-
Mona Elhaj,
Julio Charles,
Claudia Pedroza,
Xiaochun Liu,
Xiaodong Zhou,
Rosa M Estrada-Y-Martin,
Emilio B Gonzalez,
Dorothy E Lewis,
Hilda T Draeger,
Sarah Kim, Frank C Arnett,
Maureen D Mayes,
Shervin Assassi
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease. METHODS: The pneumoproteins were determined in the baseline plasma samples of 266 patients with early SSc enrolled in the GENISOS observational cohort. They also were measured in 83 followup patient samples. Pulmonary function tests were obtained annually. The primary outcome was decline in forced vital capacity (FVC percentage predicted) over time. The predictive significance for longterm change in FVC was investigated by a joint analysis of longitudinal measurements (sequentially obtained FVC percentage predicted) and survival data. RESULTS: SP-D and CCL18 levels were both higher in patients with SSc than in matched controls (p < 0.001 and p = 0.015, respectively). Baseline SP-D levels correlated with lower concomitantly obtained FVC (r = -0.27, p < 0.001), but did not predict the short-term decline in FVC at 1 year followup visit or its longterm decline rate. CCL18 showed a significant correlation with steeper short-term decline in FVC (p = 0.049), but was not a predictor of its longterm decline rate. Similarly, a composite score of SP-D and CCL18 was a significant predictor of short-term decline in FVC but did not predict its longterm decline rate. Further, the longitudinal change in these 2 pneumoproteins did not correlate with the concomitant percentage change in FVC. CONCLUSION: SP-D correlated with concomitantly obtained FVC, while CCL18 was a predictor of short-term decline in FVC. However, neither SP-D nor CCL18 was a longterm predictor of FVC course in patients with early SSc.
The Journal of Rheumatology 04/2013; · 3.69 Impact Factor
-
F David Carmona,
M Carmen Cénit,
Lina-Marcela Diaz-Gallo,
Jasper C A Broen,
Carmen P Simeón,
Patricia E Carreira,
José-Luis Callejas-Rubio,
Vicente Fonollosa,
Francisco J López-Longo,
Miguel A González-Gay, [......],
Carmen Fonseca,
Christopher P Denton,
Ariane Herrick,
Jane Worthington, Frank C Arnett,
Filemon K Tan,
Shervin Assassi,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martín
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). METHODS: We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. RESULTS: IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (P(FDR)=4.12×10(-3), OR=1.27, 95% CI 1.09 to 1.47, and P(FDR)=5.26×10(-4), OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (P(FDR)=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF- (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). CONCLUSIONS: Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
Annals of the rheumatic diseases 02/2013; · 8.11 Impact Factor
-
Lina-Marcela Diaz-Gallo,
Carmen P Simeon,
Jasper C Broen,
Norberto Ortego-Centeno,
Lorenzo Beretta,
Madelon C Vonk,
Patricia E Carreira,
Sofia Vargas,
José Andrés Román-Ivorra,
Miguel A González-Gay, [......],
Jane Worthington,
Christopher P Denton,
Xiaodong Zhou, Frank C Arnett,
Carmen Fonseca,
Bobby Pc Koeleman,
Shervin Assasi,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martín
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (p(c)=6.6E-4 and p(c)=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (p(c)=1.7E-03 and p(c)=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
-
Lara Bossini-Castillo,
Jose Ezequiel Martin,
Jasper Broen,
Carmen P Simeon,
Lorenzo Beretta,
Olga Y Gorlova,
Madelon C Vonk,
Norberto Ortego-Centeno,
Gerard Espinosa,
Patricia Carreira, [......],
Jane Worthington,
Carmen Fonseca,
Christopher Denton,
Filemon K Tan, Frank C Arnett,
Shervin Assassi,
Bobby P Koeleman,
Maureen D Mayes,
Timothy R D J Radstake,
Javier Martin
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION: A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. METHODS: 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. RESULTS: Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 p(MH)=1.94×10(-4), OR 1.19; rs4958881 p(MH)=3.26×10(-5), OR 1.19; rs3792783 p(MH)=2.16×10(-4), OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. CONCLUSIONS: These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.
Annals of the rheumatic diseases 08/2012; · 8.11 Impact Factor
-
Roozbeh Sharif,
Maureen D Mayes,
Filemon K Tan,
Olga Y Gorlova,
Laura Kathleen Hummers,
Ami A Shah,
Daniel E Furst,
Dinesh Khanna,
Javier Martin,
Lara Bossini-Castillo,
Emilio B Gonzalez,
Jun Ying,
Hilda Torres Draeger,
Sandeep K Agarwal,
John D Reveille, Frank C Arnett,
Fredrick M Wigley,
Shervin Assassi
[show abstract]
[hide abstract]
ABSTRACT: The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc.
