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1.  Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis 
The Journal of rheumatology  2012;39(5):997-1003.
Objective
Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.
Methods
Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.
Results
Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intracohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)].
Conclusion
We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype. (First Release March 15 2012; J Rheumatol 2012;39:997–1003; doi:10.3899/jrheum.111270)
doi:10.3899/jrheum.111270
PMCID: PMC3687343  PMID: 22422496
SYSTEMIC SCLEROSIS; TNFSF4; AUTOIMMUNITY; AUTOANTIBODIES
2.  Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis 
Annals of the Rheumatic Diseases  2011;71(1):114-119.
Objective
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features.
Methods
Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc.
Results
Four out of five analysed SNPs were Significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: pFDR=6.14 × 10−4, OR=0.78; rs4963128: pFDR=6.14 × 10−4, OR=0.79; rs702966: pFDR=3.83 × 10−3, OR=0.82; and rs2246614: pFDR=3.83 × 10−3, OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant.
Conclusions
The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.
doi:10.1136/annrheumdis-2011-200275
PMCID: PMC3369428  PMID: 21926187
3.  Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts 
The Journal of Rheumatology  2011;38(6):1033-1038.
Objective
Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.
Methods
SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort.
Results
The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls.
Conclusion
These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes.
doi:10.3899/jrheum.101053
PMCID: PMC3404507  PMID: 21362770
SYSTEMIC SCLEROSIS; SYSTEMIC LUPUS ERYTHEMATOSUS; AUTOIMMUNITY SINGLE NUCLEOTIDE POLYMORPHISM; ITGAM; ITGAX; CD58
4.  Whole-blood Gene Expression Profiling in Ankylosing Spondylitis Shows Upregulation of Toll-like Receptor 4 and 5 
The Journal of rheumatology  2010;38(1):87-98.
Objective
To identify differentially expressed genes in peripheral blood cells (PBC) of patients with ankylosing spondylitis (AS) relative to healthy controls and controls with systemic inflammation.
Methods
We investigated PBC samples of 16 patients with AS and 14 matched controls, in addition to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) samples utilizing Illumina Human Ref-8 BeadChips. Candidate genes were confirmed using quantitative PCR. Subsequently, these genes were also validated in a separate sample of 27 patients with AS [before and after antitumor necrosis factor (anti-TNF) treatment] and 27 matched controls.
Results
We identified 83 differentially expressed transcripts between AS patients and controls. This gene list was filtered through the lists of differentially expressed transcripts in SLE and SSc, which resulted in identification of 52 uniquely dysregulated transcripts in AS. Many of the differentially expressed genes belonged to Toll-like receptor (TLR) and related pathways. TLR4 and TLR5 were the only dysregulated TLR subtypes among AS patients. We confirmed the overexpression of TLR4 and TLR5 in AS patients in comparison to controls (p = 0.012 and p = 0.006, respectively) and SLE (p = 0.002, p = 0.008) using quantitative PCR in the same sample. Similarly, TLR4 (p = 0.007) and TLR5 (p = 0.012) were significantly upregulated among the AS patients before anti-TNF treatment in the confirmatory sample. TLR4 (p = 0.002) and TLR5 (p = 0.025) decreased significantly after anti-TNF treatment.
Conclusion
PBC gene expression profiling in AS shows an upregulation of TLR4 and TLR5. This supports the importance of TLR subtypes in the pathogenesis of AS that are responsible for the immune response to Gram-negative bacteria.
