93 results on '"Gourh P"'
Search Results
2. HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry
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Gourh, Pravitt, Safran, Sarah A, Alexander, Theresa, Boyden, Steven E, Morgan, Nadia D, Shah, Ami A, Mayes, Maureen D, Doumatey, Ayo, Bentley, Amy R, Shriner, Daniel, Domsic, Robyn T, Medsger, Thomas A, Ramos, Paula S, Silver, Richard M, Steen, Virginia D, Varga, John, Hsu, Vivien, Saketkoo, Lesley Ann, Schiopu, Elena, Khanna, Dinesh, Gordon, Jessica K, Kron, Brynn, Criswell, Lindsey A, Gladue, Heather, Derk, Chris T, Bernstein, Elana J, Bridges, S Louis, Shanmugam, Victoria K, Kolstad, Kathleen D, Chung, Lorinda, Kafaja, Suzanne, Jan, Reem, Trojanowski, Marcin, Goldberg, Avram, Korman, Benjamin D, Steinbach, Peter J, Chandrasekharappa, Settara C, Mullikin, James C, Adeyemo, Adebowale, Rotimi, Charles, Wigley, Fredrick M, Kastner, Daniel L, Boin, Francesco, and Remmers, Elaine F
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Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Clinical Research ,Scleroderma ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Black or African American ,Alleles ,Amino Acid Sequence ,Antigens ,Viral ,Autoantibodies ,Autoantigens ,Computational Biology ,Datasets as Topic ,Female ,Genetic Predisposition to Disease ,HLA Antigens ,Humans ,Male ,Mimiviridae ,Molecular Mimicry ,Phycodnaviridae ,Protein Structure ,Secondary ,Risk Assessment ,Scleroderma ,Systemic ,Sequence Homology ,Amino Acid ,White People ,scleroderma ,HLA ,autoantibodies ,molecular mimicry ,mimivirus - Abstract
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominant HLA-DRB1*08:04 and HLA-DRB1*11:02 alleles were associated with overall SSc risk, and the HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1*13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1*13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
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- 2020
3. Study of metabolic syndrome in patients of Vitiligo: A single-center observational study
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Vishal Gourh, Anita Arya, Anand Dubey, and Simmi Dube
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advancing age ,central india ,metabolic syndrome ,ncep atp iii criteria ,vitiligo ,Medicine - Abstract
Background: Metabolic syndrome (MetS) has been observed in patients with vitiligo. Literature suggests that there is some link between vitiligo and MetS. Autoimmunity, oxidative stress, and decreased number of melanocytes are involved in its pathogenesis. Aims and Objectives: This study aimed to assess MetS in patients of vitiligo, its association with different types of vitiligo, age of patients, and duration of vitiligo. Materials and Methods: We enrolled 62 vitiligo patients who met inclusion criteria in this cross-sectional study from August 1, 2020 to July 31, 2021. Detailed history, physical examination, and blood investigations were done in all patients and NCEP ATP III criteria were used for diagnosis of MetS. Results: Mean age of participants was 35.98±15.48 years; M: F: was 1:2.3. MetS was observed in 12.9% vitiligo patients. Advancing age and non-segmental vitiligo were significantly associated with MetS (P
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- 2022
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- View/download PDF
4. Clinical and serological features of systemic sclerosis in a multicenter African American cohort
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Morgan, Nadia D, Shah, Ami A, Mayes, Maureen D, Domsic, Robyn T, Medsger, Thomas A, Steen, Virginia D, Varga, John, Carns, Mary, Ramos, Paula S, Silver, Richard M, Schiopu, Elena, Khanna, Dinesh, Hsu, Vivien, Gordon, Jessica K, Gladue, Heather, Saketkoo, Lesley A, Criswell, Lindsey A, Derk, Chris T, Trojanowski, Marcin A, Shanmugam, Victoria K, Chung, Lorinda, Valenzuela, Antonia, Jan, Reem, Goldberg, Avram, Remmers, Elaine F, Kastner, Daniel L, Wigley, Fredrick M, Gourh, Pravitt, and Boin, Francesco
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Biomedical and Clinical Sciences ,Clinical Sciences ,Lung ,Autoimmune Disease ,Rare Diseases ,Scleroderma ,Clinical Research ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Inflammatory and immune system ,Adult ,Black or African American ,Chromosome Mapping ,Cohort Studies ,Cross-Sectional Studies ,Databases ,Factual ,Female ,Humans ,Male ,Prevalence ,Prospective Studies ,Retrospective Studies ,Scleroderma ,Systemic ,Severity of Illness Index ,Socioeconomic Factors ,United States ,African Americans ,autoantibodies ,systemic sclerosis - Abstract
Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.
- Published
- 2017
5. Floppy epiglottis together with extra-laryngeal mass causing an inducible laryngeal obstruction and hypoxemic event in an adult: A case report
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Manish Keshwani, Habib M R. Karim, and Govind Gourh
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airway obstruction ,emergencies ,epiglottis ,intratracheal ,intubation ,respiratory insufficiency ,Anesthesiology ,RD78.3-87.3 - Abstract
Floppy epiglottis in an adult is rare and often pathological. Airway obstruction caused by floppy epiglottis in an adult is rarely reported. Neck mass, however, can affect the airway in many ways; however, inducible upper airway obstruction by extra-laryngeal neck mass is hardly been reported. In most of the instances of inducible laryngeal obstruction, the tumor is found in and around the laryngeal inlet. Herein, we report such an unusual incident happened to a 40-year-old gentleman, a case of oral carcinoma for 3 months and a rapidly increasing swelling (6 × 5 cm) over the right side of the neck for 8 days. He presented to us for emergency tracheostomy with the feature of acute upper airway obstruction, unable to lie down; and having difficulty in breathing, desaturation, and chocking even in propped up position. The case highlights the importance of clinical findings and difficulties faced for airway management in such patients.
