<i>TRAF1</i> Gene Polymorphism Correlates with the Titre of Gp210 Antibody in Patients with Primary Biliary Cirrhosis

Kempinska-Podhorodecka, Agnieszka; Shums, Zakera; Wasilewicz, Michał; Wunsch, Ewa; Milkiewicz, Malgorzata; Bogdanos, Dimitrios P.; Norman, Gary L.; Milkiewicz, Piotr

doi:https://doi.org/10.1155/2012/487521

Journal of Immunology Research

On this page

Abstract Background Methods Results Discussion References Copyright Related Articles

Special Issue

Serum Autoantibodies: From Identification to Clinical Relevance

View this Special Issue

Clinical Study | Open Access

Volume 2012 | Article ID 487521 | https://doi.org/10.1155/2012/487521

TRAF1 Gene Polymorphism Correlates with the Titre of Gp210 Antibody in Patients with Primary Biliary Cirrhosis

Agnieszka Kempinska-Podhorodecka,¹Zakera Shums,²Michał Wasilewicz,³Ewa Wunsch,³Malgorzata Milkiewicz,¹Dimitrios P. Bogdanos,⁴Gary L. Norman,²and Piotr Milkiewicz³

Academic Editor: Pietro Invernizzi

Received28 Aug 2012

Accepted22 Sept 2012

Published22 Oct 2012

Abstract

Background. Polymorphisms of TRAF1 (Tumor necrosis factor receptor-associated factor 1) are associated with rheumatoid arthritis (RA). Whether TRAF1 polymorphisms confer increased risk for primary biliary cirrhosis (PBC), an autoimmune liver disease which can co-exist with RA, is unknown. Aim of the Study. To assess the frequency of the RA-conferring susceptibility TRAF1 polymorphisms rs3761847 and rs2900180 in a cohort of PBC patients. The association of TRAF1 polymorphisms with clinical features and autoantibody markers was also analyzed. Methods. We studied 179 PBC patients and 300 controls. Samples were genotyped for TRAF1 gene polymorphisms by real-time PCR. Autoantibodies were tested by ELISA. Results. The frequency of rs3761847 and rs2900180 polymorphisms did not differ between patients and controls. Laboratory or clinical features were not associated with specific polymorphisms. Gp210 autoantibody titres were conspicuously higher among GG homozygotes of rs3761847 as compared with AA homozygotes (). In contrast, antichromatin titers were higher in AA compared to GG rs3761847 homozygotes (). Rheumatoid factor IgG titres were significantly higher in rs2900180 TT homozygotes than CC homozygotes (). Conclusions. TRAF1 polymorphisms occur with the similar frequency in PBC patients and in the general population, but their presence is probably involved in the regulation of specific PBC-related autoantibodies.

1. Background

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease leading to cirrhosis and eventually liver failure and predominantly affects middle-aged women [1, 2]. Highly-specific antimitochondrial antibodies (AMA), as well as PBC-specific antinuclear antibodies such as those against sp100 and gp210, are serological hallmarks of the disease [3–10]. Significant proportion of patients with PBC suffer from concomitant autoimmune conditions such as Sjögren’s syndrome, Hashimoto’s thyroiditis, or systemic sclerosis (SS) [2, 11–15]. Several patients with PBC are found positive for IgG rheumatoid factor (RF), and up to 5% of patients with PBC may also have rheumatoid arthritis (RA) [16–18].

Although the etiology of PBC remains elusive, genetic factors are known to contribute to its pathogenesis [19–21]. Several studies in the past postulated major histocompatibility complex (MHC) class II polymorphisms as expressing the strongest association, but consensus has been reached mainly for genes exerting a reduced risk of developing PBC [22]. More recently, four genome wide association studies (GWAS) which included North American, Italian, predominantly North American, and British cohorts, respectively, identified a number of genes in non-HLA loci associated with PBC and highlighted the role of the IL-12 and tumor necrosis factor (TNF) signaling pathways in the pathogenesis of PBC [23–26].