doi:10.3899/jrheum.100469
PMCID: PMC3014385  PMID: 20952467
ANKYLOSING SPONDYLITIS; TOLL-LIKE RECEPTORS; IMMUNE SYSTEM; AUTOIMMUNITY; BACTERIA; GENE EXPRESSION PROFILING
5.  Correction: Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy 
Gorlova, Olga | Martin, Jose-Ezequiel | Rueda, Blanca | Koeleman, Bobby P. C. | Ying, Jun | Teruel, Maria | Diaz-Gallo, Lina-Marcela | Broen, Jasper C. | Vonk, Madelon C. | Simeon, Carmen P. | Alizadeh, Behrooz Z. | Coenen, Marieke J. H. | Voskuyl, Alexandre E. | Schuerwegh, Annemie J. | van Riel, Piet L. C. M. | Vanthuyne, Marie | van 't Slot, Ruben | Italiaander, Annet | Ophoff, Roel A. | Hunzelmann, Nicolas | Fonollosa, Vicente | Ortego-Centeno, Norberto | González-Gay, Miguel A. | García-Hernández, Francisco J. | González-Escribano, María F. | Airo, Paolo | van Laar, Jacob | Worthington, Jane | Hesselstrand, Roger | Smith, Vanessa | de Keyser, Filip | Houssiau, Fredric | Chee, Meng May | Madhok, Rajan | Shiels, Paul G. | Westhovens, Rene | Kreuter, Alexander | de Baere, Elfride | Witte, Torsten | Padyukov, Leonid | Nordin, Annika | Scorza, Raffaella | Lunardi, Claudio | Lie, Benedicte A. | Hoffmann-Vold, Anna-Maria | Palm, Øyvind | García de la Peña, Paloma | Carreira, Patricia | Varga, John | Hinchcliff, Monique | Lee, Annette T. | Gourh, Pravitt | Amos, Christopher I. | Wigley, Frederick M. | Hummers, Laura K. | Nelson, J. Lee | Riemekasten, Gabriella | Herrick, Ariane | Beretta, Lorenzo | Fonseca, Carmen | Denton, Christopher P. | Gregersen, Peter K. | Agarwal, Sandeep | Assassi, Shervin | Tan, Filemon K. | Arnett, Frank C. | Radstake, Timothy R. D. J. | Mayes, Maureen D. | Martin, Javier
PLoS Genetics  2011;7(8):10.1371/annotation/3aeebb2e-64e5-4548-8d65-1f2d5dfeb073.
doi:10.1371/annotation/3aeebb2e-64e5-4548-8d65-1f2d5dfeb073
PMCID: PMC3166261
6.  Correction: Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy 
Gorlova, Olga | Martin, Jose-Ezequiel | Rueda, Blanca | Koeleman, Bobby P. C. | Ying, Jun | Teruel, Maria | Diaz-Gallo, Lina-Marcela | Broen, Jasper C. | Vonk, Madelon C. | Simeon, Carmen P. | Alizadeh, Behrooz Z. | Coenen, Marieke J. H. | Voskuyl, Alexandre E. | Schuerwegh, Annemie J. | van Riel, Piet L. C. M. | Vanthuyne, Marie | van 't Slot, Ruben | Italiaander, Annet | Ophoff, Roel A. | Hunzelmann, Nicolas | Fonollosa, Vicente | Ortego-Centeno, Norberto | González-Gay, Miguel A. | García-Hernández, Francisco J. | González-Escribano, María F. | Airo, Paolo | van Laar, Jacob | Worthington, Jane | Hesselstrand, Roger | Smith, Vanessa | de Keyser, Filip | Houssiau, Fredric | Chee, Meng May | Madhok, Rajan | Shiels, Paul G. | Westhovens, Rene | Kreuter, Alexander | de Baere, Elfride | Witte, Torsten | Padyukov, Leonid | Nordin, Annika | Scorza, Raffaella | Lunardi, Claudio | Lie, Benedicte A. | Hoffmann-Vold, Anna-Maria | Palm, Øyvind | García de la Peña, Paloma | Carreira, Patricia | Varga, John | Hinchcliff, Monique | Lee, Annette T. | Gourh, Pravitt | Amos, Christopher I. | Wigley, Frederick M. | Hummers, Laura K. | Nelson, J. Lee | Riemekasten, Gabriella | Herrick, Ariane | Beretta, Lorenzo | Fonseca, Carmen | Denton, Christopher P. | Gregersen, Peter K. | Agarwal, Sandeep | Assassi, Shervin | Tan, Filemon K. | Arnett, Frank C. | Radstake, Timothy R. D. J. | Mayes, Maureen D. | Martin, Javier
PLoS Genetics  2011;7(8):10.1371/annotation/7a52649c-0942-4bd8-a5d3-3cdacca03cd8.