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- 2020
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6. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
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Gorlova, Olga, Martin, Jose-Ezequiel, Rueda, Blanca, Koeleman, Bobby PC, Ying, Jun, Teruel, Maria, Diaz-Gallo, Lina-Marcela, Broen, Jasper C, Vonk, Madelon C, Simeon, Carmen P, Alizadeh, Behrooz Z, Coenen, Marieke JH, Voskuyl, Alexandre E, Schuerwegh, Annemie J, van Riel, Piet LCM, 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, Oyvind, García de la Peña, Paloma, Carreira, Patricia, Spanish Scleroderma Group, 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 RDJ, Mayes, Maureen D, and Martin, Javier
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Spanish Scleroderma Group ,Humans ,Scleroderma ,Systemic ,Genetic Predisposition to Disease ,Genetic Markers ,Autoantibodies ,HLA Antigens ,Phenotype ,Polymorphism ,Single Nucleotide ,Alleles ,Middle Aged ,Female ,Male ,Genome-Wide Association Study ,Genetic Loci ,Polymorphism ,Single Nucleotide ,Scleroderma ,Systemic ,Genetics ,Developmental Biology - 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.
- Published
- 2011
7. Correction: Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy.
- Author
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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, Behrooz Z. Alizadeh, Marieke J. H. Coenen, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Piet L. C. M. van Riel, Marie Vanthuyne, Ruben van 't Slot, Annet Italiaander, Roel A. Ophoff, Nicolas Hunzelmann, Vicente Fonollosa, Norberto Ortego-Centeno, Miguel A. González-Gay, Francisco J. García-Hernández, María F. González-Escribano, Paolo Airo, Jacob van Laar, Jane Worthington, Roger Hesselstrand, Vanessa Smith, Filip de Keyser, Fredric Houssiau, Meng May Chee, Rajan Madhok, Paul G. Shiels, Rene Westhovens, Alexander Kreuter, Elfride de Baere, Torsten Witte, Leonid Padyukov, Annika Nordin, Raffaella Scorza, Claudio Lunardi, Benedicte A. Lie, Anna-Maria Hoffmann-Vold, Øyvind Palm, Paloma García de la Peña, Patricia Carreira, John Varga, Monique Hinchcliff, Annette T. Lee, Pravitt Gourh, Christopher I. Amos, Frederick M. Wigley, Laura K. Hummers, J. Lee Nelson, Gabriella Riemekasten, Ariane Herrick, Lorenzo Beretta, 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, and Javier Martin
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Genetics ,QH426-470 - Published
- 2011
- Full Text
- View/download PDF
8. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
- Author
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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, Behrooz Z Alizadeh, Marieke J H Coenen, Alexandre E Voskuyl, Annemie J Schuerwegh, Piet L C M van Riel, Marie Vanthuyne, Ruben van 't Slot, Annet Italiaander, Roel A Ophoff, Nicolas Hunzelmann, Vicente Fonollosa, Norberto Ortego-Centeno, Miguel A González-Gay, Francisco J García-Hernández, María F González-Escribano, Paolo Airo, Jacob van Laar, Jane Worthington, Roger Hesselstrand, Vanessa Smith, Filip de Keyser, Fredric Houssiau, Meng May Chee, Rajan Madhok, Paul G Shiels, Rene Westhovens, Alexander Kreuter, Elfride de Baere, Torsten Witte, Leonid Padyukov, Annika Nordin, Raffaella Scorza, Claudio Lunardi, Benedicte A Lie, Anna-Maria Hoffmann-Vold, Oyvind Palm, Paloma García de la Peña, Patricia Carreira, Spanish Scleroderma Group, John Varga, Monique Hinchcliff, Annette T Lee, Pravitt Gourh, Christopher I Amos, Frederick M Wigley, Laura K Hummers, J Lee Nelson, Gabriella Riemekasten, Ariane Herrick, Lorenzo Beretta, 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, and Javier Martin
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Genetics ,QH426-470 - 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.
- Published
- 2011
- Full Text
- View/download PDF
9. S.12.1 Is H1N1 influenza vaccine safe and effective in patients with SSc?
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Carmona, F., Gutala, R., Simeón, C. P., Carreira, P., Ortego Centeno, N., Vicente Rabaneda, E., García Hernández, F. J., García De La Peña, P., Fernández Castro, M., Martínez Estupiñán, L., Egurbide, M. V., Tsao, B. P, Gourh, P., Agarwal, S. K., Assassi, S., Mayes, M. D., Arnett, F. C., Tan, F. K., and Martín, J.
