Risk Of Multiple Autoimmune Diseases Research Articles

Leukocyte Ig-like receptor A3 facilitates inflammation, migration and invasion of synovial tissue-derived fibroblasts via ERK/JNK activation.

Leukocyte Ig-like receptor A3 (LILRA3) is a soluble receptor belongs to the immunoglobulin superfamily. Our previous studies demonstrated that LILRA3 is a common genetic risk for multiple autoimmune diseases, including RA. Functional LILRA3 conferred increased risk of joint destruction in patients with early RA. We undertook this study to further investigate the pathological role of LILRA3 in joint inflammation of RA. Soluble LILRA3 was measured by ELISA. LILRA3 plasmids were transfected into human fibroblast-like synoviocytes (FLSs) using electroporation. Activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was determined by western blots. Cytokine transcripts were quantified by real-time PCR. Migratory and invasive capacities of FLSs were evaluated using transwell migration and Matrigel invasion assays. FLS apoptosis was analysed using flow cytometry. Colocalization of LILRA3, LILRB1 and HLA-G in RA-FLSs was visualized by immunofluorescence staining. Soluble LILRA3 was specifically expressed in synovial fluid and serum LILRA3 was significantly increased and positively correlated with disease activity/severity in RA patients. LILRA3 induced an increased expression of IL-6, IL-8 and MMP3 in RA-FLSs. In vitro LILRA3 stimulation or overexpression promoted RA-FLS migration and invasion, and enhanced phosphorylation of ERK/JNK. Inhibition of ERK/JNK resulted in suppression of IL-6/IL-8 expression in LILRA3-stimulated RA-FLSs. LILRA3 was co-localized with its homologue LILRB1 and shared ligand HLA-G in RA-FLSs. The present study provides the first evidence that soluble LILRA3 is a novel proinflammatory mediator involved in synovial inflammation by promoting RA-FLS activation, migration and invasion, probably through the ERK/JNK signalling pathways.

PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses.

A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive T cells to generate PTPN22 risk edited (620W), non-risk edited (620R), or knockout T cells from the same donor. PTPN22 risk edited cells exhibited increased activation marker expression following non-specific TCR engagement, findings that mimicked PTPN22 KO cells. Next, using lentiviral delivery of T1D patient-derived TCRs against the pancreatic autoantigen, islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP), we demonstrate that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR, but not a high-avidity TCR. In this setting, loss of PTPN22 mediated enhanced proliferation and Th1 skewing. Importantly, expression of the risk variant in association with a lower avidity TCR also increased proliferation relative to PTPN22 non-risk T cells. Together, these findings suggest that, in primary human T cells, PTPN22 rs2476601 contributes to autoimmunity risk by permitting increased TCR signaling and activation in mildly self-reactive T cells, thereby potentially expanding the self-reactive T cell pool and skewing this population toward an inflammatory phenotype.

HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors.

Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. Here we investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which confers antigen recognition. We observed unexpectedly strong HLA-CDR3 associations. The strongest association was found at HLA-DRB1 amino acid position 13, the position that mediates genetic risk for multiple autoimmune diseases. We identified multiple CDR3 amino acid features enriched by HLA risk alleles. Moreover, the CDR3 features promoted by HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (e.g., citrullinated-epitope-specific TCRs in rheumatoid arthritis patients). Together, these results provide novel genetic evidence supporting the central hypothesis.

Epstein-Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci.

The interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein–Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we showed that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on a genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding in a B cell line that was (1) uninfected, (2) infected with a strain of EBV lacking EBNA2, or (3) infected with a strain that expresses EBNA2. We identified more than 400 EBNA2-dependent differentially expressed human genes and more than 5000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed more than 2000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP data revealed more than 1700 regions where EBNA2 altered chromatin looping interactions. Autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype–dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

Overexpression of the PTPN22 Autoimmune Risk Variant LYP-620W Fails to Restrain Human CD4+ T Cell Activation.