doi:10.1371/annotation/7a52649c-0942-4bd8-a5d3-3cdacca03cd8
PMCID: PMC3166262
7.  Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy 
Gorlova, Olga | Martin, Jose-Ezequiel | Rueda, Blanca | Koeleman, Bobby P. C. | Ying, Jun | Teruel, Maria | Diaz-Gallo, Lina-Marcela | Broen, Jasper C. | Vonk, Madelon C. | Simeon, Carmen P. | Alizadeh, Behrooz Z. | Coenen, Marieke J. H. | Voskuyl, Alexandre E. | Schuerwegh, Annemie J. | van Riel, Piet L. C. M. | Vanthuyne, Marie | van 't Slot, Ruben | Italiaander, Annet | Ophoff, Roel A. | Hunzelmann, Nicolas | Fonollosa, Vicente | Ortego-Centeno, Norberto | González-Gay, Miguel A. | García-Hernández, Francisco J. | González-Escribano, María F. | Airo, Paolo | van Laar, Jacob | Worthington, Jane | Hesselstrand, Roger | Smith, Vanessa | de Keyser, Filip | Houssiau, Fredric | Chee, Meng May | Madhok, Rajan | Shiels, Paul G. | Westhovens, Rene | Kreuter, Alexander | de Baere, Elfride | Witte, Torsten | Padyukov, Leonid | Nordin, Annika | Scorza, Raffaella | Lunardi, Claudio | Lie, Benedicte A. | Hoffmann-Vold, Anna-Maria | Palm, Øyvind | García de la Peña, Paloma | Carreira, Patricia | Varga, John | Hinchcliff, Monique | Lee, Annette T. | Gourh, Pravitt | Amos, Christopher I. | Wigley, Frederick M. | Hummers, Laura K. | Hummers, J. | Nelson, J. Lee | Riemekasten, Gabriella | Herrick, Ariane | Beretta, Lorenzo | Fonseca, Carmen | Denton, Christopher P. | Gregersen, Peter K. | Agarwal, Sandeep | Assassi, Shervin | Tan, Filemon K. | Arnett, Frank C. | Radstake, Timothy R. D. J. | Mayes, Maureen D. | Martin, Javier
PLoS Genetics  2011;7(7):e1002178.
The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10−12, OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10−6, OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10−7, OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10−61, OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10−76, OR = 8.84), and in NOTCH4 with ACA P = 8.84×10−21, OR = 0.55) and ATA (P = 1.14×10−8, OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
Author Summary
Scleroderma or systemic sclerosis is a complex autoimmune disease affecting one individual of every 100,000 in Caucasian populations. Even though current genetic studies have led to better understanding of the pathogenesis of the disease, much remains unknown. Scleroderma is a heterogeneous disease, which can be subdivided according to different criteria, such as the involvement of organs and the presence of specific autoantibodies. Such subgroups present more homogeneous genetic groups, and some genetic associations with these manifestations have already been described. Through reanalysis of a genome-wide association study data, we identify three novel genes containing genetic variations which predispose to subphenotypes of the disease (IRF8, GRB10, and SOX5). Also, we better characterize the patterns of associated loci found in the HLA region. Together, our findings lead to a better understanding of the genetic component of scleroderma.
doi:10.1371/journal.pgen.1002178
PMCID: PMC3136437  PMID: 21779181
8.  Association of the C8orf13-BLK Region with Systemic Sclerosis in North-American and European Populations 
Journal of autoimmunity  2009;34(2):155.
Objective
Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.
Methods
Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain.
Results
The “T” allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P=6.8×10−5, OR 1.27, 95%CI 1.1–1.4). The “A” allele at rs13277113 variant was associated with SSc in the U.S. series only (P=3.6×10−4, OR 1.32, 95%CI 1.1–1.6) and was significant in the combined analyses of the two series (P=2.0×10−3; OR 1.20, 95%CI 1.1–1.3). Both variants demonstrated an association with the anti-centromere antibody (P=2.2×10−6 and P=5.5×10−4, respectively) and limited SSc (P=3.3×10−5 and P=2.9×10−3, respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFκB signaling are dysregulated based on the risk haplotype of these variants.