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- 2012
10. Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development
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Broen, J C A, Gourh, P, Vonk, M C, Beretta, L, Niederer, F, Rueda, B, Geurts-van Bon, L, Brouwer, C, Hesselstrand, R, Herrick, A, Worthington, J, Hunzelman, N, Fonseca, Denton C, Riemekasten, G, Kiener, H, Scorza, R, Simeon, C P, Fonollosa, V, Carreira, P, Ortego-Centeno, N, Gonzalez-Gay, M A, Airoʼ, P, Coenen, M J H, Mayes, M, Kyburz, D, Arnett, F C, Martin, J, and Radstake, T R D J
- Published
- 2011
- Full Text
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11. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis
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Diaz-Gallo, LM, Gourh, P, Broen, J, Simeon, C, Fonollosa, V, Ortego-Centeno, N, Agarwal, S, Vonk, MC, Coenen, M, Riemekasten, G, Hunzelmann, N, Hesselstrand, R, Tan, FK, Reveille, JD, Assassi, S, García-Hernandez, FJ, Carreira, P, Camps, MT, Fernandez-Nebro, A, de la Peña, P Garcia, Nearney, T, Hilda, D, González-Gay, MA, 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, M, Mayes, MD, Radstake, TRDJ, Arnett, FC, Martin, J, and Rueda, B
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- 2011
- Full Text
- View/download PDF
12. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians
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Rueda, B, Gourh, P, Broen, J, Agarwal, S K, Simeon, C, Ortego-Centeno, N, Vonk, M C, Coenen, M, Riemekasten, G, Hunzelmann, N, Hesselstrand, R, Tan, F K, Reveille, J D, Assassi, S, Garcia-Hernandez, F J, Carreira, P, Camps, M, Fernandez-Nebro, A, de la Peña, P Garcia, Nearney, T, Hilda, D, Gónzalez-Gay, M A, Airo, P, Beretta, L, Scorza, R, Radstake, T R, Mayes, M D, Arnett, F C, and Martin, J
- Published
- 2010
- Full Text
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13. The FAS −670A>G polymorphism influences susceptibility to systemic sclerosis phenotypes
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Broen, J., Gourh, P., Rueda, B., Coenen, M., Mayes, M., Martin, J., Arnett, F. C., and Radstake, T. R. D. J.
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- 2009
- Full Text
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14. Comment on: An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis
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Alkassab, F., Gourh, P., Tan, F., Arnett, F., and Mayes, M.
- Published
- 2008
15. An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis
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Alkassab, F., Gourh, P., Tan, F. K., McNearney, T., Fischbach, M., Ahn, C., Arnett, F. C., and Mayes, M. D.
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- 2007
16. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients
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Tan, F. K., Zhou, X., Mayes, M. D., Gourh, P., Guo, X., Marcum, C., Jin, L., and Arnett, F. C., Jr
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- 2006
17. Independent replication and meta-analysis establish TNFSF4 as a susceptibility gene preferentially associated with the subset of patients with positive ACAs in SSc
- Author
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Coustet, B., Bouaziz, Maissa, Dieude, P., Guedj, Mickael, Bossini-Castillo, L., Gourh, P. R., Chiocchia, G., Allanore, Y., Université Paris Descartes - Paris 5 (UPD5), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Statistique et Génome (SG), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Immunopathologie rénale, récepteurs et inflammation, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), ProdInra, Migration, and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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tnfsf4 ,[INFO]Computer Science [cs] ,[MATH] Mathematics [math] ,[INFO] Computer Science [cs] ,[MATH]Mathematics [math] ,ComputingMilieux_MISCELLANEOUS ,ssc - Abstract
International audience
- Published
- 2012
18. Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy
- Author
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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
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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.
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- 2011
19. Corrigendum: Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus
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Radstake, T.R.D.J., Gorlova, O., Rueda, B., Martin, J.E., Alizadeh, B.Z., Palomino-Morales, R., Coenen, M., Vonk, M.C., Voskuyl, A.E., Schuerwegh, A.J., Broen, J.C.A., Riel, P.L.C.M. van, Slot, R. van 't, Italiaander, A., Ophoff, R.A., Riemekasten, G., Hunzelmann, N., Simeon, C.P., Ortego-Centeno, N., Gonzalez-Gay, M.A., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Herrick, A., Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P., Westhovens, R., Kreuter, A., Kiener, H., Baere, E. de, Witte, T.J.M. de, Padykov, L., Klareskog, L., Beretta, L., Scorza, R., Lie, B.A., Hoffmann-Vold, A.M., Carreira, P., Varga, J., Hinchcliff, M., Gregersen, P.K., Lee, A.T., Ying, J., Han, Y., Weng, S.F., Amos, C.I., Wigley, F.M., Hummers, L., Nelson, J.L., Agarwal, S.K., Assassi, S., Gourh, P., Tan, F.K., Koeleman, B.P., Arnett, F.C., Martin, J., and Mayes, M.D.
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Infection and autoimmunity Auto-immunity, transplantation and immunotherapy [NCMLS 1] - Abstract
Contains fulltext : 97765.pdf (Publisher’s version ) (Closed access) 01 mei 2010
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- 2011
20. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus
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Radstake, T.R.D.J., Gorlova, O., Rueda, B., Martin, J.E., Alizadeh, B.Z., Palomino-Morales, R., Coenen, M.J., Vonk, M.C., Voskuyl, A.E., Schuerwegh, A.J., Broen, J.C., Riel, P.L.C.M. van, van't Slot, R., Italiaander, A., Ophoff, R.A., Riemekasten, G., Hunzelmann, N., Simeon, C.P., Ortego-Centeno, N., Gonzalez-Gay, M.A., Gonzalez-Escribano, M.F., Airo, P., Laar, J. van, Herrick, A., Worthington, J., Hesselstrand, R., Smith, V., Keyser, F. de, Houssiau, F., Chee, M.M., Madhok, R., Shiels, P., Westhovens, R., Kreuter, A., Kiener, H., Baere, E. de, Witte, T., Padykov, L., Klareskog, L., Beretta, L., Scorza, R., Lie, B.A., Hoffmann-Vold, A.M., Carreira, P., Varga, J., Hinchcliff, M., Gregersen, P.K., Lee, A.T., Ying, J., Han, Y., Weng, S.F., Amos, C.I., Wigley, F.M., Hummers, L., Nelson, J.L., Agarwal, S.K., Assassi, S., Gourh, P., Tan, F.K., Koeleman, B.P.C., Arnett, F.C., Martin, J., Mayes, M.D., and Spanish Scleroderma Grp
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cd4 t-cells lupus-erythematosus functional polymorphism japanese population cd3-zeta expression complex risk scleroderma mechanisms phenotype - Abstract
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 new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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- 2010
21. Studying the influence of PTPN22 gene in systemic scleroderma
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Díaz-Gallo, L. M., Gourh, P., Broen, Jasper C., ECSG, Radstake, T. R., Mayes, Maureen D., Arnett, F. C., Martín, J., and Rueda, B.