The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 - discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 - replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study.
Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant.
An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.
Annals of the rheumatic diseases 03/2012; 71(7):1197-202. · 8.11 Impact Factor
-
Jose-Ezequiel Martin,
Jasper C Broen,
F David Carmona,
Maria Teruel,
Carmen P Simeon,
Madelon C Vonk,
Ruben van 't Slot,
Luis Rodriguez-Rodriguez,
Esther Vicente,
Vicente Fonollosa, [......],
Ariane Herrick,
Christopher Denton,
Filemon K Tan, Frank C Arnett,
Shervin Assassi,
Carmen Fonseca,
Maureen D Mayes,
Timothy R D J Radstake,
Bobby P C Koeleman,
Javier Martin
[show abstract]
[hide abstract]
ABSTRACT: Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.
Human Molecular Genetics 03/2012; 21(12):2825-35. · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Osteopontin (OPN) is a matricellular protein with proinflammatory and profibrotic properties. Previous reports demonstrate a role for OPN in wound healing and pulmonary fibrosis. Here, we determined whether OPN levels are increased in a large cohort of patients with systemic sclerosis (SSc) and whether OPN contributes to the development of dermal fibrosis. The plasma OPN levels were increased in SSc patients, including patients with limited and diffuse disease, compared with healthy controls. Immunohistology demonstrated OPN on fibroblast-like and inflammatory cells in SSc skin and lesional skin from mice in the bleomycin (bleo)-induced dermal fibrosis model. OPN-deficient (OPN(-/-)) mice developed less dermal fibrosis compared with wild-type (WT) mice in the bleo-induced dermal fibrosis model. Additional in vivo studies have demonstrated that lesional skin from OPN(-/-)mice had fewer Mac-3-positive cells, fewer myofibroblasts, decreased transforming growth factor (TGF)-β and genes in the TGF-β pathway, and decreased numbers of cells expressing phosphorylated SMAD2 (pSMAD) and extracellular signal-regulated kinase. In vitro, OPN(-/-) dermal fibroblasts had decreased migratory capacity but similar phosphorylation of SMAD2 by TGF-β. Finally, TGF-β production by OPN-deficient macrophages was reduced compared with WT. These data demonstrate an important role for OPN in the development of dermal fibrosis and suggest that it may be a new therapeutic target in SSc.
Journal of Investigative Dermatology 03/2012; 132(6):1605-14. · 6.31 Impact Factor
-
Lara Bossini-Castillo,
Jose-Ezequiel Martin,
Jasper Broen,
Olga Gorlova,
Carmen P Simeón,
Lorenzo Beretta,
Madelon C Vonk,
Jose Luis Callejas,
Ivan Castellví,
Patricia Carreira, [......],
Jane Worthington,
Christopher Denton,
Filemon K Tan, Frank C Arnett,
Sandeep K Agarwal,
Shervin Assassi,
Carmen Fonseca,
Maureen D Mayes,
Timothy R D J Radstake,
Javier Martin
[show abstract]
[hide abstract]
ABSTRACT: A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
Human Molecular Genetics 11/2011; 21(4):926-33. · 7.64 Impact Factor
-
F David Carmona,
Ramana Gutala,
Carmen P Simeón,
Patricia Carreira,
Norberto Ortego-Centeno,
Esther Vicente-Rabaneda,
Francisco J García-Hernández,
Paloma García de la Peña,
Mónica Fernández-Castro,
Lina Martínez-Estupiñán,
María Victoria Egurbide,
Betty P Tsao,
Pravitt Gourh,
Sandeep K Agarwal,
Shervin Assassi,
Maureen D Mayes, Frank C Arnett,
Filemon K Tan,
Javier Martín
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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: p(FDR)=6.14 × 10(-4), OR=0.78; rs4963128: p(FDR)=6.14 × 10(-4), OR=0.79; rs702966: p(FDR)=3.83 × 10(-3), OR=0.82; and rs2246614: p(FDR)=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.
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.