Conclusion
We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.
doi:10.1016/j.jaut.2009.08.014
PMCID: PMC2821978  PMID: 19796918
Scleroderma; Systemic Sclerosis/SSc; Polymorphism/SNP; BLK; C8orf13; Anti- Topoisomerase-I; Anti-Centromere; Genetics; Autoantibody; rs13277113; rs2736340
9.  Polymorphisms in TBX21 and STAT4 Increase the Risk of Systemic Sclerosis 
Arthritis and rheumatism  2009;60(12):3794-3806.
Objective
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility.
Methods
We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene–gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs.
Results
Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr = 1.4 × 10−15, odds ratio 3.37, 95% confidence interval 2.4–4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr = 2.4 × 10−5, odds ratio 1.29, 95% confidence interval 1.2–1.5). Furthermore, we identified gene–gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor α levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP.
Conclusion
The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation.
doi:10.1002/art.24958
PMCID: PMC2998060  PMID: 19950257
10.  Genome-wide association study of systemic sclerosis identifies CD247 as a novel susceptibility locus 
Nature genetics  2010;42(5):426-429.
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify novel SSc susceptibility loci we conducted the first genome wide association study (GWAS) in a population of Caucasian ancestry including a total of 2296 SSc patients and 5171 controls. Analysis of 279,621 autosomal single nucleotide polymorphisms (SNPs) followed by replication testing in an independent case-control set of European ancestry (2,753 SSc patients / 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23; rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of MHC (2.31 × 10−18), IRF5 (P =1.86 × 10−13) and STAT4 (P =3.37 × 10−9) gene regions as SSc genetic risk factors.
doi:10.1038/ng.565
PMCID: PMC2861917  PMID: 20383147
11.  Primary Biliary Cirrhosis (PBC), PBC Autoantibodies, and Hepatic Parameter Abnormalities in a Large Population of Systemic Sclerosis Patients 
The Journal of rheumatology  2009;36(10):2250-2256.
Objective
To investigate the diagnostic accuracy of antimitochondrial antibodies (AMA), sp100, and gp210 antibodies for primary biliary cirrhosis (PBC) in a large population of patients with systemic sclerosis (SSc); to examine concordance of these antibodies with subsets of SSc. Further, to assess the association of SSc-related antibodies with hepatic parameter abnormalities.
Methods
We obtained medical records to verify the diagnoses of SSc and PBC. Sera from all participants were examined for the presence of SSc- and PBC-related antibodies, as well as for abnormalities in hepatic parameters.
Results
We examined 817 patients with SSc, of whom 16 (2%) had confirmed PBC. The sensitivity and specificity of AMA by a MIT3 ELISA for PBC were 81.3% and 94.6%, respectively. Sp100 had a sensitivity and specificity of 31.3% and 97.4%, respectively, while gp210 had an even lower sensitivity. We were able to detect all PBC cases using AMA(MIT3) and sp100 as a combined marker, resulting in a significantly improved sensitivity of 100% (p = 0.042) with an incremental decrease in specificity to 92.6%. Independent of AMA or sp100 status, there was an association of anticentromere B (CENP-B) and anti-topoisomerase antibodies (ATA) with higher alkaline phosphatase levels (p = 0.051 and p = 0.003, respectively) while anti-RNA polymerase III (anti-RNAP) was associated with lower alkaline phosphatase levels (p = 0.019) among the patients with SSc.
Conclusion
Utilization of AMA(MIT3) and sp100 antibodies as a combined diagnostic marker leads to an improved detection of PBC in patients with SSc. CENP-B and ATA are associated with alkaline phosphatase elevation.
doi:10.3899/jrheum.090340
PMCID: PMC2885441  PMID: 19723904
LIVER CIRRHOSIS; BILIARY; SCLERODERMA; SYSTEMIC SCLEROSIS
12.  Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls 
Annals of the rheumatic diseases  2009;69(5):822-827.
Objective
To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case–control association study.