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Autoimmune diseases ,PTPN22 gene ,Systemic sclerosis ,Genetic polymorphisms - Abstract
1 página., Resumen póster.
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- 2010
22. S.12.1 Is H1N1 influenza vaccine safe and effective in patients with SSc?
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Andrade, D., primary, Seguro, L., additional, Ribeiro, A., additional, Moraes, J., additional, Saad, C., additional, Aikawa, N., additional, Calich, A., additional, Viana, V., additional, Pasoto, S., additional, Levy-Neto, M., additional, Laurindo, I., additional, Timenestsky, M., additional, Precioso, A., additional, Bonfa, E., additional, Sampaio-Barros, P., additional, Wang, J. C., additional, Assassi, S., additional, Guo, G., additional, Tu, W. Z., additional, Tan, F. K., additional, Mayes, M. D., additional, Reveille, J. D., additional, Wu, W. Y., additional, Zou, H. J., additional, Zhao, Y. Q., additional, Chu, H. Y., additional, Liu, J., additional, Zhou, X. D., additional, Dieude, P., additional, Bouaziz, M., additional, Riemekasten, G., additional, Airo, P., additional, Muller, M., additional, Cusi, D., additional, Chiocchia, G., additional, Boileau, C., additional, Allanore, Y., additional, Carmona, F., additional, Gutala, R., additional, Simeon, C. P., additional, Carreira, P., additional, Ortego Centeno, N., additional, Vicente Rabaneda, E., additional, Garcia Hernandez, F. J., additional, Garcia De La Pena, P., additional, Fernandez Castro, M., additional, Martinez Estupinan, L., additional, Egurbide, M. V., additional, Tsao, B. P., additional, Gourh, P., additional, Agarwal, S. K., additional, Arnett, F. C., additional, and Martin, J., additional
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- 2012
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23. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis
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Diaz-Gallo, LM, primary, Gourh, P, additional, Broen, J, additional, Simeon, C, additional, Fonollosa, V, additional, Ortego-Centeno, N, additional, Agarwal, S, additional, Vonk, MC, additional, Coenen, M, additional, Riemekasten, G, additional, Hunzelmann, N, additional, Hesselstrand, R, additional, Tan, FK, additional, Reveille, JD, additional, Assassi, S, additional, García-Hernandez, FJ, additional, Carreira, P, additional, Camps, MT, additional, Fernandez-Nebro, A, additional, de la Peña, P Garcia, additional, Nearney, T, additional, Hilda, D, additional, González-Gay, MA, additional, Airo, P, additional, Beretta, L, additional, Scorza, R, additional, Herrick, A, additional, Worthington, J, additional, Pros, A, additional, Gómez-Gracia, I, additional, Trapiella, L, additional, Espinosa, G, additional, Castellvi, I, additional, Witte, T, additional, de Keyser, F, additional, Vanthuyne, M, additional, Mayes, MD, additional, Radstake, TRDJ, additional, Arnett, FC, additional, Martin, J, additional, and Rueda, B, additional
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- 2010
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24. Identification of novel genetic markers associated with the clinical phenotypes of systemic sclerosis through a genome wide association strategy
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Gorlova, O, primary, Martin, J M, additional, Rueda, B, additional, Koeleman, BPC, additional, Ying, J, additional, Teruel, M, additional, Diaz-Gallo, L M, additional, Broen, J C, additional, Vonk, M C, additional, Simeon, C P, additional, Alizadeh, B Z, additional, Coenen, MJH, additional, Voskuyl, A E, additional, Schuerwegh, A J, additional, van Riel, PLCM, additional, Vanthuyne, M, additional, van ‘t Slot, R, additional, Italiaander, A, additional, Ophoff, R A, additional, Hunzelmann, N, additional, Fonollosa, V, additional, Ortego-Centeno, N, additional, González-Gay, M A, additional, García-Hernández, F J, additional, González-Escribano, M F, additional, Airo, P, additional, van Laar, J, additional, Worthington, J, additional, Hesselstrand, R, additional, Smith, V, additional, De Keyser, F, additional, Houssiau, F, additional, Chee, M M, additional, Madhok, R, additional, Shiels, P, additional, Westhovens, R, additional, Kreuter, A, additional, de Baere, E, additional, Witte, T, additional, Padyukov, L, additional, Nordin, A, additional, Scorza, R, additional, Lunardi, C, additional, Lie, B A, additional, Hoffmann-Vold, A M, additional, García de la Peña, P, additional, Carreira, P, additional, Varga, J, additional, Hinchcliff, M, additional, Lee, A T, additional, Gourh, P, additional, Amos, C I, additional, Riemekasten, G, additional, Herrick, A, additional, Beretta, L, additional, Fonseca, C, additional, Denton, C P, additional, Gregersen, P K, additional, Agarwal, S, additional, Assassi, S, additional, Tan, F K, additional, Arnett, F C, additional, Radstake, TRDJ, additional, Mayes, M D, additional, and Martin, J, additional
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- 2010
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25. Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development
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Broen, JCA, primary, Gourh, P, additional, Vonk, M C, additional, Beretta, L, additional, Niederer, F, additional, Rueda, B, additional, Geurts-van Bon, L, additional, Brouwer, C, additional, Hesselstrand, R, additional, Herrick, A, additional, Worthington, J, additional, Hunzelman, N, additional, Denton, C, additional, Fonseca, C, additional, Riemekasten, G, additional, Kiener, H, additional, Scorza, R, additional, Simeon, C P, additional, Fonollosa, V, additional, Carreira, P, additional, Ortego-Centeno, N, additional, Gonzalez-Gay, M A, additional, Airò, P, additional, Coenen, MJH, additional, Mayes, M, additional, Kyburz, D, additional, Arnett, F C, additional, Martin, J, additional, and Radstake, TRDJ, additional
