Scleroderma Publications
1. Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts. Journal of Rheumatology
BAPTISTE COUSTET, SANDEEP K. AGARWAL, PRAVITT GOURH, MICKAEL GUEDJ, MAUREEN D. MAYES,
PHILIPPE DIEUDE, JULIEN WIPFF, JEROME AVOUAC, ERIC HACHULLA, ELISABETH DIOT,
JEAN LUC CRACOWSKI, KIET TIEV, JEAN SIBILIA, LUC MOUTHON, CAMILLE FRANCES, ZAHIR AMOURA,
PATRICK CARPENTIER, OLIVIER MEYER, ANDRE KAHAN, CATHERINE BOILEAU, FRANK C. ARNETT,
and YANNICK ALLANORE
ABSTRACT.
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.
(J Rheumatol First Release March 1 2011; doi:10.3899/jrheum.101053)
2. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis
LM Diaz-Gallo, P Gourh J Broen, C Simeon, V Fonollosa, N Ortego-Centeno, S Agarwal, 2 MC Vonk, 3 M Coenen, 6 G Riemekasten, 7 N Hunzelmann, R Hesselstrand,
FK Tan, JD Reveille, S Assassi, FJ García-Hernandez, P Carreira, MT Camps,
A Fernandez-Nebro, P Garcia de la Peña, T Nearney, D Hilda,
MA González- Gay, P Airo, L Beretta, R Scorza, A Herrick, J Worthington,
A Pros, I Gómez-Gracia, L Trapiella, G Espinosa, I Castellvi, T Witte,
F de Keyser, M Vanthuyne, MD Mayes, TRDJ Radstake, FC Arnett, J Martin, B Rueda
ABSTRACT.
Objective. Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601
and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate
the role of the R263Q SNP for the fi rst time and to re-evaluate the role of the R620W SNP in the genetic
predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.
Methods. 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc)
and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional
independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22
polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to
test the overall effect of these PTPN22 polymorphisms in SSc.
Results. The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc
susceptibility (p FDRcorrected =0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was
signifi cantly associated with anticentromere-positive status (p FDRcorrected =0.02 pooled, OR 1.22, 95% CI 1.05 to
1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population
(p FDRcorrected =0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confi rmed in the meta-analysis
(p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).
Conclusion. The study suggests that the PTPN22 R620W polymorphism infl uences SSc genetic
susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W
mutation is a common risk factor in autoimmune diseases. Systemic sclerosis (SSc) is a complex disease.
3. HLA–DRB1*0407 and *1304 Are Risk Factors for Scleroderma Renal Crisis
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, and Shervin Assassi
ABSTRACT.
Objective. 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).
Methods. 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.
Results. 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.
Conclusion. The results of this study suggest that DRB1*0407 and *1304 are independent risk factors,
beyond the know clinical correlates, for the development
of SRC.
4. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians.
V B Rueda, P Gourh, J Broen, S K Agarwal, C Simeon, N Ortego-Centeno, M C Vonk, M Coenen, G Riemekasten, N Hunzelmann, R Hesselstrand, F K Tan, J D Reveille, S Assassi, F J Garcia-Hernandez, P Carreira, M Camps, A Fernandez-Nebro,
P Garcia de la Peña, T Nearney, D Hilda, M A Gónzalez-Gay, P Airo, L Beretta, R Scorza, T R D J Radstake, M D Mayes, F C Arnett, J Martin
ABSTRACT.
Objective. To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic
sclerosis (SSc) and its sub phenotypes.
Methods. A large multicentre case–control association study including 2380 patients with SSc and 3270
healthy controls from six independent case–control sets of Caucasian ancestry (American, Spanish, Dutch,
German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594
T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5´ allelic
discrimination assay.
Results. A signifi cant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25;p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation.
Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08to1.41,p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratifi cation for specifi c SSc autoantibodies showed that the association
of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively).
Conclusion. The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.
5. Anti-Fibrillarin Antibody in African American Patients with Systemic Sclerosis: Immunogenetics,ClinicalFeatures, and Survival Analysis.
Roozbeh Sharif, Marvin J. Fritzler, Maureen D. Mayes, Emilio B. Gonzalez,Terry A. McNearney, Hilda Draeger,
Murray Baron, the Canadian Scleroderma Research Group,
Daniel E. Furst, Dinesh K. Khanna, Deborah J. Del junco, Jerry A. Molitor, Elena Schiopu,
Kristine Phillips, James R. Seibold, Richard M. Silver, Robert W. Simms, GENISOS Study Group,
Marilyn Perry, Carlos Rojo, Julio Charles, Xiajong Zhou, Sandeep K. Agarwal,
John D. Reveille, Shervin Assassi, and Frank C. Arnett.
ABSTRACT.
Objective. 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.
Methods. 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.
Results. 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).
Conclusion. 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.
(J Rheumatol First Release May 15 2011)