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1. Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

Author

Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., Universitat de Barcelona, Rheumatology, and CCA - Immuno-pathogenesis

Subjects
Male, Genotype, systemic sclerosis, Autoimmune diseases, Immunology, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, GWAS, IL-2/IL-21 region, Gene Frequency, Rheumatology, Scleroderma, Limited, Medizinische Fakultät, Genetic variation, Genetics, Genetic predisposition, Humans, Immunology and Allergy, Genetic Predisposition to Disease, ddc:610, Allele, Allele frequency, Scleroderma, Systemic, Malalties autoimmunitàries, Interleukins, Logistic Models, Scleroderma (Disease), Case-Control Studies, Scleroderma, Diffuse, Interleukin-2, Evaluation of complex medical interventions Auto-immunity, transplantation and immunotherapy [NCEBP 2], Female, Gene polymorphism, Esclerodèrmia, Genètica
Abstract

ObjectiveThe 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 methodsThe 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.ResultsWe observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=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 (pc=1.7E-03 and pc=8E-4, respectively).ConclusionsThese 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.

Published
2012
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2. A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci

Author

Martin, J.E., Assassi, S., Diaz-Gallo, L.M., Broen, J.C.A., Simeon, C.P., Castellvi, I., Vicente-Rabaneda, E., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Espinosa, G., Carreira, P., Scleroderma, G. Spanish, consortium, S., group, U.S.S.G., Biolupus, ., Camps, M., Sabio, J.M., D'Alfonso, S., Vonk, M.C., Voskuyl, A.E., Schuerwegh, A.J., Kreuter, A., Witte, T. de, Riemekasten, G., Hunzelmann, N., Airo, P., Beretta, L., Scorza, R., Lunardi, C., Laar, J. van, Chee, M.M., Worthington, J., Herrick, A., Denton, C., Fonseca, C., Tan, F.K., Arnett, F., Zhou, X., Reveille, J.D., Gorlova, O., Koeleman, B.P., Radstake, T.R.D.J., Vyse, T., Mayes, M.D., Alarcon-Riquelme, M.E., Martin, J., Rheumatology, and CCA - Disease profiling

Subjects
SLE, Genome-wide association study, Disease, medicine.disease_cause, Systemic scleroderma, Autoimmunity, 0302 clinical medicine, Risk Factors, Lupus Erythematosus, Systemic, skin and connective tissue diseases, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, Association Studies Articles, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, General Medicine, Neoplasm Proteins, 3. Good health, DNA-Binding Proteins, SYSTEMIC SCLEROSIS, Evaluation of complex medical interventions Auto-immunity, transplantation and immunotherapy [NCEBP 2], Co-Repressor Proteins, Population, Nerve Tissue Proteins, Receptors, Cell Surface, Single-nucleotide polymorphism, Protein Serine-Threonine Kinases, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, genome-wide association studies, education, Molecular Biology, 030304 developmental biology, Genetic association, 030203 arthritis & rheumatology, Scleroderma, Systemic, Genetic Variation, Reproducibility of Results, medicine.disease, Genetic Loci, Case-Control Studies, Immunology, Genome-Wide Association Study
Abstract

Item does not contain fulltext Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21 109 (6835 cases and 14 274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 x 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 x 10(-11), OR = 1.20) and JAZF1 (P = 1.11 x 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.

Published
2013
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3. Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Author

Gorlova, O., Martin, J.E., Rueda, B., Koeleman, B.P.C., Ying, J., Teruel, M., Diaz-Gallo, L.M., Broen, J.C., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M.J.H., Voskuyl, A.E., Schuerwegh, A.J., Riel, P.L.C.M. van, Vanthuyne, M., van't Slot, R., Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Garcia-Hernandez, F.J., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P.G., Westhovens, R., Kreuter, A., Baere, E. de, Witte, T., Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.M., Palm, O., Pena, P.G. de la, Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Hummers, J., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F.K., Arnett, F.C., Radstake, T.R.D.J., Mayes, M.D., Martin, J., Spanish Scleroderma Grp, Rheumatology, Human genetics, CCA - Disease profiling, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, UCL - (MGD) Service de rhumatologie, and McCarthy, Mark I

Subjects
Oncology, Male, Cancer Research, systemic sclerosis, Genome-wide association study, SUSCEPTIBILITY, FUNCTIONAL POLYMORPHISM, Genètica mèdica, STAT4, 0302 clinical medicine, HLA Antigens, SCLERODERMA, IRF5, 2.1 Biological and endogenous factors, Aetiology, skin and connective tissue diseases, Genetics (clinical), Genetics, 0303 health sciences, Medical genetics, Translational research Immune Regulation [ONCOL 3], Single Nucleotide, Middle Aged, Infection and autoimmunity Auto-immunity, transplantation and immunotherapy [NCMLS 1], 3. Good health, Phenotype, genome-wide association study, Evaluation of complex medical interventions Auto-immunity, transplantation and immunotherapy [NCEBP 2], Medicine, ALOPECIA-AREATA, Female, Research Article, Genetic Markers, medicine.medical_specialty, Spanish Scleroderma Group, lcsh:QH426-470, functional polymorphism japanese population pulmonary-fibrosis signaling pathways alopecia-areata risk-factor susceptibility scleroderma stat4 irf5, Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, SIGNALING PATHWAYS, 03 medical and health sciences, Clinical Research, RISK-FACTOR, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, JAPANESE POPULATION, Allele, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, Autoantibodies, Rheumatology and Autoimmunity, 030203 arthritis & rheumatology, Scleroderma, Systemic, PULMONARY-FIBROSIS, Inflammatory and immune system, Systemic, Human Genome, Biology and Life Sciences, lcsh:Genetics, Meta-analysis, Scleroderma (Disease), Genetic marker, Genetic Loci, Clinical Immunology, Esclerodèrmia, Metaanàlisi, Developmental Biology, Genome-Wide Association Study
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., 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.