Polymorphisms of genes involved in TNF-receptor signaling such as TNF receptor-associated factor 1 (TRAF1) have been associated with RA [27] and other autoimmune conditions including systemic lupus erythematosus (SLE) [28], but not with giant cell arteritis [29]. TRAF1 gene encodes an important protein which acts as a mediator of the TNF and CD40 transduction pathways [30, 31]. The presence of TRAF1 polymorphisms seems to affect the natural history of RA, increasing the risk of erosions [32]. Their effect on mortality in RA remains controversial [33, 34].

The association of TRAF1 polymorphisms with the risk of developing PBC has not been studied. In the present study, we assessed the prevalence of the TRAF1 polymorphisms rs3761847 and rs2900180, both identified by a large GWAS as genetic risk factors for RA [27], in a homogenous cohort of Caucasian patients with PBC. As TRAF1 is a potent immune modulator, we postulated that the presence of TRAF1 polymorphisms may predispose to a distinctive autoantibody profile and performed a comprehensive analysis of PBC-specific and nonspecific autoantibodies detected in our patients with PBC with the presence of TRAF1 polymorphisms.

2. Methods

2.1. Patients

A group of 179 patients with PBC were analyzed. All patients met the criteria for the diagnosis of PBC recently introduced by EASL guidelines, according to which PBC can be diagnosed if at least 2 out of the following 3 criteria are fulfilled: elevation of alkaline phosphatase, typical liver histology, and AMA seropositivity [35]. In 132 (74%) patients, the diagnosis of PBC was confirmed by a liver biopsy, and in 46 (35%) of these patients histological assessment showed liver cirrhosis. Patients with clear clinical and imaging features of liver cirrhosis were not subjected to liver biopsy on ethical grounds. In total, 61 (34%) patients had histological, clinical, and imaging features typical for liver cirrhosis. Demographic and laboratory data on analyzed subjects are summarized in Table 1. A cohort of 300 blood donors from the National Blood Services comprised a control group. Appropriate informed consent was obtained from each patient and blood donors included in the study. The study protocol was approved by the ethics committee of Pomeranian Medical University and conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008).

3. Analysis of Autoantibodies

Autoantibody tests were performed at one site (INOVA Diagnostics, San Diego, CA, USA) on blinded serum specimens. A total of twelve autoantibody specificities (M2 EP (MIT3) IgG, gp210 IgG, sp100 IgG, chromatin IgG, centromere IgG, f-actin IgG, Scl-70 IgG, Jo-1 IgG, RNA polymerase III IgG, Ro52 IgG, CCP 3.0 IgG, and RF IgG) were analyzed by QUANTA Lite ELISA (INOVA Diagnostics, San Diego, CA, USA) as described elsewhere [4]. All QUANTA Lite ELISA tests were run and interpreted according to the manufacturer’s instructions and are cleared for “in vitro diagnostic use” by United States Food and Drug Administration (FDA). Detailed performance data and instructions for the QUANTA Lite ELISA tests can be found online (http://www.inovadx.com).

4. TRAF1 Genotyping

DNA from peripheral blood mononuclear cells was isolated using the DNeasy Blood & Tissue Kit (Qiagen). Oligonucleotide primers and TaqMan probes for two TRAF1 polymorphisms (rs2900180 and rs3761847) were designed and synthesized by Applied Biosystems (assay ID: C_15849116_10 and C_2783640_10, resp.). The fluorescence data were analyzed with allelic discrimination 7500 software v.2.0.2.

5. Statistical Analysis

Data are shown as mean and standard error. All statistical analyses (chi square, odds ratios, confidence intervals) were performed using StatView software (Carry, NC, USA). The genotype and allelic frequencies were compared between patients and controls using Fisher’s PLSD test. The analysis of genotype frequency within PBC patients with regards to the analyzed factors was performed using Fisher’s PLSD test. P value < 0.05 was considered to be statistically significant.

