Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

• Published in: PLoS genetics Vol. 7; no. 7; p. e1002178
• Main Authors: Gorlova, Olga, Martin, Jose-Ezequiel, Rueda, Blanca, Koeleman, Bobby P C, Ying, Jun, Teruel, Maria, Diaz-Gallo, Lina-Marcela, Broen, Jasper C, Vonk, Madelon C, Simeon, Carmen P, Alizadeh, Behrooz Z, Coenen, Marieke J H, Voskuyl, Alexandre E, Schuerwegh, Annemie J, van Riel, Piet L C M, Vanthuyne, Marie, van 't Slot, Ruben, Italiaander, Annet, Ophoff, Roel A, Hunzelmann, Nicolas, Fonollosa, Vicente, Ortego-Centeno, Norberto, González-Gay, Miguel A, García-Hernández, Francisco J, González-Escribano, María F, Airo, Paolo, van Laar, Jacob, Worthington, Jane, Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul G, Westhovens, Rene, Kreuter, Alexander, de Baere, Elfride, Witte, Torsten, Padyukov, Leonid, Nordin, Annika, Scorza, Raffaella, Lunardi, Claudio, Lie, Benedicte A, Hoffmann-Vold, Anna-Maria, Palm, Oyvind, García de la Peña, Paloma, Carreira, Patricia, Varga, John, Hinchcliff, Monique, Lee, Annette T, Gourh, Pravitt, Amos, Christopher I, Wigley, Frederick M, Hummers, Laura K, Nelson, J Lee, Riemekasten, Gabriella, Herrick, Ariane, Beretta, Lorenzo, Fonseca, Carmen, Denton, Christopher P, Gregersen, Peter K, Agarwal, Sandeep, Assassi, Shervin, Tan, Filemon K, Arnett, Frank C, Radstake, Timothy R D J, Mayes, Maureen D, Martin, Javier
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2011; Public Library of Science (PLoS)
• Subjects: Alleles; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Biology; Clinical Medicine; Development and progression; Disease; Female; Genetic aspects; Genetic Loci - genetics; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study - methods; Genomes; Grants; HLA Antigens - genetics; Humans; Klinisk medicin; Male; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Medicine; Middle Aged; Phenotype; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Regression analysis; Reumatologi och inflammation; Rheumatology and Autoimmunity; Scleroderma; Scleroderma (Disease); Scleroderma, Systemic - classification; Scleroderma, Systemic - genetics; Scleroderma, Systemic - immunology; Systemic scleroderma; United States; Netherlands; Spain
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002178

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.