A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- (p < 0.05) and 3.6-fold (p < 0.001) more PTPN22 transcripts in resting CD4+ memory and regulatory T cells (Tregs), respectively, over naive CD4+ T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4+ T cells, TCR signaling and activation were blunted by LYP-620R (p < 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3- and anti-CD28-coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4+ T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4+ T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders.

Lorna Macfarlane

<h3>ABSTRACT</h3> Polymorphisms in the <i>human leukocyte antigen</i> (<i>HLA</i>) genes within the <i>major histocompatibility complex</i> (<i>MHC</i>) locus strongly influence autoimmune disease risk^1–5. Two non-exclusive hypotheses exist about the pathogenic role of...

Gene Edited Human CD4+ T Cells Reveal that Loss of PTPN22 Function Enhances Mildly Autoreactive T Cell Responses

Abstract A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases. PTPN22 is a non-receptor tyrosine phosphatase that negatively regulates proximal T cell receptor (TCR) signaling. PTPN22 deficiency increases TCR signaling in mouse and human T cells. Mouse models of the variant similarly exhibit increased TCR signaling, while primary T cells from human carriers of the variant exhibit decreased signaling. Here, we utilize gene editing in primary human T cells to address these discordant findings and explore how the risk variant impacts TCR signaling. Using Crispr/Cas9 nucleases and DNA repair templates, we established a robust platform for precise homology-directed-repair based gene editing of PTPN22, allowing the generation of PTPN22 risk edited, control edited (silent modification), and knock-out T cells from the same donor. In contrast to control edited cells, PTPN22 risk edited T cells exhibit increased activation in response to TCR engagement with higher expression of activation markers including CD40L and CD25, mimicking PTPN22 KO cells. Further, using lentiviral delivery of transgenic TCRs (derived from autoreactive T cells of T1D patients), we demonstrate that loss of PTPN22 leads to enhanced TCR signaling in weakly autoreactive, but not strongly autoreactive T cells, causing increased phosphorylation of S6 kinase, enhanced proliferation, and greater Th1 skewing. Taken together, these findings suggest that direct effects of the PTPN22 rs2476601 variant represents a loss of function in T cells, increasing TCR signaling in mildly autoreactive T cells, potentially expanding the pool of autoreactive T cells and skewing them toward an inflammatory phenotype.

Risk of new-onset autoimmune diseases in primary aldosteronism: a nation-wide population-based study.

The association between hyperaldosteronism and autoimmune disorders has been postulated. However, long-term incidence of a variety of new-onset autoimmune diseases (NOAD) among patients with primary aldosteronism has not been well investigated. From Taiwan's National Health Insurance Research Database with a 23-million population insurance registry, the identification of primary aldosteronism, essential hypertension and NOAD as well as all-cause mortality were ascertained by a validated algorithm. From 1997 to 2009, 2319 primary aldosteronism patients without previously autoimmune disease were identified and propensity score-matched with 9276 patients with essential hypertension. Among those primary aldosteronism patients, 806 patients with aldosterone-producing adenomas (APA) were identified and matched with 3224 essential hypertension controls. NOAD incidence is augmented in primary aldosteronism patients compared with its matched essential hypertension (hazard ratio 3.82, P < 0.001, versus essential hypertension). Furthermore, NOAD incidence is also higher in APA patients compared with its matched essential hypertension (hazard ratio = 2.96, P < 0.001, versus essential hypertension). However, after a mean 8.9 years of follow-up, primary aldosteronism patients who underwent adrenalectomy (hazard ratio = 3.10, P < 0.001, versus essential hypertension) and took mineralocorticoid receptor antagonist (MRA) still had increased NOAD incidence (hazard ratio = 4.04, P < 0.001, versus essential hypertension). Primary aldosteronism patients had an augmented risk for a variety of incident NOAD and all-cause of mortality, compared with matched essential hypertension controls. Notably, the risk of incident NOAD remained increased in patients treated by adrenalectomy or MRA compared with matched essential hypertension controls. This observation supports the theory of primary aldosteronism being associated with a higher risk of multiple autoimmune diseases.

Efficient CRISPR/Cas9 Disruption of Autoimmune-Associated Genes Reveals Key Signaling Programs in Primary Human T Cells.