Annals of the rheumatic diseases 09/2011; 71(1):114-9. · 8.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Sumoylation is involved in nucleolus-nucleoplasm transport of DNA topoisomerase I (topo I), which may associate with changes of cellular and topo I functions. Skin fibroblasts of patients with systemic sclerosis (SSc) exhibit profibrotic cellular changes. The aims of this study were to examine the catalytic function and sumoylation of topo I in the nuclei of SSc fibroblasts, a major cell type involved in the fibrotic process.
Eleven pairs of fibroblast strains obtained from nonlesional skin biopsies of SSc patients and age/sex/ethnicity-matched normal controls were examined for catalytic function of nuclear topo I. Immunoprecipitation (IP)-Western blots were used to examine sumoylation of fibroblast topo I. Real-time quantitative RT-PCR was used to measure transcript levels of SUMO1 and COL1A2 in the fibroblasts.
Topo I in nuclear extracts of SSc fibroblasts generally showed a significantly lower efficiency than that of normal fibroblasts in relaxing equivalent amounts of supercoiled DNA. Increased sumoylation of topo I was clearly observed in 7 of 11 SSc fibroblast strains. Inhibition of SUMO1 with SUMO1 siRNA improved the catalytic efficiency of topo I in the SSc fibroblasts. In contrast, sumoylation of recombinant topo I proteins reduced their catalytic function.
The catalytic function of topo I was decreased in SSc fibroblasts, to which increased sumoylation of topo I may contribute.
Arthritis research & therapy 08/2011; 13(4):R128. · 4.27 Impact Factor
-
Olga Gorlova,
Jose-Ezequiel Martin,
Blanca Rueda,
Bobby P C Koeleman,
Jun Ying,
Maria Teruel,
Lina-Marcela Diaz-Gallo,
Jasper C Broen,
Madelon C Vonk,
Carmen P Simeon, [......],
Carmen Fonseca,
Christopher P Denton,
Peter K Gregersen,
Sandeep Agarwal,
Shervin Assassi,
Filemon K Tan, Frank C Arnett,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martin
PLoS Genetics 08/2011; 7(8). · 8.69 Impact Factor
-
Arthritis & Rheumatism 07/2011; · 7.87 Impact Factor
-
Olga Gorlova,
Jose-Ezequiel Martin,
Blanca Rueda,
Bobby P C Koeleman,
Jun Ying,
Maria Teruel,
Lina-Marcela Diaz-Gallo,
Jasper C Broen,
Madelon C Vonk,
Carmen P Simeon, [......],
Carmen Fonseca,
Christopher P Denton,
Peter K Gregersen,
Sandeep Agarwal,
Shervin Assassi,
Filemon K Tan, Frank C Arnett,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martin
[show abstract]
[hide abstract]
ABSTRACT: 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.
PLoS Genetics 07/2011; 7(7):e1002178. · 8.69 Impact Factor
-
Prateek Chaudhary,
Xing Chen,
Shervin Assassi,
Olga Gorlova,
Hilda Draeger,
Brock E Harper,
Emilio Gonzalez,
Terry McNearney,
Marilyn Perry, Frank C Arnett,
Maureen D Mayes
[show abstract]
[hide abstract]
ABSTRACT: To investigate the association of cigarette smoking with susceptibility to systemic sclerosis (SSc) in a large, well-defined patient population.
We conducted a review of 1,379 patients with SSc enrolled in the Scleroderma Family Registry and DNA Repository and/or the Genetics versus Environment in Scleroderma Outcome Study cohort. Smoking history was obtained from chart review or via telephone interview. Patients with SSc were subsequently categorized as never smokers or ever smokers. Patients with SSc for whom smoking data were available were matched 2:1 by age, sex, ethnicity, and state of residence to control subjects, using the Behavioral Risk Factor Surveillance System.
The majority of patients were white (74.2%), with Hispanics and blacks representing 11.3% and 9.7%, respectively. Most patients had limited cutaneous involvement (54%). For our comparative analyses, 621 patients were matched with control subjects. There was no significant difference in age, sex, ethnicity, and SSc subtype between matched versus unmatched patients. The majority of patients had never smoked (57%), while 43% of patients were classified as ever smokers. The patients with SSc did not differ from control subjects in terms of their smoking behavior (odds ratio [OR] 1.020, 95% confidence interval [95% CI] 0.839-1.240, P=0.842). Anti-topoisomerase I antibody-positive patients were more likely to be never smokers (OR 0.648, 95% CI 0.421-0.998, P=0.049), whereas no such association was observed with anticentromere and anti-RNA polymerase III antibodies.
Unlike its role in rheumatoid arthritis, smoking does not confer a risk for development of SSc, although it may impact disease severity.
