TY - JOUR T1 - Phenotype-Haplotype Correlation of IRF5 in Systemic Sclerosis: Role of 2 Haplotypes in Disease Severity JF - The Journal of Rheumatology JO - J Rheumatol DO - 10.3899/jrheum.091163 SP - jrheum.091163 AU - Philippe Dieude AU - Karen Dawidowicz AU - Mickaël Guedj AU - Yona Legrain AU - Julien Wipff AU - Eric Hachulla AU - Elisabeth Diot AU - Jean Sibilia AU - Luc Mouthon AU - Jean Cabane AU - Zahir Amoura AU - Jean-Luc Crakowski AU - Patrick Carpentier AU - Jerome Avouac AU - Olivier Meyer AU - Andre Kahan AU - Catherine Boileau AU - Yannick Allanore Y1 - 2010/03/15 UR - http://www.jrheum.org/content/early/2010/03/12/jrheum.091163.abstract N2 - Objective 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. Methods 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. Results 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” (padj = 0.024, OR 1.23, 95% CI 1.07–1.40) and a mirrored protective haplotype “P” (padj = 8.8 × 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). Conclusion 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. ER -