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- 2010
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26. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians
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Rueda, B., primary, Gourh, P., additional, Broen, J., additional, Agarwal, S. K., additional, Simeon, C., additional, Ortego-Centeno, N., additional, Vonk, M. C., additional, Coenen, M., additional, Riemekasten, G., additional, Hunzelmann, N., additional, Hesselstrand, R., additional, Tan, F. K., additional, Reveille, J. D., additional, Assassi, S., additional, Garcia-Hernandez, F. J., additional, Carreira, P., additional, Camps, M., additional, Fernandez-Nebro, A., additional, de la Pena, P. G., additional, Nearney, T., additional, Hilda, D., additional, Gonzalez-Gay, M. A., additional, Airo, P., additional, Beretta, L., additional, Scorza, R., additional, Radstake, T. R. D. J., additional, Mayes, M. D., additional, Arnett, F. C., additional, and Martin, J., additional
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- 2009
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27. 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
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Arnett, F. C., primary, Gourh, P., additional, Shete, S., additional, Ahn, C. W., additional, Honey, R. E., additional, Agarwal, S. K., additional, Tan, F. K., additional, McNearney, T., additional, Fischbach, M., additional, Fritzler, M. J., additional, Mayes, M. D., additional, and Reveille, J. D., additional
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- 2009
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28. Comment on: An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis: reply
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Alkassab, F., primary, Gourh, P., additional, Tan, F., additional, Arnett, F., additional, and Mayes, M., additional
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- 2007
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29. Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis.
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Coustet, Baptiste, Bouaziz, Matthieu, Dieudé, Philippe, Guedj, Mickael, Bossini-Castillo, Lara, Agarwal, Sandeep, Radstake, Timothy, Martin, Javier, Gourh, Pravitt, Elhai, Muriel, Koumakis, Eugénie, Avouac, Jérôme, Ruiz, Barbara, Mayes, Maureen, Arnett, Frank, Hachulla, Eric, Diot, Elisabeth, Cracowski, Jean-Luc, Tiev, Kiet, and Sibilia, Jean
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- 2012
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30. 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.
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COUSTET, BAPTISTE, BOUAZIZ, MATTHIEU, DIEUDÉ, PHILIPPE, GUEDJ, MICKAEL, BOSSINI-CASTILLO, LARA, AGARWAL, SANDEEP, RADSTAKE, TIMOTHY, MARTIN, JAVIER, GOURH, PRAVITT, ELHAI, MURIEL, KOUMAKIS, EUGENIE, AVOUAC, JÉRÔME, RUIZ, BARBARA, MAYES, MAUREEN, ARNETT, FRANK, HACHULLA, ERIC, DIOT, ELISABETH, CRACOWSKI, JEAN-LUC, TIEV, KIET, and SIBILIA, JEAN
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- 2012
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31. Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts.
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COUSTET, BAPTISTE, AGARWAL, SANDEEP K., GOURH, PRAVITT, GUEDJ, MICKAEL, MAYES, MAUREEN D., DIEUDE, PHILIPPE, WIPFF, JULIEN, AVOUAC, JEROME, HACHULLA, ERIC, DIOT, ELISABETH, CRACOWSKI, JEAN LUC, TIEV, KIET, SIBILIA, JEAN, MOUTHON, LUC, FRANCES, CAMILLE, AMOURA, ZAHIR, CARPENTIER, PATRICK, MEYER, OLIVIER, KAHAN, ANDRE, and BOILEAU, CATHERINE
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- 2011
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32. Systemic sclerosis and lupus: points in an interferon-mediated continuum.
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Assassi S, Mayes MD, Arnett FC, Gourh P, Agarwal SK, McNearney TA, Chaussabel D, Oommen N, Fischbach M, Shah KR, Charles J, Pascual V, Reveille JD, and Tan FK
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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. [ABSTRACT FROM AUTHOR]
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- 2010
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33. Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: Evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.
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Gourh P, Agarwal SK, Divecha D, Assassi S, Paz G, Arora-Singh RK, Reveille JD, Shete S, Mayes MD, Arnett FC, and Tan FK
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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 (P(corr) = 1.4 x 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 (P(corr) = 2.4 x 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 alpha 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. [ABSTRACT FROM AUTHOR]
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- 2009
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34. The FAS -670A>G Polymorphism Influences Susceptibility to Systemic Sclerosis Phenotypes.
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Broen, J., Gourh, P., Rueda, B., Coenen, M., Mayes, M., Martin, J., Arnett, F. C., and Radstake, T. R. D. J.