6. Results

A summary of the obtained data is provided in Tables 2 and 3. No significant difference in genotype frequencies between patients with PBC and healthy controls was seen. The presence of these polymorphisms did not correlate with clinical features such as gender, age at presentation, pruritus, or cirrhosis at presentation (data not shown). Also they did not correlate with liver biochemistry at the diagnosis (Table 3). With regards to the rs3761847 polymorphism, analysis of autoantibodies revealed that the titres of gp210 were significantly higher among GG homozygotes as compared with AA homozygotes (42.6 ± 14.7 versus 10.8 ± 4.2; P = 0.02) and at the same time AA homozygoity was associated with higher titres of antichromatin autoantibodies (11.8 ± 2.8 versus 5.2 ± 1.2; AA versus GG P = 0.04). The analysis of the second polymorphism (rs 2900180) showed that TT homozygotes demonstrated significantly higher titres of rheumatoid factor IgG than CC homozygotes (16.7 ± 9.7 versus 7.6 ± 0.5, resp., P = 0.02). No statistically significant difference was found in terms of other autoantibodies. These data are summarized in Tables 4 and 5.

7. Discussion

The TRAF1 gene encodes a TNF receptor-associated factor 1, belonging to the TNF receptor (TNFR) associated factor (TRAF) protein family [36]. These proteins are responsible for mediation of signaling from various receptors of the TNFR superfamily. TRAF1 together with TRAF2 form a heterodimeric protein complex which is required for TNF-alpha-stimulated activation of MAPK8/JNK and NF-kappaB [37, 38]. This complex also interacts with proteins responsible for inhibition of apoptosis, affecting the antiapoptotic signals from TNFRs [39]. TNFα has been found to play a critical role in the pathogenesis of various autoimmune conditions including RA and PBC [40].

Various polymorphisms of TRAF1/C5 have been studied and were found to occur more commonly in patients with RA of different origin [41–44]. In addition to their higher prevalence in patients with RA, TRAF1/C5 polymorphisms also seem to affect the natural history of the disease [45–47]. They have also been linked with SLE in some populations [48, 49], juvenile idiopathic arthritis [50] and alopecia areata [51], but not with giant cell arteritis [29] and pemphigus [52].

TRAF1 SNPs have never been investigated in PBC which is a chronic autoimmune liver condition. Since pathways involving TNF and IL-12 have been described [53–55] in the pathogenesis of PBC, seeking a potential relationship between TRAF1 SNPs and PBC could be of interest. Additionally, PBC is associated with various autoimmune conditions including Sjögren’s syndrome and systemic sclerosis, and the mechanisms responsible for this cooccurrence are the focus of ongoing research [56]. RA is found in up to 5% of patients with PBC, but the literature surrounding this association is scarce.

For this study, we selected two polymorphisms originally reported to confer increased risk for RA in GWAS [27]. The frequencies of the SNPs that we studied are comparable to those noted previously in European and other populations (displayed in http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?searchType=&rs=rs3761847 and http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?searchType=adhoc_search&type=rs&rs=rs2900180). They were also not significantly different from the ones seen in patients with PBC, suggesting that the TRAF1 locus does not confer risk to PBC. This may also explain why RA is not highly prevalent in patients with PBC compared to other extrahepatic autoimmune manifestations such as sicca syndrome and Hashimoto’s thyroiditis. These findings support the view that genes other than TRAF1 which are related to the homeostasis of TNFα could be involved in the pathogenesis of PBC. Indeed, a recent GWAS by Mells et al. reported that 1q31 (DENND1B), 14q32 (TNFAIP2), and 12p13 (TNFRSF1A) confer susceptibility to PBC. These three loci relate to genes involved in TNF signaling pathways. Of those, TNFRSF1A belongs to the TNFR family, which also contains TNFRSF1B. Of interest, TNFRSF1A appears to interact with TRAF2 but not with TRAF1 [57–59]. Our analysis has found that the GG homozygotes had significantly higher titres of gp210 autoantibodies compared to AA homozygotes. Antibodies against the nuclear complex gp210 antigen are highly-specific for PBC [6, 9, 60] and their presence is strongly associated with a more rapid progression of PBC and worse outcome [61–64]. The fact that the presence of this polymorphism is not associated with other PBC-specific antinuclear antibodies, such as those against the sp100 nuclear body antigen, further underlines the unique association between TRAF1 and gp210 autoantibody development. The mechanism that could explain this association needs to be explored. TRAF1 has an inhibitory role in antigen-induced apoptosis of CD8+ T lymphocytes. It remains to be seen whether such an antiapoptotic role involves gp210-specific autoreactive lymphocytes present in PBC patients [65]. As TRAF1 is also a negative regulator of TNF-receptor signalling, it may regulate the induction a cytokine milieu that promotes the persistence of gp210-specific autoreactive lymphocytes and the T-cell dependent production of antibodies against this nuclear pore complex protein. These speculations may serve as working hypotheses for future studies. However, our data need to be interpreted with caution, as there is no solid evidence to support the view that anti-gp210 seropositivity per se is a negative prognostic factor in patients with PBC. Nevertheless, the idea to correlate polymorphisms of immunoregulatory genes with humoral autoimmunity markers is not new, as previous researchers have attempted the same in diseases such as type 1 diabetes mellitus, systemic lupus erythematosus, and indeed RA [66–68]. In doing that, several studies identified relationships between HLA and non-HLA polymorphisms and the presence or the titres of disease-related autoantibodies. To date, no serious attempts have been made to correlate TRAF1 polymorphisms and specific autoantibodies in autoimmune diseases such as RA and SLE.

