an additive effect of the two variables. M phenotype appears correlated positively with an increased susceptibility to nonallergic asthma in all age groups, whereas N phenotype appears correlated positively with age at onset but in allergic asthma only. The MN system codifies for glycophorin A, a sialoglycoprotein that represents a major ligand for several bacteria and viruses that recognize the N-acetylneuraminic acid present in this protein. The present data suggest that genetic variability in this system might influence bacterial and viral competition and mucosal damage influencing susceptibility to asthmatic reactions in absence of IgE hyperproduction.

Asunto(s)

RESUMEN

We carried out a study of adenosine deaminase (ADA) and MN blood group genetic polymorphisms in relation to past malarial morbidity in Sardinia and in relation to susceptibility to allergic asthma (a Th2 disorder) and Crohn's disease (a Th1 disorder) in the population of Rome. Eight hundred and eight schoolchildren, aged 7--14 years from 14 Sardinian villages located in the central area of the island, were considered. One hundred and twenty-two children with allergic asthma and 39 adult patients with Crohn's disease from the population of Rome were also studied. The data suggest an interaction between the two systems concerning resistance/susceptibility, both to malaria and to the diseases considered. In Sardinia, the frequency of the *L(M)/ADA*2 gametic type is negatively correlated with past malarial endemia, suggesting an increased susceptibility to malaria leading to its decrease in areas with high malarial endemia. In Rome, this gametic type is correlated negatively to allergic asthma and positively to Crohn's disease, suggesting a protective effect against allergic asthma and increased susceptibility to Crohn's disease.

Asunto(s)

RESUMEN

BACKGROUND: We have investigated the possible role of ACP1 (also known as cLMWPTP: cytosolic low molecular weight phosphotyrosine phosphatase), a highly polymorphic enzyme involved in signal transduction of T-cell receptor, insulin receptor and other growth factors in the relationship between maternal age at delivery and risk of type 1 diabetes in the offspring. METHODS: One hundred and eighty-nine consecutive children with type 1 diabetes (TIDM) diagnosed at the Department of Pediatrics of the University of Sassari (Sardinia) were studied. A control sample of 5460 consecutive newborns from the same population was also studied. RESULTS: Maternal age at birth of children with type 1 diabetes has shifted towards high values. There is also an effect of birth order on the susceptibility to type 1 diabetes, which is independent of that due to maternal age. The proportion of low activity ACPl genotypes is much higher among children born from older mothers than among diabetic children born from relatively young mothers. There is a significant effect of sex, maternal age, sex-ACPl two-way interaction and sex-ACP1-maternal age three-way interaction on the age at diagnosis of diabetes. CONCLUSIONS: The present data confirm the strong association between maternal age at delivery and risk of type 1 diabetes in the child. In addition, our analysis suggests a complex interaction among maternal age, sex of infant and ACP1 concerning age at diagnosis of diabetes. Thus, risk and clinical course of type 1 diabetes seem to be dependent on both maternal environment during intrauterine development and foetal genetic factors.

Asunto(s)