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SYSTEMIC scleroderma , *GENETIC polymorphisms , *GENETICS of autoimmune diseases , *GENE frequency , *COHORT analysis , *GENETICS of disease susceptibility , *GENETICS - Abstract
The article presents a study on the role of the functional polymorphism FAS -670>G in the genetic predisposition to susceptibility in systemic sclerosis (SSc). It is stated in the study that the FAS gene causes autoimmune diseases when dysregulated and FAS - 670A allele influences SSc predisposition. It notes that the study performed genotyping in nine distinct ethnic cohorts. It also mentions that the study found that the FAS -670G allele is associated with limited cutaneous SSc (lcSSC).
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- 2009
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35. Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis.
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Gourh P, Tan FK, Assassi S, Ahn CW, McNearney TA, Fischbach M, Arnett FC, and Mayes MD
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CHROMOSOMES , *AUTOANTIBODIES , *POPULATION , *GENETIC polymorphisms , *SYSTEMIC scleroderma , *CHOCTAW (North American people) , *DISEASE susceptibility , *ENZYMES , *GENOTYPES , *ODDS ratio - Abstract
OBJECTIVE: To determine any associations of the PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)-positive or anti-topoisomerase I (anti-topo I) antibody-positive SSc, in a case-control study of US white, black, Hispanic, and Choctaw Indian individuals. METHODS: A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5' allelic discrimination assay and pyrosequencing. RESULTS: The PTPN22 CT/TT genotype showed significant association with anti-topo I antibody-positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3-3.7) and with ACA-positive white patients with SSc (OR 1.70, 95% CI 1.1-2.7). Frequency of the PTPN22*T allele also showed significant association with anti-topo I antibody-positive SSc in white patients (OR 2.03, 95% CI 1.3-3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA-positive and anti-topo I antibody-positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2-2.2; for ACA-positive patients with SSc, OR 1.63, 95% CI 1.0-2.6; for anti-topo I antibody-positive SSc, OR 2.33, 95% CI 1.5-3.7). CONCLUSION: Our results indicate that the PTPN22 R620W polymorphism is associated with ACA-positive and anti-topo I antibody-positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways. [ABSTRACT FROM AUTHOR]
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- 2006
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36. Whole-blood Gene Expression Profiling in Ankylosing Spondylitis Shows Upregulation of Toll-like Receptor 4 and 5
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ASSASSI, SHERVIN, REVEILLE, JOHN D., ARNETT, FRANK C., WEISMAN, MICHAEL H., WARD, MICHAEL M., AGARWAL, SANDEEP K., GOURH, PRAVITT, BHULA, JITEN, SHARIF, ROOZBEH, SAMPAT, KEERAN, MAYES, MAUREEN D., and TAN, FILEMON K.
- Abstract
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 anti-tumor 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.
- Published
- 2011
37. Association of Interleukin 23 Receptor Polymorphisms with Anti-Topoisomerase-I Positivity and Pulmonary Hypertension in Systemic Sclerosis
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AGARWAL, SANDEEP K., GOURH, PRAVITT, SHETE, SANJAY, PAZ, GENE, DIVECHA, DIPAL, REVEILLE, JOHN D., ASSASSI, SHERVIN, TAN, FILEMON K., MAYES, MAUREEN D., and ARNETT, FRANK C.
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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 = 3x10–5, p = 1x10–5, respectively). CONCLUSION: Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.
- Published
- 2009
38. Clinical and genetic factors predictive of mortality in early systemic sclerosis
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Assassi, Shervin, del Junco, Deborah, Sutter, Kari, McNearney, Terry A., Reveille, John D., Karnavas, Andrew, Gourh, Pravitt, EstradaYMartin, Rosa M., Fischbach, Michael, Arnett, Frank C., and Mayes, Maureen D.
- Abstract
ObjectiveTo investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study GENISOS cohort.MethodsGENISOS 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.ResultsThe 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 DRB10802and DQA10501were significant predictors of mortality in addition to the predictors mentioned above.ConclusionA 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.
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- 2009
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39. Primary Biliary Cirrhosis (PBC), PBC Autoantibodies, and Hepatic Parameter Abnormalities in a Large Population of Systemic Sclerosis Patients
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ASSASSI, SHERVIN, FRITZLER, MARVIN J., ARNETT, FRANK C., NORMAN, GARY L., SHAH, KAIRAV R., GOURH, PRAVITT, MANEK, NEIL, PERRY, MARILYN, GANESH, DEVI, RAHBAR, MOHAMMAD H., and MAYES, MAUREEN D.
- Abstract
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.
- Published
- 2009
40. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations
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Gourh, Pravitt, Arnett, Frank, Assassi, Shervin, Tan, Filemon, Huang, Mei, Diekman, Laura, Mayes, Maureen, Reveille, John, and Agarwal, Sandeep
- Abstract
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.
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- 2009
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41. Racial variability in immune responses only partially explains differential systemic sclerosis disease severity.