Our study is the first to assess the presence of these polymorphisms with the titres of twelve different autoantibodies, including not only closely-related and clinically significant autoantibody specificities but also others not immediately relevant to the diagnosis or prognosis of PBC. Hence, we showed that antichromatin autoantibodies occurred in significantly higher titres in AA homozygotes compared to GG homozygotes of rs3761847. The significance of antichromatin antibodies has not yet been studied in great detail in patients with PBC. In patients with autoimmune hepatitis, however, the presence of antichromatin antibodies is associated with an active disease and increased risk of relapse after steroid withdrawal [69, 70]. It has been speculated that they may define a subgroup of patients with AIH with worse outcome [71]. We also observed significantly higher titres of RF IgG in TT homozygotes of rs2900180. Again, a direct interpretation of this finding is difficult to be made. Rheumatoid factor is related to more aggressive articular destruction in patients with RA. RF-IgG can occur in 16–70% of patients with PBC, but its relevance in the natural history of this condition has not been studied. Further studies should define the association of these autoantibodies and TRAF1 polymorphisms in patients with PBC. Our study has moved this process one step forward.

References

J. Neuberger, “Primary biliary cirrhosis,” The Lancet, vol. 350, no. 9081, pp. 875–879, 1997.
View at: Publisher Site | Google Scholar
M. M. Kaplan and M. E. Gershwin, “Primary biliary cirrhosis,” The New England Journal of Medicine, vol. 353, no. 12, pp. 1261–1273, 2005.
View at: Publisher Site | Google Scholar
M. E. Gershwin, I. R. Mackay, A. Sturgess, and R. L. Coppel, “Identification and specificity of a cDNA encoding the 70 KD mitochondrial antigen recognized in primary biliary cirrhosis,” The Journal of Immunology, vol. 138, no. 10, pp. 3525–3531, 1987.
View at: Google Scholar
P. Milkiewicz, H. Buwaneswaran, C. Coltescu, Z. Shums, G. L. Norman, and E. J. Heathcote, “Value of autoantibody analysis in the differential diagnosis of chronic cholestatic liver disease,” Clinical Gastroenterology and Hepatology, vol. 7, no. 12, pp. 1355–1360, 2009.
View at: Publisher Site | Google Scholar
A. J. Czaja and G. L. Norman, “Autoantibodies in the diagnosis and management of liver disease,” Journal of Clinical Gastroenterology, vol. 37, no. 4, pp. 315–329, 2003.
View at: Publisher Site | Google Scholar
D. P. Bogdanos, P. Invernizzi, I. R. Mackay, and D. Vergani, “Autoimmune liver serology: current diagnostic and clinical challenges,” World Journal of Gastroenterology, vol. 14, no. 21, pp. 3374–3387, 2008.
View at: Publisher Site | Google Scholar
C. Dähnrich, A. Pares, L. Caballeria et al., “New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies,” Clinical Chemistry, vol. 55, no. 5, pp. 978–985, 2009.
View at: Publisher Site | Google Scholar
H. Liu, G. L. Norman, Z. Shums et al., “PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis,” Journal of Autoimmunity, vol. 35, no. 4, pp. 436–442, 2010.
View at: Publisher Site | Google Scholar
D. P. Bogdanos and L. Komorowski, “Disease-specific autoantibodies in primary biliary cirrhosis,” Clinica Chimica Acta, vol. 412, no. 7-8, pp. 502–512, 2011.
View at: Publisher Site | Google Scholar
M. G. Mytilinaiou, W. Meyer, T. Scheper et al., “Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis,” Clinica Chimica Acta, vol. 413, no. 15-16, pp. 1211–1216, 2012.
View at: Publisher Site | Google Scholar
