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The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus.

ABSTRACT: The C1858T polymorphism in PTPN22 has been associated with the risk of systemic lupus erythematosus (SLE) as well as multiple other autoimmune diseases. We have previously shown that high serum interferon-alpha (IFNalpha) activity is a heritable risk factor for SLE. The aim of this study was to determine whether the PTPN22 risk variant may shift serum cytokine profiles to higher IFNalpha activity, resulting in risk of disease.IFNalpha was measured in 143 patients with SLE, using a functional reporter cell assay, and tumor necrosis factor alpha (TNFalpha) was measured by enzyme-linked immunosorbent assay. The rs2476601 single-nucleotide polymorphism in PTPN22 (C1858T) was genotyped in the same patients. Patients were grouped, using a clustering algorithm, into 4 cytokine groups (IFNalpha predominant, IFNalpha and TNFalpha correlated, TNFalpha predominant, and both IFNalpha and TNFalpha low).SLE patients carrying the risk allele of PTPN22 had higher serum IFNalpha activity than patients lacking the risk allele (P = 0.027). TNFalpha levels were lower in carriers of the risk allele (P = 0.030), and the risk allele was more common in patients in the IFNalpha-predominant and IFNalpha and TNFalpha-correlated groups as compared with patients in the TNFalpha-predominant and both IFNalpha and TNFalpha-low groups (P = 0.001). Twenty-five percent of male patients carried the risk allele, compared with 10% of female patients (P = 0.024); however, cytokine skewing was similar in both sexes.The autoimmune disease risk allele of PTPN22 is associated with skewing of serum cytokine profiles toward higher IFNalpha activity and lower TNFalpha levels in vivo in patients with SLE. This serum cytokine pattern may be relevant in other autoimmune diseases associated with the PTPN22 risk allele.

SUBMITTER: Kariuki SN

PROVIDER: S-EPMC2621106 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus.

Kariuki Silvia N SN Crow Mary K MK Niewold Timothy B TB

Arthritis and rheumatism 20080901 9

<h4>Objective</h4>The C1858T polymorphism in PTPN22 has been associated with the risk of systemic lupus erythematosus (SLE) as well as multiple other autoimmune diseases. We have previously shown that high serum interferon-alpha (IFNalpha) activity is a heritable risk factor for SLE. The aim of this study was to determine whether the PTPN22 risk variant may shift serum cytokine profiles to higher IFNalpha activity, resulting in risk of disease.<h4>Methods</h4>IFNalpha was measured in 143 patient ...[more]

PMID: 18759295

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Project description:ObjectiveInflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon alfa-based treatments. Evidence also indicates a central nervous system role for tumor necrosis factor alpha (TNF-alpha), whose expression may be increased by interferon alfa. A polymorphism in the promoter region of TNF-alpha has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-alpha polymorphism would influence susceptibility to psychiatric symptoms during interferon alfa therapy.MethodsOne hundred five patients with hepatitis C, initially without active major depression (major depressive disorder), were treated with interferon alfa and then prospectively monitored using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Beck Depression Inventory II, the Anger Irritability and Assault Questionnaire, and circulating TNF-alpha levels. The A-308G polymorphism (rs1800629) was determined using the 5'-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time.ResultBeck Depression Inventory II score increased during interferon alfa therapy (F = 6.2; P < 0.001), with 27% developing MDD. The TNF-alpha A allele was associated with worsened labile anger (F = 2.5; P < 0.05) and fatigue (F = 2.9; P < 0.05) during treatment but not with major depression incidence (chi = 0.0; P = 0.99) or increased Beck Depression Inventory II (F = 1.2; P = 0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; P = 0.59).DiscussionDuring treatment with an exogenous cytokine, vulnerability to worsening labile anger-distinct from major depression-is associated with genetic variability in TNF-alpha. This has implications both for patients being treated with interferon alfa and our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

Project description:It was previously published that single-nucleotide polymorphism rs2476601 (PTPN22 [protein tyrosine phosphatase non-receptor type 22]-C1858T) might be related to increased sensibility to Mycobacterium tuberculosis and M. leprae infection. However, the results were inconclusive despite a high degree of similarity between both parameters. Herein, we carried out this meta-analysis to systematically summarize and articulate the correlation between PTPN22-C1858T polymorphism and mycobacterial infection. The susceptibility of PTPN22-C1858T carriers with autoimmune conditions receiving immunosuppressive therapy to M. tuberculosis and M. leprae infection was determined. A systematic retrieval of studies on relevance of PTPN22-C1858T polymorphism to susceptibility of M. tuberculosis or M. leprae infection was performed in Chinese National Knowledge Infrastructure, PubMed and Embase databases. We regarded Odds ratios (ORs) and 95% confidence intervals (CIs) as the determined effect size. Finally, four and two case-control studies on tuberculosis and leprosy, respectively, were included. In all genetic models, without indicated association between PTPN22-C1858T polymorphism and tuberculosis's susceptibility. [C versus T: OR = 0.22 (95% CI: 0.09-0.50, PH = 0.887); CT versus CC: OR = 0.21 (95% CI: 0.09-0.49, PH = 0.889); TT+CT versus CC: OR = 0.21 (95% CI: 0.09-0.49, PH = 0.889)]. A significantly increased risk of leprosy was perceived in patients with the PTPN22-C1858T polymorphism [C versus T: OR = 2.82 (95% CI: 1.02-7.81, PH = 0.108)]. While the PTPN22-C1858T polymorphism is irrelevant to higher susceptibility to the infection of M. tuberculosis in Caucasians and Asians, it is relevant to increased susceptibility to the infection of M. leprae. However, the results of M. leprae are supposed to interpreted with prudence owing to the limited quantity of studies and heterogeneity. Further well-designed studies with sufficient populations are required to verify our conclusions.

Dataset Information

The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus.

Publications

The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus.

Similar Datasets

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