Published
2011
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4. New insight on the Xq28 association with systemic sclerosis

Author

Carmona, F.D., Cenit, M.C., Diaz-Gallo, L.M., Broen, J.C., Simeon, C.P., Carreira, P.E., Callejas-Rubio, J.L., Fonollosa, V., Lopez-Longo, F.J., Gonzalez-Gay, M.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Madhok, R., Shiels, P., Laar, J.M. van, Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Fonseca, C., Denton, C.P., Herrick, A., Worthington, J., Arnett, F.C., Tan, F.K., Assassi, S., Radstake, T.R., Mayes, M.D., Martin, J., Scleroderma, G. Spanish, Carmona, F.D., Cenit, M.C., Diaz-Gallo, L.M., Broen, J.C., Simeon, C.P., Carreira, P.E., Callejas-Rubio, J.L., Fonollosa, V., Lopez-Longo, F.J., Gonzalez-Gay, M.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Madhok, R., Shiels, P., Laar, J.M. van, Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Fonseca, C., Denton, C.P., Herrick, A., Worthington, J., Arnett, F.C., Tan, F.K., Assassi, S., Radstake, T.R., Mayes, M.D., Martin, J., and Scleroderma, G. Spanish

Abstract

Item does not contain fulltext, 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 (PFDR=4.12x10(-3), OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26x10(-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 (PFDR=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.

Published
2013

5. Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

Author

Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., et al., Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., and et al.

Abstract

Item does not contain fulltext, 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 (pc=6.6E-4 and pc=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 (pc=1.7E-03 and pc=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.

Published
2013

6. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis

Author

Diaz-Gallo, L.M., Gourh, P., Broen, J., Simeon, C., Fonollosa, V., Ortego-Centeno, N., Agarwal, S., Vonk, M.C., Coenen, M.J.H., Riemekasten, G., Hunzelmann, N., Hesselstrand, R., Tan, F.K., Reveille, J.D., Assassi, S., Garcia-Hernandez, F.J., Carreira, P., Camps, M.T., Fernandez-Nebro, A., Pena, P.G. de la, Nearney, T., Hilda, D., Gonzalez-Gay, M.A., Airo, P., Beretta, L., Scorza, R., Herrick, A., Worthington, J., Pros, A., Gomez-Gracia, I., Trapiella, L., Espinosa, G., Castellvi, I., Witte, T.J.M. de, Keyser, F. de, Vanthuyne, M., Mayes, M.D., Radstake, T.R.D.J., Arnett, F.C., Martin, J., Rueda, B., Diaz-Gallo, L.M., Gourh, P., Broen, J., Simeon, C., Fonollosa, V., Ortego-Centeno, N., Agarwal, S., Vonk, M.C., Coenen, M.J.H., Riemekasten, G., Hunzelmann, N., Hesselstrand, R., Tan, F.K., Reveille, J.D., Assassi, S., Garcia-Hernandez, F.J., Carreira, P., Camps, M.T., Fernandez-Nebro, A., Pena, P.G. de la, Nearney, T., Hilda, D., Gonzalez-Gay, M.A., Airo, P., Beretta, L., Scorza, R., Herrick, A., Worthington, J., Pros, A., Gomez-Gracia, I., Trapiella, L., Espinosa, G., Castellvi, I., Witte, T.J.M. de, Keyser, F. de, Vanthuyne, M., Mayes, M.D., Radstake, T.R.D.J., Arnett, F.C., Martin, J., and Rueda, B.

Abstract

Contains fulltext : 96632.pdf (publisher's version ) (Closed access), 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 first 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 significantly 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 confirmed 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 influences 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.

Published
2011

7. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis

Author

UCL - (MGD) Service de rhumatologie, Diaz-Gallo, L.M., Gourh, P., Broen, J., Simeon, C., Fonollosa, V., Ortego-Centeno, N., Agarwal, S., Vonk, M.C., Coenen, M., Riemekasten, G., Hunzelmann, N., Hesselstrand, R., Tan, F.K., Reveille, J.D., Assassi, S., García-Hernandez, F.J., Carreira, P., Camps, M.T., Fernandez-Nebro, A., Garcia De La Peña, P., Nearney, T., Hilda, D., González-Gay, M.A., Airo, P., Beretta, L., Scorza, R., Herrick, A., Worthington, J., Pros, A., Gómez-Gracia, I., Trapiella, L., Espinosa, G., Castellvi, I., Witte, T., De Keyser, F., Vanthuyne, Marie, Mayes, M.D., Radstake, T.R.D.J., Arnett, F.C., Martin, J., Rueda, B., UCL - (MGD) Service de rhumatologie, Diaz-Gallo, L.M., Gourh, P., Broen, J., Simeon, C., Fonollosa, V., Ortego-Centeno, N., Agarwal, S., Vonk, M.C., Coenen, M., Riemekasten, G., Hunzelmann, N., Hesselstrand, R., Tan, F.K., Reveille, J.D., Assassi, S., García-Hernandez, F.J., Carreira, P., Camps, M.T., Fernandez-Nebro, A., Garcia De La Peña, P., Nearney, T., Hilda, D., González-Gay, M.A., Airo, P., Beretta, L., Scorza, R., Herrick, A., Worthington, J., Pros, A., Gómez-Gracia, I., Trapiella, L., Espinosa, G., Castellvi, I., Witte, T., De Keyser, F., Vanthuyne, Marie, Mayes, M.D., Radstake, T.R.D.J., Arnett, F.C., Martin, J., and Rueda, B.

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 first 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 significantly 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 confirmed 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 influences 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.

Published
2011

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