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      Coronary Artery Disease: Evidence of Interaction between PTPN22 and p53 Genetic Polymorphisms

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          Abstract

          Objectives: We recently reported an association between the PTPN22 genetic polymorphism and coronary artery disease (CAD) in nondiabetic subjects. Since recent studies suggest that p53 may be involved in coronary atherosclerosis, we have investigated a possible interaction between PTPN22 and p53 codon 72 genetic polymorphisms regarding their effects on susceptibility to CAD in nondiabetic subjects. Methods: The genotypes of p53 codon 72 and PTPN22 were determined by DNA analysis in 128 nondiabetic subjects with CAD, 122 healthy blood donors and 117 nondiabetic subjects with cardiovascular diseases without CAD. Results: In subjects with the *Arg/*Arg genotype of p53 codon 72, no association was observed between CAD and PTPN22. However, this association was very strong in subjects carrying the *Pro allele of p53 codon 72. Subjects carrying both the *T allele of PTPN22 and the *Pro allele of p53 were overrepresented in CAD nondiabetic cases relative to the other two groups (p = 0.001). Conclusions: Since both p53 and PTPN22 are involved in autoimmune inflammation, an interaction between the two systems appears biologically plausible. In the analysis of multifactorial disorders, the simultaneous analysis of multiple genes functionally related to diseases will provide a more productive approach than studies of single genetic factors performed from a Mendelian perspective.

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          Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function.

          Mohammed S. Lamhamedi, Lingyun Xu, Shi-Biao Zheng … (2005)
          The tumor suppressor p53 regulates apoptosis, cell cycle, and oncogenesis. To explore the roles of p53 in autoimmunity, we studied type 1 diabetes and innate immune responses using C57BL/6 mice deficient in p53. We found that p53-deficient mice were more susceptible to streptozotocin-induced diabetes than control mice, and they produced higher levels of interleukin-1, -6, and -12. The innate immune response of p53-/- macrophages to lipopolysaccharides and gamma-interferon was significantly enhanced compared with p53+/+ cells. p53-/- macrophages produced more proinflammatory cytokines and higher levels of total and phosphorylated signal transducer and activator of transcription (STAT)-1. These results indicate that p53 inhibits autoimmune diabetes and innate immune responses through downregulating STAT-1 and proinflammatory cytokines.
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            Apoptosis of CD4+CD25high T Cells in Type 1 Diabetes May Be Partially Mediated by IL-2 Deprivation

            Parthav Jailwala, Jill Waukau, Sanja Glisic … (2009)
            Background Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease targeting the insulin-producing pancreatic β cells. Naturally occurring FOXP3+CD4+CD25high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing autoreactive CD4+ effector T cell activity. Previously, in both recent-onset T1D patients and β cell antibody-positive at-risk individuals, we observed increased apoptosis and decreased function of polyclonal Tregs in the periphery. Our objective here was to elucidate the genes and signaling pathways triggering apoptosis in Tregs from T1D subjects. Principal Findings Gene expression profiles of unstimulated Tregs from recent-onset T1D (n = 12) and healthy control subjects (n = 15) were generated. Statistical analysis was performed using a Bayesian approach that is highly efficient in determining differentially expressed genes with low number of replicate samples in each of the two phenotypic groups. Microarray analysis showed that several cytokine/chemokine receptor genes, HLA genes, GIMAP family genes and cell adhesion genes were downregulated in Tregs from T1D subjects, relative to control subjects. Several downstream target genes of the AKT and p53 pathways were also upregulated in T1D subjects, relative to controls. Further, expression signatures and increased apoptosis in Tregs from T1D subjects partially mirrored the response of healthy Tregs under conditions of IL-2 deprivation. CD4+ effector T-cells from T1D subjects showed a marked reduction in IL-2 secretion. This could indicate that prior to and during the onset of disease, Tregs in T1D may be caught up in a relatively deficient cytokine milieu. Conclusions In summary, expression signatures in Tregs from T1D subjects reflect a cellular response that leads to increased sensitivity to apoptosis, partially due to cytokine deprivation. Further characterization of these signaling cascades should enable the detection of genes that can be targeted for restoring Treg function in subjects predisposed to T1D.
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              Inflammation and immune response in atherosclerosis.

              Mats Hansson (1999)
              Atherosclerosis is an inflammatory disease with a significant autoimmune component. Studies using transgenic murine models have clarified that recruitment of mononuclear leukocytes through vascular leukocyte-adhesion molecules and chemokines, differentiation of monocytes to macrophages, and endocytosis through scavenger receptors all are of decisive importance for atherosclerosis in hypercholesterolemic mice. T and B cells modulate disease progression and lesion development is reduced in mice lacking adaptive immunity. In particular, local immune responses eliciting Th1 effector mechanisms appear to be proatherogenic, whereas protective immune responses can be induced by immunization with oxidized low-density lipoprotein. Thus, innate immunity is necessary for atherosclerosis, whereas adaptive immunity is an important modulator of disease development.
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                Author and article information

                Journal
                Journal ID (publisher-id): CRD
                Journal ID (nlm-ta): Cardiology
                Journal ID (doi): 10.1159/issn.0008-6312
                Title: Cardiology
                Publisher: S. Karger AG
                ISSN (Print): 0008-6312
                ISSN (Electronic): 1421-9751
                Publication date Subscription-year: 2011
                Publication date (Print): January 2012
                Publication date (Electronic): 29 December 2011
                Volume: 120
                Issue: 3
                Pages: 166-168
                Affiliations
                aDepartment of Biopathology and Imaging Diagnostics, University of Rome Tor Vergata, Rome, and bDepartment of Cardiology, Valmontone Hospital, Valmontone, Italy
                Author notes
                *Fulvia Gloria-Bottini, MD, Division of Biopathology of Human Populations and Environmental Pathology, Department of Biopathology and Imaging Diagnostics, University of Rome Tor Vergata, School of Medicine, Via Montpellier, IT–00133 Rome (Italy), Tel. +39 06 7259 6030, E-Mail gloria@med.uniroma2.it
                Article
                Publisher ID: 334808 Other ID: Cardiology 2011;120:166–168
                DOI: 10.1159/000334808
                PubMed ID: 22212723
                SO-VID: fb412812-271a-4abd-b571-ae451ba66d29
                Copyright © © 2011 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 29 September 2011
                Date accepted : 14 October 2011
                Page count
                Tables: 2, Pages: 3
                Categories
                Subject: Short Communication

                ScienceOpen disciplines: General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Keywords: Coronary artery disease,PTPN22,p53 codon 72
                Data availability:
                ScienceOpen disciplines: General medicine, Neurology, Cardiovascular Medicine, Internal medicine, Nephrology
                Keywords: Coronary artery disease, PTPN22, p53 codon 72

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