F. E. Watt, O. F. W. James, and D. E. J. Jones, “Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study,” QJM: An International Journal of Medicine, vol. 97, no. 7, pp. 397–406, 2004.
View at: Publisher Site | Google Scholar
Y. Shoenfeld, “Primary biliary cirrhosis and autoimmune rheumatic diseases: prediction and prevention,” Israel Journal of Medical Sciences, vol. 28, no. 2, pp. 113–116, 1992.
View at: Google Scholar
M. Tishler, I. Alosachie, N. Barka et al., “Primary Sjogren's syndrome and primary biliary cirrhosis: differences and similarities in the autoantibody profile,” Clinical and Experimental Rheumatology, vol. 13, no. 4, pp. 497–500, 1995.
View at: Google Scholar
C. Rigamonti, D. P. Bogdanos, M. G. Mytilinaiou, D. S. Smyk, E. I. Rigopoulou, and A. K. Burroughs, “Primary biliary cirrhosis associated with systemic sclerosis: diagnostic and clinical challenges,” International Journal of Rheumatology, vol. 2011, Article ID 976427, 12 pages, 2011.
View at: Publisher Site | Google Scholar
C. Selmi, S. M. De, and M. E. Gershwin, “Liver involvement in subjects with rheumatic disease,” Arthritis Research & Therapy, vol. 13, article 226, 2011.
View at: Publisher Site | Google Scholar
K. S. Culp, C. R. Fleming, J. Duffy et al., “Autoimmune associations in primary biliary cirrhosis,” Mayo Clinic Proceedings, vol. 57, no. 6, pp. 365–370, 1982.
View at: Google Scholar
J. L. Siegel, H. Luthra, J. Donlinger, P. Angulo, and K. Lindor, “Association of primary biliary cirrhosis and rheumatoid arthritis,” Journal of Clinical Rheumatology, vol. 9, no. 6, pp. 340–343, 2003.
View at: Publisher Site | Google Scholar
C. Caramella, J. Avouac, P. Sogni, X. Puéchal, A. Kahan, and Y. Allanore, “Association between rheumatoid arthritis and primary biliary cirrhosis,” Joint Bone Spine, vol. 74, no. 3, pp. 279–281, 2007.
View at: Publisher Site | Google Scholar
C. Selmi, M. J. Mayo, N. Bach et al., “Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment,” Gastroenterology, vol. 127, no. 2, pp. 485–492, 2004.
View at: Publisher Site | Google Scholar
M. E. Gershwin and I. R. Mackay, “The causes of primary biliary cirrhosis: convenient and inconvenient truths,” Hepatology, vol. 47, no. 2, pp. 737–745, 2008.
View at: Publisher Site | Google Scholar
D. P. Bogdanos, D. S. Smyk, E. I. Rigopoulou et al., “Twin studies in autoimmune disease: genetics, gender and environment,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J156–J169, 2012.
View at: Publisher Site | Google Scholar
P. Invernizzi, C. Selmi, F. Poli et al., “Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls,” Hepatology, vol. 48, no. 6, pp. 1906–1912, 2008.
View at: Publisher Site | Google Scholar
G. M. Hirschfield, X. Liu, C. Xu et al., “Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants,” The New England Journal of Medicine, vol. 360, no. 24, pp. 2544–2555, 2009.
View at: Publisher Site | Google Scholar
G. M. Hirschfield, X. Liu, Y. Han et al., “Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis,” Nature Genetics, vol. 42, no. 8, pp. 655–657, 2010.
View at: Publisher Site | Google Scholar
X. Liu, P. Invernizzi, Y. Lu et al., “Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis,” Nature Genetics, vol. 42, no. 8, pp. 658–660, 2010.
View at: Publisher Site | Google Scholar
G. F. Mells, J. A. B. Floyd, K. I. Morley et al., “Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis,” Nature Genetics, vol. 43, no. 4, pp. 329–332, 2011.
View at: Publisher Site | Google Scholar
