Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis

• Published in: Annals of the rheumatic diseases Vol. 71; no. 1; pp. 114 - 119
• Main Authors: Carmona, F David, Gutala, Ramana, Simeón, Carmen P, Carreira, Patricia, Ortego-Centeno, Norberto, Vicente-Rabaneda, Esther, García-Hernández, Francisco J, García de la Peña, Paloma, Fernández-Castro, Mónica, Martínez-Estupiñán, Lina, Egurbide, María Victoria, Tsao, Betty P, Gourh, Pravitt, Agarwal, Sandeep K, Assassi, Shervin, Mayes, Maureen D, Arnett, Frank C, Tan, Filemon K, Martín, Javier
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.01.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Antibodies, Antinuclear - biosynthesis; Antibodies, Antinuclear - blood; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Biological and medical sciences; Case-Control Studies; Deoxyribonucleic acid; Disease; Diseases of the osteoarticular system; DNA; Ethnicity; Female; Gene Frequency; Genes; Genetic Predisposition to Disease; Genotype; Humans; Interferon Regulatory Factor-7 - genetics; Male; Medical sciences; Mortality; Polymorphism, Single Nucleotide; Rheumatology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma; Scleroderma, Systemic - genetics; Scleroderma, Systemic - immunology; Software; Studies; California; Spain; Autoimmunity; Immunopathology; Connective tissue disease; Skin disease; Systemic disease; Rheumatology; Autoantibody; Autoimmune disease; Identification; Locus; Scleroderma
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2011-200275

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: pFDR=6.14 × 10−4, OR=0.78; rs4963128: pFDR=6.14 × 10−4, OR=0.79; rs702966: pFDR=3.83 × 10−3, OR=0.82; and rs2246614: pFDR=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.