Risk of autoimmunity is associated with multiple genetic variants. Genome-wide association studies have linked single-nucleotide polymorphisms in the phosphatases PTPN22 (rs2476601) and PTPN2 (rs1893217) to increased risk for multiple autoimmune diseases. Previous mouse studies of loss of function or risk variants in these genes revealed hyperactive T cell responses, whereas studies of human lymphocytes revealed contrasting phenotypes. To better understand this dichotomy, we established a robust gene editing platform to rapidly address the consequences of loss of function of candidate genes in primary human CD4+ T cells. Using CRISPR/Cas9, we obtained efficient gene disruption (>80%) of target genes encoding proteins involved in Ag and cytokine receptor signaling pathways including PTPN22 and PTPN2 Loss-of-function data in all genes studied correlated with previous data from mouse models. Further analyses of PTPN2 gene-disrupted T cells demonstrated dynamic effects, by which hyperactive IL-2R signaling promoted compensatory transcriptional events, eventually resulting in T cells that were hyporesponsive to IL-2. These results imply that altered phosphatase activity promotes evolving phenotypes based on Ag experience and/or other programming signals. This approach enables the discovery of molecular mechanisms modulating risk of autoimmunity that have been difficult to parse in traditional mouse models or cross-sectional human studies.

Frequencies of the LILRA3 6.7-kb Deletion Are Highly Differentiated Among Han Chinese Subpopulations and Involved in Ankylosing Spondylitis Predisposition.

Introduction: Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to the LILR family with unique feature of a 6.7-kb deletion variation among individuals. Frequencies of the 6.7-kb deletion vary widely across populations, but so far it has not been carefully investigated among Han Chinese subpopulations. Furthermore, we previously identified the non-deleted (functional) LILRA3 as a novel genetic risk for multiple autoimmune diseases. The current study aimed to investigate (i) whether frequencies of the LILRA3 6.7-kb deletion differ within Han Chinese subpopulations and (ii) whether the functional LILRA3 is a novel genetic risk for ankylosing spondylitis (AS).Methods: The LILRA3 6.7-kb deletion was genotyped in two independent cohorts, including 1,567 subjects from Shenzhen Hospital and 2,507 subjects from People’s Hospital of Peking University. Frequencies of the 6.7-kb deletion were first investigated in combined healthy cohort according to the Chinese administrative district divisions. Association analyses were performed on whole dataset and subsets according to the geographic regions. Impact of the functional LILRA3 on AS disease activity was evaluated.Results: Frequencies of LILRA3 6.7-kb deletion were highly differentiated within Han Chinese subpopulations, being gradually decreased from Northeast (80.6%) to South (47.4%). Functional LILRA3 seemed to be a strong genetic risk in susceptibility to AS under almost all the alternative genetic models, if the study subjects were not geographically stratified. However, stratification analysis revealed that the functional LILRA3 was consistently associated with AS susceptibility mainly in Northern Han subgroup under the alternative genetic models, but not in Central and Southern Hans. Functional LILRA3 conferred an increased disease activity in AS patients (P < 0.0001 both for CRP and ESR, and P = 0.003 for BASDAI).Conclusions: The present study is the first to report that the frequencies of LILRA3 6.7-kb deletion vary among Chinese Hans across geographic regions. The functional LILRA3 is associated with AS susceptibility mainly in Northern Han, but not in Central and Southern Han subgroups. Our finding provides new evidence that LILRA3 is a common genetic risk for multiple autoimmune diseases and highlights the genetic differentiation among different ethnicities, even within the subpopulations of an ethnic group.

Eosinophilic Esophagitis due to Gluten without Celiac Disease and Unusual Comorbidities

In recent years, it has become recognized that patients with eosinophilic esophagitis (EoE) have an increased risk of multiple autoimmune diseases. Possible shared genetic aetiologies have been observed between EoE and autoimmune diseases. Currently, it is believed that EoE is not associated with a higher risk of neoplasms since such published cases are very rare and there are only isolated reports. Herein, we describe a unique case of EoE due to gluten without coeliac disease. The patient presented some unusual comorbidities, such as hypothyroidism (autoimmune disease) and essential thrombocythemia (neoplasm of haematologic origin).

Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study.

Recent genome-wide association studies have suggested possible genetic associations between eosinophilic esophagitis (EoE) and genes associated with autoimmunity. No studies to date have looked at potential genetic association of EoE with specific autoimmune diseases by evaluating such diagnoses within family members. Investigate the risk of specific autoimmune disease within EoE probands and their extended family members. The Utah Population Database offers a unique opportunity to link medical records from over 85% of Utah's population to genealogy records representing Utah. We searched for associations of specific autoimmune diseases in probands diagnosed with EoE and their extended family members (e.g., first cousins). Comparisons were made to age- and sex-matched controls and their respective families at a 5:1 ratio. Excess risk for multiple autoimmune conditions was detected in subjects with a diagnosis of EoE. Celiac, Crohn's, ulcerative colitis (UC), rheumatoid arthritis, IgA deficiency, CVID, multiple sclerosis (MS), and Hashimoto's thyroiditis were found at increased risk in first-degree relatives of EoE subjects. UC, systemic sclerosis, and MS had nominally significant associations within second-degree family members of EoE subjects; and, in reverse analysis, probands and their families with the above three conditions were at an increased risk for EoE suggesting shared genetic factors with EoE. Patients with EoE have an increased risk of multiple autoimmune diseases. Possible shared genetic etiologies were observed between EoE and UC, systemic sclerosis, and MS. Practitioners should be aware of these comorbid associations and query all EoE patients and family members for symptoms of these diseases.

Enhanced PI3K/AKT/mTOR responses are associated with resistance to activation-induced cell death and expansion of memory CD4+ T cells in T1D subjects and healthy carriers of the PTPN22 risk variant

Abstract The genetic variant PTPN22 1858T, encoding Lyp620W, confers increased risk for multiple autoimmune diseases including Type 1 diabetes (T1D). To date, Lyp620W has been associated with increased CD4+memory T cells and enhanced Th1 responses in healthy carriers. However, it is not clear whether this is due to altered lineage commitment and/or survival within the CD4+memory T cell compartment. Here, we determined the mechanism by which Lyp620W alters human CD4+memory T cell homeostasis in PTPN22 1858T carriers and T1D subjects. T1D subjects displayed significantly increased CD4+ memory T cells as compared to healthy individuals irrespective of PTPN22 genotype, which was further increased in homozygous carriers of PTPN22 1858T, suggesting a partial role for this variant. Among healthy 1858T carriers, we found a significant increase in the magnitude of Th1 effector responses, but not enhanced Th1 differentiation. Consistent with increased survival, TCR-induced PI3K/AKT/mTOR pathway responses and BCL-2 expression were augmented in CD4+ memory T cells from healthy 1858T carriers. Importantly, these alterations were associated with increased resistance to TCR-mediated apoptosis in CD4+ memory T cells. Similar changes in PI3K/AKT signaling and T cell survival were observed in the Th1 memory compartment of T1D individuals, and selective inhibition of PI3Kδ reversed the survival phenotypes in memory T cells from both healthy 1858T carriers and T1D subjects. Thus, our combined findings reveal a novel immune ‘signature’ associated with Lyp620W and highlight a clinically-relevant T cell intrinsic mechanism that promotes the survival of potentially pathogenic Th1 effector T cells in T1D.

Association Between PTPN22 Gene Polymorphism and Type1 Diabetes in Egyptian Population

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps at human chromosome 1p13.3which encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase(Lyp). The PTPN22 gene has been shown to associate with a risk for multiple autoimmune diseases,including type1 diabetes (T1DM). This study aimed to analyze the association of three PTPN22polymorphisms in Egyptian population .The single nucleotide polymorphisms (SNP) at positions -1123(rs#2488457), 1858 (rs#2476601), and +2740 (rs#1217412) were genotyped in 60 persons with T1DM,and 60 control persons, all three SNPs were genotyping using two technique, allele specific PCRtechnique and restriction fragment length polymorphism – PCR (RFLP-PCR). The 1858 C/T did notshow any significance differences between patients and control groups. (MCP=1.0) whereas, respectively-1123 G/C and +2740 A/G were significantly associated with T1DM disease (P≤0.0001) and(P=0.012).These results suggest that the PTPN22 gene of SNPs polymorphisms were associated withtype 1 diabetes in Egyptian population. The difference in the association of the aforementioned SNPsvariants with T1DM among different populations may be attributed to the presence of multiplesusceptibility alleles.