R. M. Plenge, M. Seielstad, L. Padyukov et al., “TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study,” The New England Journal of Medicine, vol. 357, no. 12, pp. 1199–1209, 2007.
View at: Publisher Site | Google Scholar
F. A. S. Kurreeman, G. N. Goulielmos, B. Z. Alizadeh et al., “The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases,” Annals of the Rheumatic Diseases, vol. 69, no. 4, pp. 696–699, 2010.
View at: Publisher Site | Google Scholar
O. Torres, R. Palomino-Morales, T. R. Vazquez-Rodriguez et al., “Lack of association between TRAF1/C5 gene polymorphisms and biopsy-proven giant cell arteritis,” The Journal of Rheumatology, vol. 37, no. 1, pp. 131–135, 2010.
View at: Publisher Site | Google Scholar
M. Fotin-Mleczek, F. Henkler, A. Hausser et al., “Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-κB activation,” The Journal of Biological Chemistry, vol. 279, no. 1, pp. 677–685, 2004.
View at: Publisher Site | Google Scholar
P. Xie, B. S. Hostager, M. E. Munroe, C. R. Moore, and G. A. Bishop, “Cooperation between TNF receptor-associated factors 1 and 2 in CD40 signaling,” The Journal of Immunology, vol. 176, no. 9, pp. 5388–5400, 2006.
View at: Google Scholar
D. Plant, W. Thomson, M. Lunt et al., “The role of rheumatoid arthritis genetic susceptibility markers in the prediction of erosive disease in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register,” Rheumatology, vol. 50, no. 1, pp. 78–84, 2011.
View at: Publisher Site | Google Scholar
J. A. B. van Nies, R. B. Marques, S. Trompet et al., “TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies,” Arthritis Research & Therapy, vol. 12, no. 2, article R38, 2010.
View at: Publisher Site | Google Scholar
V. F. Panoulas, J. P. Smith, P. Nightingale, and G. D. Kitas, “Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 60, no. 1, pp. 39–46, 2009.
View at: Publisher Site | Google Scholar
European Association for the Study of the Liver, “EASL Clinical Practice Guidelines: management of cholestatic liver diseases,” Journal of Hepatology, vol. 51, no. 2, pp. 237–267, 2009.
View at: Publisher Site | Google Scholar
M. Rothe, S. C. Wong, W. J. Henzel, and D. V. Goeddel, “A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor,” Cell, vol. 78, no. 4, pp. 681–692, 1994.
View at: Publisher Site | Google Scholar
S. Ansieau, I. Scheffrahn, G. Mosialos et al., “Tumor necrosis factor receptor-associated factor (TRAF)-1, TRAF-2, and TRAF-3 interact in vivo with the CD30 cytoplasmic domain; TRAF-2 mediates CD30-induced nuclear factor kappa B activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 14053–14058, 1996.
View at: Publisher Site | Google Scholar
A. Lavorgna, R. de Filippi, S. Formisano, and A. Leonardi, “TNF receptor-associated factor 1 is a positive regulator of the NF-κB alternative pathway,” Molecular Immunology, vol. 46, no. 16, pp. 3278–3282, 2009.
View at: Publisher Site | Google Scholar
O. Micheau and J. Tschopp, “Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes,” Cell, vol. 114, no. 2, pp. 181–190, 2003.
View at: Publisher Site | Google Scholar
M. Chang, C. M. Rowland, V. E. Garcia et al., “A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2,” PLoS Genetics, vol. 4, no. 6, Article ID e1000107, 2008.
View at: Publisher Site | Google Scholar
K. Nishimoto, Y. Kochi, K. Ikari et al., “Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese,” Annals of the Rheumatic Diseases, vol. 69, no. 2, pp. 368–373, 2010.
View at: Publisher Site | Google Scholar
T. U. Han, S. Y. Bang, C. Kang, and S. C. Bae, “TRAF1 polymorphisms associated with rheumatoid arthritis susceptibility in Asians and in Caucasians,” Arthritis & Rheumatism, vol. 60, no. 9, pp. 2577–2584, 2009.
