Patrizia Saccucci

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.

Autism: evidence of association with adenosine deaminase genetic polymorphism

Abstract Reduced adenosine deaminase (ADA) activity has been reported in sera of autistic children relative to controls. Additionally, the Asn allele of the ADA Asp8Asn polymorphism has been associated with reduced enzymatic activity. Therefore, we studied this polymorphism in autistic children and controls from two Italian populations. We observed a significantly elevated frequency of the low-activity Asn allele in the total sample of autistic cases relative to controls (P<0.00001), and in both study populations (P<0.001 and P<0.025). We suggest that this putative genotype-dependent reduction in ADA activity may be a risk factor for the development of autism.

Association between PTPN22 C1858T and type 1 diabetes: a replication in continental Italy

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.

IL-4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two-locus haplotypes are more informative than individual SNPs.

The IL‐4RA locus encodes for the alpha chain of the IL‐4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL‐4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs).

ACP1 genetic polymorphism and coronary artery disease: an association study.

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.

Genetic control of serum IgE levels: a study of low molecular weight protein tyrosine phosphatase.

Protein tyrosine phosphatases (PTPases) have recently been recognized as important modulators of various signal transduction pathways in immune cells. Genetic polymorphisms have been described in genes codifying for members of this family of enzymes, and the genetics of PTPases is predicted to play an important role in the etiology of immune diseases and of their clinical variability. The low molecular weight protein tyrosine phosphatase (ACP1 or LMPTP) is one of the few PTPases with a known genetic polymorphism, and has been proposed to be associated with atopic dermatitis in a small sample from an Italian population. In this paper we describe the association of the ACP1 polymorphism with total IgE levels in two independent samples from English and Italian populations. In both the samples the mean value of serum IgE is lower among subjects carrying the BC genotype than in other ACP1 genotypes. The BC genotype is associated with the highest total ACP1 enzymatic activity. Our data suggest that one or both of the ACP1 isoforms exert an inhibitory role on some signal transduction pathway relevant for IgE hyperproduction.

Is there a role of p53 codon 72 polymorphism in the susceptibility to type 2 diabetes in overweight subjects? A study in patients with cardiovascular diseases

Two hundred and eighty six subjects with cardiovascular diseases and 147 healthy newborns were studied. P53 codon 72 polymorphism was determined by DNA analysis. The association between BMI and diabetes depends on p53 polymorphism: Odds Ratio shows a high significant association between BMI and diabetes in *Arg/*Arg subjects (p=0.00001). No significant association is observed in *Pro allele carriers (p=0.203).

Genetic polymorphism and Th1/Th2 orientation

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.

Risk of type 1 diabetes in childhood and maternal age at delivery, interaction with ACPI and sex

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.

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

Abstract 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.