CD226 Gly307Ser association with multiple autoimmune diseases: A meta-analysis

Recently, there has been increasing evidence shown that a non-synonymous exchange (Gly307Ser/rs763361) of the CD226 gene on chromosome 18q22 is linked to several autoimmune diseases (ADs) including type 1 diabetes (T1D), celiac disease (CED), rheumatoid arthritis (RA), multiple sclerosis (MS), Grave's disease, Wegener's granulomatosis (WG), psoriasis, and primary sicca syndrome (pSS). Taking into consideration that different autoimmune diseases may share some common pathogenic pathways and in order to assess the overall relationship between CD226 Gly307Ser (rs763361) polymorphism and multiple autoimmune diseases, we performed this meta-analysis. All eligible case-control studies were searched in the US National Library of Medicine's PubMed and Embase database. Crude odds ratios (OR) with 95% confidence intervals (CI) were conducted to assess the association. 7876 cases and 8558 controls from 7 published studies which were selected from 149 articles identified by a search of the US National Library of Medicine's PubMed and Embase databases for the period up to 25th April 2012. The total OR for ADs associated with the T allele was 1.19 (95%CI=1.12-1.27) by random effects model. Significantly increased risks were also observed in the South American (OR=1.72, 95%CI=1.34-2.20), Asian (OR=1.46, 95%CI=1.01-2.10), and European (OR=1.29, 95%CI=1.07-1.58). Similarly, significant associations were observed in two genetic models (OR=1.41, 95%CI=1.23-1.62 in a codominant model; OR=1.33, 95%CI=1.18-1.50 in a recessive model). This meta-analysis provided evidence that CD226 Gly307Ser (rs763361) is significantly associated with the risk of multiple autoimmune diseases.

Common immunogenetic profile in children with multiple autoimmune diseases: the signature of HLA-DQ pleiotropic genes

Type 1 diabetes mellitus (T1DM), celiac disease (CD) and autoimmune thyroid disease (ATD) are autoimmune conditions relatively common in paediatric age and frequently occur in association in the same subject. This event is not by chance and requires an explanation. Here, we studied the distribution of HLA-DQ αβ heterodimers in 334 Italian children with T1DM, ATD and CD alone or in association and in 224 Italian healthy controls. In particular, 164 patients had T1DM (133 alone, 20+ATD, 7+CD and 4+CD+ATD), 118 had ATD (110 alone, 8+CD) and 52 had CD (40 alone, 11+ATD and 1+T1DM). 51 patients suffered from multiple autoimmune diseases. The risk for multiple autoimmune diseases was significantly associated with the increased number of HLA-DQ markers of susceptibility for both T1DM (p = 0.003) and CD (p = 0.006). The presence of one or more diabetogenic DQ molecules significantly increased the probability of developing not only T1DM (p < 0.001) but also CD (p < 0.001) and ATD (p = 0.001). Similarly, the presence of one or more celiac HLA-DQ heterodimers significantly increased the likelihood of developing not only CD (p < 0.001), but also T1DM (p < 0.001) and ATD (p < 0.001). We confirm that the sharing of the immunogenetic background is responsible for the development of multiple autoimmune diseases although with a different risk according to the number and type of susceptible HLA-DQ heterodimers as reported in the algorithm proposed here. It is likely that combinations of DQA1 and DQB1 alleles are the real culprits of the progression towards multiple autoimmune diseases and HLA-DQ genomic typing will improve the capability to predict associated autoimmune diseases in infancy.

Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT

A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes. We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells. This selective uncoupling of AKT from other downstream BCR signaling pathways is a result of inhibition of a negative regulatory circuit involving LYN, CD22, and SHIP. Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli. Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors.

Positive association between STAT4 polymorphisms and polymyositis/dermatomyositis in a Japanese population

ObjectivesTo investigate associations between signal transducer and activator of transcription 4 (STAT4), one of the most commonly acknowledged genes for the risk of multiple autoimmune diseases, with susceptibility to adult-onset...

No independent role of the −1123 G > C and + 2740 A > G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations

Introduction The PTPN22 is a negative regulator of the T cell response. Its +1858C > T (R620W) polymorphism has been shown to associate with a risk for multiple autoimmune diseases, including type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The minor (susceptibility) allele is absent in Asian populations, but a recent study suggested an independent involvement of another polymorphism located within the promoter −1123 nucleotides relative to the translational start site. Aims We aimed to analyse the association of three PTPN22 polymorphisms in two distinct Caucasian populations, the Czechs (with T1D and with JIA) and Azeri (with T1D). Methods The single nucleotide polymorphisms (SNP) at positions −1123 (rs2488457), +1858 (rs2476601, the R620W substitution), and +2740 (rs1217412) were genotyped using TaqMan assays in 372 subjects with childhood-onset T1D, 130 subjects with JIA, and 400 control subjects of Czech origin, and in 160 subjects with T1D and 271 healthy controls of Azeri origin. Results In the Czechs, all three SNPs were in a tight linkage disequlibrium, while in the Azeri, the linkage disequlibrium was limited to between the promoter and 3′-UTR polymorphism, D′(−1123, +2740) = 0.99, r 2 = 0.72. Haplotype reconstruction via the expectation–maximization algorithm showed in both populations that only the haplotype containing the minor (W) allele at codon 620 was associated with T1D (OR = 2.26, 95% CI 1.68–3.02 in Czechs, OR = 14.8, 95% CI 2.0–651 in Azeri) or JIA (OR = 2.43, 95% CI 1.66–3.56 in Czechs). The haplotypes having the wild-type (R) allele at codon 620 and minor alleles at −1123 and/or +2740 were neutral as to the risk of autoimmune conditions in both populations. Conclusions In two different Caucasian populations, the Czechs and the Azeri, no independent contribution can be detected either of the −1123 promoter SNP or the +2740 3′-UTR SNP, and only the minor allele at PTPN22 codon 620 contributes to the risk of autoimmunity.

Understanding the genetic contribution to rheumatoid arthritis

The identification of the genetic variants that mediate the risk for susceptibility and severity of rheumatoid arthritis will allow the development of new drug targets and also increase the ability to predict disease course. Technical and methodologic progress has fueled the advances in this field. The second risk factor for rheumatoid arthritis, the PTPN22 polymorphism, has been identified. This genetic variant regulates the threshold of T cell activation. Intriguingly, this variant is a risk factor for diabetes as well. Moreover, it has been shown that multiple genetic variants in one pathway (both in a transcription factor, RUNX-1, as in the transcription factor binding site of RUNX1 in the SLC22A4 gene) can each confer very small risks but by gene-gene interactions can confer a ninefold risk for rheumatoid arthritis. These genetic risk factors have been found to confer risk for multiple autoimmune diseases. Phenotype-genotype interactions were described by the enhanced prevalence of a rheumatoid arthritis-specific autoantibody (anti-cyclic citrullinated peptide antibodies) in rheumatoid arthritis patients that harbor the rheumatoid arthritis-associated human leukocyte antigen class II genes, the shared epitope alleles. An environmental factor, smoking was demonstrated to confer risk for rheumatoid arthritis, especially in patients positive for both shared epitope and rheumatoid arthritis-specific anti-cyclic citrullinated peptide antibodies. Two new pathways, T cell receptor signaling and a hematopoietic-specific signal transduction pathway, have been discovered that allow future pharmacologic interventions. The description of the new genetic risk factors and the interaction with environmental triggers as well as phenotypic features are gradually expanding the ability to predict disease susceptibility and course.