Patients and methods
1300 SSc cases (961 white, 178 black and 161 Hispanic subjects) characterised for clinical skin forms (limited vs diffuse), SSc-specific autoantibodies (anticentromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 ribonucleoprotein (fibrillarin)) and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modelling for dominant, additive and recessive effects from HLA.
Results
The strongest positive class II associations with SSc in white and Hispanic subjects were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate between limited and diffuse SSc. SSc in black subjects was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR = 14). Moreover, it showed no linkage disequilibrium or gene interaction with DR/DQ. ACA was best explained by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in white and Hispanic subjects but DRB1*08 in black subjects.
Conclusion
These data indicate unique and multiple HLA-class II effects in SSc, especially on autoantibody markers of different subphenotypes.
doi:10.1136/ard.2009.111906
PMCID: PMC2916702  PMID: 19596691
13.  Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls 
Annals of the Rheumatic Diseases  2010;69(5):822-827.
Objective
To determine human leucocyte antigen-class II (HLA-class II) (DRB1, DQB1, DQA1 and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis (SSc)) and its subphenotypes in a large multi-ethnic US cohort by a case–control association study.
Patients and methods
1300 SSc cases (961 white, 178 black and 161 Hispanic subjects) characterised for clinical skin forms (limited vs diffuse), SSc-specific autoantibodies (anticentromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 ribonucleoprotein (fibrillarin)) and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modelling for dominant, additive and recessive effects from HLA.
Results
The strongest positive class II associations with SSc in white and Hispanic subjects were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate between limited and diffuse SSc. SSc in black subjects was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR = 14). Moreover, it showed no linkage disequilibrium or gene interaction with DR/DQ. ACA was best explained by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in white and Hispanic subjects but DRB1*08 in black subjects.
Conclusion
These data indicate unique and multiple HLA-class II effects in SSc, especially on autoantibody markers of different subphenotypes.
doi:10.1136/ard.2009.111906
PMCID: PMC2916702  PMID: 19596691
14.  Association of Interleukin 23 Receptor Polymorphisms with Anti-Topoisomerase-I Positivity and Pulmonary Hypertension in Systemic Sclerosis 
The Journal of rheumatology  2009;36(12):2715-2723.
Objective
IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
Methods
We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease.
Results
Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3×10−5, p = 1×10−5, respectively).
Conclusion
Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.
doi:10.3899/jrheum.090421
PMCID: PMC2895677  PMID: 19918037
SYSTEMIC SCLEROSIS; SCLERODERMA; IL23R; POLYMORPHISM; AUTOANTIBODIES; PULMONARY HYPERTENSION
15.  Clinical and Genetic Factors Predictive of Mortality in Early Systemic Sclerosis 
Arthritis and rheumatism  2009;61(10):1403-1411.
Objective
To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort.
Methods
GENISOS is a prospective, observational study of a multiethnic early systemic sclerosis (SSc) cohort. To date, a total of 250 patients have been enrolled. In addition to clinical and laboratory data, electrocardiograms (EKGs), chest radiographs, and pulmonary function tests have been obtained from each patient. A modified Rodnan skin thickness score, HLA class II genotyping, and a Medsger Damage Index also have been collected. We performed multivariable analyses utilizing the Cox regression following a purposeful model building strategy.
Results
The study analyzed 122 white, 47 African American, and 71 Hispanic SSc patients with an average disease duration of 2.6 years at enrollment. At the time of analysis, 52 (20.8%) of the 250 patients had died. In the final multivariable model excluding HLA genes, 7 variables emerged as significant predictors of mortality: age ≥65 years at enrollment, forced vital capacity <50% predicted, clinically significant arrhythmia on EKG, absence of anticentromere antibodies, hypertension, chest radiograph suggestive of pulmonary fibrosis, and low body mass index (BMI). In separate modeling that included HLA genes, HLA alleles DRB1*0802 and DQA1*0501 were significant predictors of mortality in addition to the predictors mentioned above.