View at: Publisher Site | Google Scholar
L. B. Hughes, R. J. Reynolds, E. E. Brown et al., “Most common SNPs associated with rheumatoid arthritis in subjects of European ancestry confer risk of rheumatoid arthritis in African-Americans,” Arthritis & Rheumatism, vol. 62, no. 12, pp. 3547–3553, 2010.
View at: Google Scholar
J. Zhu, D. Zhang, F. Wu et al., “Single nucleotide polymorphisms at the TRAF1/C5 locus are associated with rheumatoid arthritis in a Han Chinese population,” BMC Medical Genetics, vol. 12, article 53, 2011.
View at: Publisher Site | Google Scholar
R. Knevel, D. P. de Rooy, P. K. Gregersen et al., “Studying associations between variants in TRAF1-C5 and TNFAIP3-OLIG3 and the progression of joint destruction in rheumatoid arthritis in multiple cohorts,” Annals of the Rheumatic Diseases, vol. 71, no. 10, pp. 1753–1755, 2012.
View at: Google Scholar
R. H. Mohamed, H. F. Pasha, and E. E. El-Shahawy, “Influence of TRAF1/C5 and STAT4 genes polymorphisms on susceptibility and severity of rheumatoid arthritis in Egyptian population,” Cellular Immunology, vol. 273, no. 1, pp. 67–72, 2012.
View at: Publisher Site | Google Scholar
A. W. Morgan, J. I. Robinson, P. G. Conaghan et al., “Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort,” Arthritis Research & Therapy, vol. 12, no. 2, article R57, 2010.
View at: Publisher Site | Google Scholar
M. T. Vuong, I. Gunnarsson, S. Lundberg et al., “Genetic risk factors in lupus nephritis and IgA nephropathy—no support of an overlap,” PloS ONE, vol. 5, no. 5, Article ID e10559, 2010.
View at: Publisher Site | Google Scholar
M. I. Zervou, V. M. Vazgiourakis, N. Yilmaz et al., “TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey,” Human Immunology, vol. 72, no. 12, pp. 1210–1213, 2011.
View at: Publisher Site | Google Scholar
H. M. Albers, F. A. S. Kurreeman, J. J. Houwing-Duistermaat et al., “The TRAF1/C5 region is a risk factor for polyarthritis in juvenile idiopathic arthritis,” Annals of the Rheumatic Diseases, vol. 67, no. 11, pp. 1578–1580, 2008.
View at: Publisher Site | Google Scholar
S. Redler, F. F. Brockschmidt, L. Forstbauer et al., “The TRAF1/C5 locus confers risk for familial and severe alopecia areata,” British Journal of Dermatology, vol. 162, no. 4, pp. 866–869, 2010.
View at: Publisher Site | Google Scholar
K. Mejri, H. Mbarek, M. Kallel-Sellami et al., “TRAF1/C5 polymorphism is not associated with pemphigus,” British Journal of Dermatology, vol. 160, no. 6, pp. 1348–1350, 2009.
View at: Publisher Site | Google Scholar
B. D. Juran, E. J. Atkinson, J. J. Larson et al., “Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: evidence for a gene-gene interaction,” Hepatology, vol. 52, no. 1, pp. 223–229, 2010.
View at: Publisher Site | Google Scholar
M. Neuman, P. Angulo, I. Malkiewicz et al., “Tumor necrosis factor-α and transforming growth factor-β reflect severity of liver damage in primary biliary cirrhosis,” Journal of Gastroenterology and Hepatology, vol. 17, no. 2, pp. 196–202, 2002.
View at: Publisher Site | Google Scholar
A. Lleo, M. E. Gershwin, A. Mantovani, and P. Invernizzi, “Towards common denominators in primary biliary cirrhosis: the role of IL-12,” Journal of Hepatology, vol. 56, no. 3, pp. 731–733, 2012.
View at: Publisher Site | Google Scholar
D. Fenoglio, F. Bernuzzi, F. Battaglia et al., “Th17 and regulatory T lymphocytes in primary biliary cirrhosis and systemic sclerosis as models of autoimmune fibrotic diseases,” Autoimmunity Reviews. In press.
