Phenotype-Haplotype Correlation of IRF5 in Systemic Sclerosis: Role of 2 Haplotypes in Disease Severity

• Published in: Journal of rheumatology 2010-05, Vol.37 (5), p.987-992
• Main Authors: DIEUDE, Philippe, DAWIDOWICZ, Karen, AMOURA, Zahir, CRAKOWSKI, Jean-Luc, CARPENTIER, Patrick, AVOUAC, Jerome, MEYER, Olivier, KAHAN, Andre, BOILEAU, Catherine, ALLANORE, Yannick, GUEDJ, Mickael, LEGRAIN, Yona, WIPFF, Julien, HACHULLA, Eric, DIOT, Elisabeth, SIBILIA, Jean, MOUTHON, Luc, CABANE, Jean
• Format: Article
• Language: English
• Subjects: Autoantibodies - genetics; Biological and medical sciences; Case-Control Studies; Diseases of the osteoarticular system; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Haplotypes - genetics; Humans; Interferon Regulatory Factors - genetics; Medical sciences; Odds Ratio; Phenotype; Polymerase Chain Reaction; Polymorphism, Single Nucleotide - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma, Systemic - genetics; Scleroderma, Systemic - physiopathology; Severity of Illness Index
• ISSN: 0315-162X; 1499-2752
• DOI: 10.3899/jrheum.091163

Identification of an association between IRF5 rs2004640 and systemic sclerosis (SSc) has highlighted a key role for type 1 interferon (IFN). Additional functional IRF5 variants have been identified as autoimmune susceptibility factors. Our aim was to investigate whether IRF5 haplotypes confer susceptibility to SSc, and to perform genotype haplotype-phenotype correlation analyses. We genotyped IRF5 rs377385, rs2004640, and rs10954213 in 1623 individuals of French European Caucasian origin. SSc patient subphenotypes were analyzed according to cutaneous subsets and for SSc-related pulmonary fibrosis. Case-control studies of single markers revealed an association between IRF5 rs3757385, rs2004640, and rs10954213 variants and SSc. We identified an IRF5 risk haplotype "R" (p(adj) = 0.024, OR 1.23, 95% CI 1.07-1.40) and a mirrored protective haplotype "P" (p(adj) = 8.8 x 10(-3), OR 0.78, 95% CI 0.68-0.90) for SSc susceptibility. Genotype-phenotype correlation analyses failed to detect any association with a single marker. By contrast, phenotype-haplotype correlation analysis was able to detect intra-cohort association and to discriminate SSc patients with from those without the following clinical traits: "R" and/or "P" haplotypes identified diffuse cutaneous SSc (p = 0.0081) and fibrosing alveolitis (p = 0.018). IRF5 haplotypes are more informative than single markers, suggesting that they could be helpful for risk stratification of SSc patients. Our study provides further evidence of a key role of IRF5 in SSc severity.