Conclusion
A limited number of variables collected at presentation, including BMI, are able to predict mortality in patients with early SSc. In addition, some of the HLA genes associated with SSc susceptibility are useful for predicting SSc outcome.
doi:10.1002/art.24734
PMCID: PMC2883167  PMID: 19790132
16.  Systemic Sclerosis and Lupus 
Arthritis and rheumatism  2010;62(2):589-598.
Objective
To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE).
Methods
We investigated PB cell samples from 74 SSc patients, 21 healthy controls, and 17 SLE patients using Illumina Human Ref-8 BeadChips and quantitative polymerase chain reaction confirmation. None of the study participants were receiving immunosuppressive agents other than low-dose steroids and hydroxychloroquine. In addition to conventional statistical and modular analysis, a composite score for the interferon (IFN)–inducible genes was calculated. Within the group of patients with SSc, the correlation of the IFN score with the serologic and clinical subtypes was investigated, as were single-nucleotide polymorphisms in a selected number of IFN pathway genes.
Results
Many of the most prominently overexpressed genes in SSc and SLE were IFN-inducible genes. Forty-three of 47 overexpressed IFN-inducible genes in SSc (91%) were similarly altered in SLE. The IFN score was highest in the SLE patients, followed by the SSc patients, and then the controls. The difference in IFN score among all 3 groups was statistically significant (P < 0.001 for all 3 comparisons). SSc and SLE PB cell samples showed striking parallels to our previously reported SSc skin transcripts in regard to the IFN-inducible gene expression pattern. In SSc, the presence of antitopoisomerase and anti–U1 RNP antibodies and lymphopenia correlated with the higher IFN scores (P = 0.005, P = 0.001, and P = 0.004, respectively); a missense mutation in IFNAR2 was significantly associated with the IFN score.
Conclusion
SLE and SSc fit within the same spectrum of IFN-mediated diseases. A subset of SSc patients shows a “lupus-like” high IFN-inducible gene expression pattern that correlates with the presence of antitopoisomerase and anti–U1 RNP antibodies.
doi:10.1002/art.27224
PMCID: PMC2879587  PMID: 20112391
17.  Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis 
Annals of the Rheumatic Diseases  2010;69(3):550-555.
Objective
It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.
Methods
A total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls.
Results
Case-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, pFDR=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, pFDR=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, pFDR=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, pFDR=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility.
Conclusions
Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases.
doi:10.1136/ard.2009.116434
PMCID: PMC2927683  PMID: 19778912
18.  Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations 
Arthritis Research & Therapy  2009;11(5):R147.
Introduction
Systemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets.
Methods
Plasma from 444 SSc patients and 216 healthy controls was obtained from the Scleroderma Family Registry and University of Texas Rheumatology Division. Patients were classified according to the presence of ACAs, ATAs, ARAs, or none of the above (antibody-negative). Levels of 13 cytokines were determined using multiplex assays.
Results
Compared with females, healthy control males had higher plasma levels of IL-2 (P = 0.008), IL-5 (P = 0.01) and IL-8 (P = 0.01). In addition, in controls, IL-6 (P = 0.02) and IL-17 (P = 0.01) levels increased with advancing age. After adjusting for age and gender, SSc patients had higher circulating levels of TNFα (P < 0.0001), IL-6 (P < 0.0001), and IFNγ (P = 0.05) and lower IL-17 (P = 0.0005) and IL-23 (P = 0.014). Additional analyses demonstrated that disease duration also influenced these cytokine profiles. IL-6 was elevated in ATA-positive and ARA-positive patients, but not in ACA-positive patients. IL-8 was uniquely increased in the ATA-positive subset while both ATA-positive and ACA-positive subsets had elevated IFNγ and IL-10. IL-5 was only significantly increased in the ACA-positive subset. Lastly, patients with interstitial lung disease had elevated IL-6 and patients with pulmonary hypertension had elevated IL-6 and IL-13.
Conclusions
Plasma cytokine profiles differ in SSc patients based on the presence of SSc-associated autoantibodies. Plasma cytokine profiles in SSc patients may also be affected by disease duration and the pattern of internal organ involvement.
doi:10.1186/ar2821
PMCID: PMC2787259  PMID: 19799786

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