View at: Publisher Site | Google Scholar
H. Hsu, H. B. Shu, M. G. Pan, and D. V. Goeddel, “TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways,” Cell, vol. 84, no. 2, pp. 299–308, 1996.
View at: Publisher Site | Google Scholar
H. Hsu, J. Huang, H. B. Shu, V. Baichwal, and D. V. Goeddel, “TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex,” Immunity, vol. 4, no. 4, pp. 387–396, 1996.
View at: Publisher Site | Google Scholar
H. B. Shu, M. Takeuchi, and D. V. Goeddel, “The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 13973–13978, 1996.
View at: Google Scholar
F. Tartakovsky and H. J. Worman, “Detection of gp210 autoantibodies in primary biliary cirrhosis using a recombinant protein containing the predominant autoepitope,” Hepatology, vol. 21, no. 2, pp. 495–500, 1995.
View at: Google Scholar
M. Nakamura, A. Komori, M. Ito et al., “Predictive role of anti-gp210 and anticentromere antibodies in long-term outcome of primary biliary cirrhosis,” Hepatology Research, vol. 37, supplement 3, pp. S412–S419, 2007.
View at: Publisher Site | Google Scholar
J. Wesierska-Gadek, E. Penner, P. M. Battezzati et al., “Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis,” Hepatology, vol. 43, no. 5, pp. 1135–1144, 2006.
View at: Publisher Site | Google Scholar
D. P. Bogdanos, C. Liaskos, A. Pares et al., “Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis,” Hepatology, vol. 45, no. 6, pp. 1583–1584, 2007.
View at: Publisher Site | Google Scholar
C. Duarte-Rey, D. Bogdanos, C. Y. Yang et al., “Primary biliary cirrhosis and the nuclear pore complex,” Autoimmunity Reviews, vol. 11, no. 12, pp. 898–902, 2012.
View at: Publisher Site | Google Scholar
D. E. Speiser, S. Y. Lee, B. Wong et al., “A regulatory role for TRAF1 in antigen-induced apoptosis of T cells,” Journal of Experimental Medicine, vol. 185, no. 10, pp. 1777–1783, 1997.
View at: Publisher Site | Google Scholar
T. U. Han, S. Y. Bang, C. Kang, and S. C. Bae, “TRAF1 polymorphisms associated with rheumatoid arthritis susceptibility in Asians and in Caucasians,” Arthritis & Rheumatism, vol. 60, no. 9, pp. 2577–2584, 2009.
View at: Publisher Site | Google Scholar
A. J. Delli, F. Vaziri-Sani, B. Lindblad et al., “Zinc transporter 8 autoantibodies and their association with SLC30A8 and HLA-DQ genes differ between immigrant and Swedish patients with newly diagnosed type 1 diabetes in the better diabetes diagnosis study,” Diabetes, vol. 61, no. 10, pp. 2556–2564, 2012.
View at: Publisher Site | Google Scholar
T. B. Niewold, J. A. Kelly, S. N. Kariuki et al., “IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 71, no. 3, pp. 463–469, 2012.
View at: Publisher Site | Google Scholar
A. J. Czaja, Z. Shums, W. L. Binder, S. J. Lewis, V. J. Nelson, and G. L. Norman, “Frequency and significance of antibodies to chromatin in autoimmune hepatitis,” Digestive Diseases and Sciences, vol. 48, no. 8, pp. 1658–1664, 2003.
View at: Publisher Site | Google Scholar
L. B. El-Din Elshazly, A. M. Youssef, N. H. Mahmoud, and M. M. Ibrahim, “Study of nonstandard auto-antibodies as prognostic markers in auto immune hepatitis in children,” Italian Journal of Pediatrics, vol. 35, no. 22, article 22, 2009.
View at: Publisher Site | Google Scholar
A. J. Czaja, “Autoantibodies as prognostic markers in autoimmune liver disease,” Digestive Diseases and Sciences, vol. 55, no. 8, pp. 2144–2161, 2010.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2012 Agnieszka Kempinska-Podhorodecka et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1363

Downloads

1579

Citations