Extended report Ann Rheum Dis 2011;70:668–674. doi:10.1136/ard.2010.131243 668 Accepted 1 November 2010 Published Online First 13 December 2010 ABSTRACT Background Recent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1β. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. Objective To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. Methods NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. Results Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. Conclusions Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease. Several lines of evidence have recently raised the paradigm of the contribution of innate immune mechanisms to autoimmunity. The concept of innate immunity as a primitive system, being non- specific in most aspects of both recognition and response, has been transformed by the identifica- tion of the membrane-associated Toll-like recep- tors and the cytosol-expressed Nod-like receptors (NLR). 1 2 The NLR family, pyrin domain containing 1 (NLRP1), is a member of the NLR family, which are cytoplasmic proteins that sense endogenous microbial products and metabolic stresses, thereby stimulating innate immunity. NLR associated with other proteins form multiprotein cytoplasmic complexes, the so-called inflammasomes. NLRP1 provides a scaffold for the assembly of the inflam- masome that activates caspases 1 and 5, which sub- sequently promote the processing and maturation of the inflammatory cytokines, pro-interleukin 1β (IL-1β), IL-18 and IL-33. 3 4 Some studies have highlighted a potential role of IL-1β in fibrotic disorders. 5 6 In systemic sclerosis (SSc), the prototypic fibrotic connective tissue dis- order, IL-1β has been reported to induce the fibro- genic phenotype of SSc fibroblasts and to increase strikingly in vitro the production of extracellular matrix by these cells. 7 8 SSc is a chronic autoim- mune disease with a complex pathogenesis driven by a combination of genetic risk factors and envi- ronmental events that lead to a break in immuno- logical self-tolerance and systemic fibrosis. 9 10 Two of the SSc susceptibility genes recently identified play a pivotal role in innate immunity: IRF5 and STAT4. 11 –14 In addition, other genes involved in innate immunity have been found to be associated with various autoimmune or auto-inflammatory disorders. NOD2 have thus been associated with a risk of Crohn’s disease. 15 Mutations of NLRP3 (also known as cryopyrin) were reported to cause three Mendelian dominant inflammatory disorders. 16 Finally, NLRP1 has been found to confer a risk for extended autoimmune/inflammatory disorders 17 –19 and more recently to autoimmune Addison’s dis- ease and type I diabetes. 20 21 Taking into consideration: (1) the potential role of IL-1β in the SSc fibrosing process; (2) the iden- tification of SSc susceptibility genes encoding pro- teins involved in innate immunity; and (3) common genetic variants shared by different autoimmune diseases, we hypothesised that the previously iden- tified NLRP1 risk variants may be involved in the susceptibility of SSc. PATIENTS AND METHODS Study population and study design We performed a case–control association study including a replication step. The discovery ▶ Supplementary data are published online only. To view these files please visit the journal online (http://ard.bmj. com. For numbered affiliations see end of article Correspondence to Dr Philippe Dieudé, Service de Rhumatologie, Paris Diderot University, INSERM U699, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France; philippe.dieude@bch.aphp.fr NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis P Dieudé, 1 M Guedj, 2 J Wipff, 3,4 B Ruiz, 3 G Riemekasten, 5 P Airo, 6 I Melchers, 7 E Hachulla, 8 M Matucci Cerinic, 9 E Diot, 10 N Hunzelmann, 11 P Caramaschi, 12 J Sibilia, 13 K Tiev, 14 L Mouthon, 15 V Riccieri, 16 J L Cracowski, 17 P H Carpentier, 18 J Distler, 19 Z Amoura, 20 I Tarner, 21 J Avouac, 3,4 O Meyer, 1 A Kahan, 4 C Boileau, 3,22 Y Allanore 3,4 group.bmj.com on October 25, 2016 - Published by http://ard.bmj.com/ Downloaded from