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Kuchinad KE, Kim JS, Woods A, Leatherman G, Gutierrez-Alamillo L, Mayes MD, Domsic R, Ramos PS, Silver RM, Varga J, Saketkoo LA, Kafaja S, Shanmugan VK, Gordon J, Chung L, Bernstein EJ, Gourh P, Boin F, Kastner DL, Zeger SL, Casciola-Rosen L, Wigley FM, and Shah AA
- Abstract
Objective: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients., Methods: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared., Results: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%., Conclusions: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups., Competing Interests: Competing interests: RD received consulting fees from CSL Behring and Astra-Zeneca. LAS received grant funding from Horizon Pharmaceuticals, aTyr Pharmaceuticals and Kinevant Pharmaceuticals and honoraria from Janssen Pharmaceuticals. She served on the data safety monitoring board for Argenx Pharmaceuticals. LC received grant funding from Boehringer Ingelheim and consulting fees from Kyverna, Eicos Sciences, Genentech, IgM Biosciences, Lilly. She participated in an advisory capacity for Mitsubishi Tanabe and Janssen. FB received honoraria from Janssen. RMS received grant funding from Boehringer Ingelheim, Merck and Amgen; he is the CEO of FibroBiologics. JV received consulting fees from TeneoBio, and Conquest; he serves on the data safety monitoring board for Conquest. MDM received grant funding from Prometheus Biosciences, Mitsubishi Tanabe, Boehringer Ingelheiem, Eicos, Corbus and Horizon Pharmaceuticals. She received consulting fees from Cabaletta Pharmaceuticals; she served on the advisory board for Mitsubishi Tanabe and Eicos Sciences. AS has grant support from Kadmon, Arena Pharmaceuticals, Medpace and Eicos Sciences., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)
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- 2024
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42. Cross-Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis.
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Luo Y, Khan A, Liu L, Lee CH, Perreault GJ, Pomenti SF, Gourh P, Kiryluk K, and Bernstein EJ
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Objective: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis., Methods: We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci., Results: We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10
-6 ). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10-8 ). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3 , and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function., Conclusion: Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.- Published
- 2024
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43. Risk Factors for COVID-19 and Rheumatic Disease Flare in a US Cohort of Latino Patients.
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Fike A, Hartman J, Redmond C, Williams SG, Ruiz-Perdomo Y, Chu J, Hasni S, Ward MM, Katz JD, and Gourh P
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- Adult, COVID-19 epidemiology, Cohort Studies, Comorbidity, Female, Hispanic or Latino, Humans, Incidence, Male, Middle Aged, Retrospective Studies, Risk Factors, Severity of Illness Index, United States, COVID-19 diagnosis, Rheumatic Diseases epidemiology
- Abstract
Objective: Latino patients are overrepresented among cases of coronavirus disease 2019 (COVID-19) and are at an increased risk of severe disease. Prevalence of COVID-19 in Latinos with rheumatic diseases is poorly reported. This study was undertaken to characterize COVID-19 clinical features and outcomes in Latino patients with rheumatic diseases., Methods: We conducted a retrospective study of Latino patients with rheumatic diseases from an existing observational cohort in the Washington, DC area. Patients seen between April 1, 2020 and October 15, 2020 were analyzed in this study. We reviewed demographic characteristics, body mass index (BMI), comorbidities, and use of immunomodulatory therapies. An exploratory classification and regression tree (CART) analysis along with logistic regression analyses were performed to identify risk factors for COVID-19 and rheumatic disease flare., Results: Of 178 Latino patients with rheumatic diseases, 32 (18%) were identified as having COVID-19, and the incidence rate of infection was found to be 3-fold higher than in the general Latino population. No patients required intensive care unit-level care. A CART analysis and multivariable logistic regression analysis identified a BMI of >30.35 as a risk factor for COVID-19 (odds ratio [OR] 3.37 [95% confidence interval (95% CI) 1.5-7.7]; P = 0.004). COVID-19 positivity was a risk factor for rheumatic disease flare (OR 4.57 [95% CI 1.2-17.4]; P = 0.02)., Conclusion: Our findings indicate that Latino patients with rheumatic diseases have a higher rate of COVID-19 compared with the general Latino population. Obesity is a risk factor for COVID-19, and COVID-19 is a risk factor for rheumatic disease flare. Latino patients with risk factors should be closely followed up, especially post-COVID-19 in anticipation of disease flare., (Published 2021. This article is a U.S.Government work and is in the public domain in the USA.)
- Published
- 2021
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44. Use of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis.
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Subedi A, Williams SG, Yao L, Maharjan S, Strauss J, Sharon E, Thomas A, Apolo AB, Gourh P, Hasni SA, Gulley JL, Kaplan MJ, Katz JD, and Gupta S
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- Aged, Arthritis, Rheumatoid chemically induced, Early Diagnosis, Female, Humans, Joints pathology, Magnetic Resonance Imaging, Male, Middle Aged, Retrospective Studies, Antineoplastic Agents, Immunological adverse effects, Arthritis, Rheumatoid diagnosis, Immunotherapy adverse effects, Joints diagnostic imaging, Neoplasms drug therapy
- Abstract
Importance: Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease., Objective: To assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis., Design, Setting, and Participants: This retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019., Exposures: Undergoing MRI of at least 1 joint., Main Outcomes and Measures: All MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions., Results: A total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option., Conclusions and Relevance: These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.
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- 2020
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45. Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.