Arthritis & Rheumatism 06/2011; 63(10):3098-102. · 7.87 Impact Factor
-
Roozbeh Sharif,
Marvin J Fritzler,
Maureen D Mayes,
Emilio B Gonzalez,
Terry A McNearney,
Hilda Draeger,
Murray Baron,
Daniel E Furst,
Dinesh K Khanna,
Deborah J del Junco, [......],
Richard M Silver,
Robert W Simms,
Marilyn Perry,
Carlos Rojo,
Julio Charles,
Xiaodong Zhou,
Sandeep K Agarwal,
John D Reveille,
Shervin Assassi, Frank C Arnett
[show abstract]
[hide abstract]
ABSTRACT: Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival.
Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493).
Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.
The Journal of Rheumatology 05/2011; 38(8):1622-30. · 3.69 Impact Factor
-
Roozbeh Sharif,
Maureen D Mayes,
Perry M Nicassio,
Emilio B Gonzalez,
Hilda Draeger,
Terry A McNearney,
Rosa M Estrada-Y-Martin,
Deepthi K Nair,
John D Reveille, Frank C Arnett,
Shervin Assassi
[show abstract]
[hide abstract]
ABSTRACT: To determine the prevalence, correlates, and predictors of work disability (WD) in the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS). We hypothesized that WD in systemic sclerosis (SSc) is a function of demographic, clinical, and psychosocial factors.
Patients enrolled in the GENISOS cohort were subdivided in 3 groups: work disabled, working, and retired or homemakers. The latter group (n = 29) was excluded from further analysis. We used logistic regression analysis with a forward hierarchical variable selection strategy to investigate the independent correlates of WD at enrollment. Cox regression proportional Hazard's model with a similar variable selection strategy was utilized to determine the predictors of WD in those working at enrollment.
Overall, 284 patients with a mean age of 48.7 years and disease duration of 2.5 (±1.6) years were enrolled into the GENISOS cohort, consisting of 83.5% female, 46.8% white, 28.9% Hispanic, and 20.4% African American. Patients were longitudinally followed in 1438 study visits. At enrollment, 124 patients (43.7%) were work disabled, whereas 131 (46.1%) were working. Lower level of education (P < 0.001), higher Medsger Lung Severity Index (P = 0.012), higher Fatigue Severity Score (P = 0.008), and less social support (P < 0.001) correlated independently with WD. Of those working at baseline, 35 (26.7%) eventually developed WD. Non-white ethnicity (P = 0.038), lower DLCO % predicted value (P = 0.038), and higher Fatigue Severity Score (P = 0.009) at enrollment independently predicted WD on follow-up visits.
WD is a major problem among SSc patients and its prevalence is substantially higher than other rheumatic conditions. Demographic, clinical, and psychosocial factors correlate with WD cross-sectionally and predict WD longitudinally in these patients.
Seminars in arthritis and rheumatism 03/2011; 41(1):38-47. · 4.72 Impact Factor
-
Qiong Fu,
Jian Zhao,
Xiaoxia Qian,
Jonathan L H Wong,
Kenneth M Kaufman,
C Yung Yu,
Mo Yin Mok,
John B Harley,
Joel M Guthridge,
Yeong Wook Song,
Soo-Kyung Cho,
Sang-Cheol Bae,
Jennifer M Grossman,
Bevra H Hahn, Frank C Arnett,
Nan Shen,
Betty P Tsao
[show abstract]
[hide abstract]
ABSTRACT: A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.
We genotyped one KIAA1542 SNP (rs4963128) and one IRF7 SNP (rs1131665 [Q412R]) in an Asian population (1,302 cases, 1,479 controls), to assess their association with SLE. Subsequently, rs1131665 was further genotyped in independent panels of Chinese subjects (528 cases, 527 controls), European American subjects (446 cases, 461 controls), and African American subjects (159 cases, 115 controls) by TaqMan genotyping assay, to seek confirmation of association in various ethnic groups. A luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF-7.
Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, European American, and African American populations (total 2,435 cases and 2,582 controls) (P(meta) = 6.18 × 10(-6) , odds ratio 1.42 [95% confidence interval 1.22-1.65]). Expression of the IRF7 412Q risk allele resulted in a 2-fold increase in interferon-stimulated response element transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting that IRF7 412Q confers elevated IRF-7 activity and may therefore affect a downstream interferon pathway.