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Gourh P, Remmers EF, Boyden SE, Alexander T, Morgan ND, Shah AA, Mayes MD, Doumatey A, Bentley AR, Shriner D, Domsic RT, Medsger TA Jr, Steen VD, Ramos PS, Silver RM, Korman B, Varga J, Schiopu E, Khanna D, Hsu V, Gordon JK, Saketkoo LA, Gladue H, Kron B, Criswell LA, Derk CT, Bridges SL Jr, Shanmugam VK, Kolstad KD, Chung L, Jan R, Bernstein EJ, Goldberg A, Trojanowski M, Kafaja S, Maksimowicz-McKinnon KM, Mullikin JC, Adeyemo A, Rotimi C, Boin F, Kastner DL, and Wigley FM
- Subjects
- Adenosine Triphosphatases genetics, Adult, Extracellular Matrix Proteins genetics, Female, Genetic Variation, Humans, Male, Middle Aged, Principal Component Analysis, White People genetics, Exome Sequencing, Black or African American genetics, Gene Regulatory Networks genetics, Genetic Predisposition to Disease ethnology, Scleroderma, Systemic ethnology, Scleroderma, Systemic genetics
- Abstract
Objective: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients., Methods: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls., Results: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10
-4 )., Conclusion: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility., (© 2018, American College of Rheumatology.)- Published
- 2018
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46. Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.
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Ramnitz MS, Gourh P, Goldbach-Mansky R, Wodajo F, Ichikawa S, Econs MJ, White KE, Molinolo A, Chen MY, Heller T, Del Rivero J, Seo-Mayer P, Arabshahi B, Jackson MB, Hatab S, McCarthy E, Guthrie LC, Brillante BA, Gafni RI, and Collins MT
- Subjects
- Adolescent, Adult, Child, Cohort Studies, Female, Fibroblast Growth Factor-23, Humans, Klotho Proteins, Male, Polypeptide N-acetylgalactosaminyltransferase, Calcinosis blood, Calcinosis genetics, Calcinosis pathology, Calcinosis therapy, Fibroblast Growth Factors genetics, Glucuronidase genetics, Hyperostosis blood, Hyperostosis genetics, Hyperostosis pathology, Hyperostosis therapy, Hyperostosis, Cortical, Congenital blood, Hyperostosis, Cortical, Congenital genetics, Hyperostosis, Cortical, Congenital pathology, Hyperostosis, Cortical, Congenital therapy, Hyperphosphatemia blood, Hyperphosphatemia genetics, Hyperphosphatemia pathology, Hyperphosphatemia therapy, N-Acetylgalactosaminyltransferases genetics
- Abstract
Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D
3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research., Competing Interests: Statement: All other authors have no conflicts of interest., (© 2016 American Society for Bone and Mineral Research.)- Published
- 2016
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47. Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.
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Carmona FD, Gutala R, Simeón CP, Carreira P, Ortego-Centeno N, Vicente-Rabaneda E, García-Hernández FJ, García de la Peña P, Fernández-Castro M, Martínez-Estupiñán L, Egurbide MV, Tsao BP, Gourh P, Agarwal SK, Assassi S, Mayes MD, Arnett FC, Tan FK, and Martín J
- Subjects
- Antibodies, Antinuclear biosynthesis, Autoimmune Diseases immunology, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Scleroderma, Systemic immunology, Antibodies, Antinuclear blood, Autoimmune Diseases genetics, Interferon Regulatory Factor-7 genetics, Scleroderma, Systemic genetics
- Abstract
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: 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., 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.
- Published
- 2012
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48. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.
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Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, Coenen MJ, Vonk MC, Voskuyl AE, Schuerwegh AJ, Broen JC, van Riel PL, van 't Slot R, Italiaander A, Ophoff RA, Riemekasten G, Hunzelmann N, Simeon CP, Ortego-Centeno N, González-Gay MA, González-Escribano MF, Airo P, van Laar J, Herrick A, Worthington J, Hesselstrand R, Smith V, de Keyser F, Houssiau F, Chee MM, Madhok R, Shiels P, Westhovens R, Kreuter A, Kiener H, de Baere E, Witte T, Padykov L, Klareskog L, Beretta L, Scorza R, Lie BA, Hoffmann-Vold AM, Carreira P, Varga J, Hinchcliff M, Gregersen PK, Lee AT, Ying J, Han Y, Weng SF, Amos CI, Wigley FM, Hummers L, Nelson JL, Agarwal SK, Assassi S, Gourh P, Tan FK, Koeleman BP, Arnett FC, Martin J, and Mayes MD
- Subjects
- Adult, Aged, Case-Control Studies, Cohort Studies, Europe, Female, Humans, Male, Middle Aged, Odds Ratio, Risk Factors, CD3 Complex genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Scleroderma, Systemic genetics
- Abstract
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 new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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- 2010
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49. 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.
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Arnett FC, Gourh P, Shete S, Ahn CW, Honey RE, Agarwal SK, Tan FK, McNearney T, Fischbach M, Fritzler MJ, Mayes MD, and Reveille JD
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- Black or African American genetics, Autoantibodies analysis, Case-Control Studies, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Hispanic or Latino genetics, Histocompatibility Testing, Humans, Scleroderma, Systemic ethnology, Scleroderma, Systemic genetics, White People genetics, Epitopes analysis, Histocompatibility Antigens Class II genetics, Scleroderma, Systemic immunology
- Abstract
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.
- Published
- 2010
- Full Text
- View/download PDF
50. Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis.
- Author
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Gourh P, Arnett FC, Tan FK, Assassi S, Divecha D, Paz G, McNearney T, Draeger H, Reveille JD, Mayes MD, and Agarwal SK
- Subjects
- Alleles, Epidemiologic Methods, Female, Genetic Markers, Genotype, Humans, Linkage Disequilibrium, Male, Lupus Erythematosus, Systemic genetics, OX40 Ligand genetics, Polymorphism, Single Nucleotide genetics, Scleroderma, Systemic genetics
- Abstract
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, p(FDR)=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, p(FDR)=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, p(FDR)=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, p(FDR)=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.
- Published
- 2010
- Full Text
- View/download PDF
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