These findings show that the major allele of a nonsynonymous SNP, rs1131665 (412Q) in IRF7, confers elevated activation of IRF-7 and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence that IRF7 may be a risk gene for human SLE.
Arthritis & Rheumatism 03/2011; 63(3):749-54. · 7.87 Impact Factor
-
Baptiste Coustet,
Sandeep K Agarwal,
Pravitt Gourh,
Mickael Guedj,
Maureen D Mayes,
Philippe Dieude,
Julien Wipff,
Jerome Avouac,
Eric Hachulla,
Elisabeth Diot, [......],
Jean Sibilia,
Luc Mouthon,
Camille Frances,
Zahir Amoura,
Patrick Carpentier,
Olivier Meyer,
Andre Kahan,
Catherine Boileau, Frank C Arnett,
Yannick Allanore
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
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.
The Journal of Rheumatology 03/2011; 38(6):1033-8. · 3.69 Impact Factor
-
Binh Nguyen,
Maureen D Mayes, Frank C Arnett,
Deborah del Junco,
John D Reveille,
Emilio B Gonzalez,
Hilda T Draeger,
Marilyn Perry,
Amir Hendiani,
Kiran K Anand,
Shervin Assassi
[show abstract]
[hide abstract]
ABSTRACT: To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc).
SSc patients from the Scleroderma Family Registry and DNA Repository, the Genetics versus Environment in Scleroderma Outcomes Study, and the rheumatology division registry at the University of Texas Health Science Center at Houston were included in the study. Relevant clinical data were obtained by chart review, and autoantibodies were detected utilizing commercially available kits. HLA class II genotyping was performed on extracted and purified genomic DNA.
Overall, 1,519 SSc patients were included in the study, of whom 90 (6%) had developed SRC. Among the 90 patients with SRC, the diffuse cutaneous disease subtype was found in 76%, antitopoisomerase antibodies (antitopo) in 9%, anticentromere antibodies (ACAs) in 2%, and anti-RNA polymerase III (anti-RNAP III) in 50% of patients. In multivariate analyses of clinical and demographic parameters, diffuse disease type and anti-RNAP III were strong risk factors for the presence of SRC, whereas ACAs and antitopo were protective. In the final multivariate analysis, which included HLA alleles, HLA-DRB1*0407 (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.27-8.08; P = 0.013) and DRB1*1304 (OR 4.51, 95% CI 1.30-15.65; P = 0.018) were identified as independent risk factors for SRC. Only 3 clinical characteristics, diffuse disease type, anti-RNAP III, and ACAs, remained significantly associated with SRC in the final model.
The results of this study suggest that DRB1*0407 and *1304 are independent risk factors, beyond the known clinical correlates, for the development of SRC.
Arthritis & Rheumatism 02/2011; 63(2):530-4. · 7.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased levels of genes in the type I interferon (IFN) pathway have been observed in patients with systemic sclerosis (SSc), or scleroderma. How type I IFN regulates the dermal fibroblast and its participation in the development of dermal fibrosis is not known. We hypothesized that one mechanism by which type I IFN may contribute to dermal fibrosis is through upregulation of specific Toll-like receptors (TLRs) on dermal fibroblasts. Therefore, we investigated the regulation of TLR expression on dermal fibroblasts by IFN.
The expression of TLRs was assessed in cultured dermal fibroblasts from control and SSc patients stimulated with IFNα2. The ability of IFNα2 to regulate TLR-induced interleukin (IL)-6 and CC chemokine ligand 2 production was also assessed. Immunohistochemical analyses were performed to determine whether TLR3 was expressed in skin biopsies in the bleomycin-induced skin fibrosis model and in patients with SSc.
IFNα2 increased TLR3 expression on human dermal fibroblasts, which resulted in enhanced TLR3-induced IL-6 production. SSc fibroblasts have an augmented TLR3 response to IFNα2 relative to control fibroblasts. Pretreatment of fibroblasts with transforming growth factor (TGF)-β increased TLR3 induction by IFNα2, but coincubation of TGF-β did not alter TLR3 induction by IFN. Furthermore, IFNα2 inhibits but does not completely block the induction of connective tissue growth factor and collagen expression by TGF-βin fibroblasts. TLR3 expression was observed in dermal fibroblasts and inflammatory cells from skin biopsies from patients with SSc as well as in the bleomycin-induced skin fibrosis model.
Type I IFNs can increase the inflammatory potential of dermal fibroblasts through the upregulation of TLR3.
Arthritis research & therapy 01/2011; 13(1):R3. · 4.27 Impact Factor
