NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis

Dieudè, P; Guedj, M; Wipff, J; Ruiz, B; Hachulla, E; Diot, E; Sibilia, J; Mouthon L, Tiev K.; Cracowski, Jl; Carpentier, P; Amoura, Z; Avouac, J; Meyer, O; Kahan, A; Boileau, C; Allanore, Y; Riemekasten, G; Melchers, I; Hunzelmann, N; Distler, J; Tarner, I; Airo, P; Matucci Cerinic, M; Caramaschi, Paola; Riccieri, V.

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.

Titolo:	NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis
Autori:	Dieudè P Guedj M Wipff J Ruiz B Hachulla E Diot E Sibilia J Tiev K. Mouthon L Cracowski JL Carpentier P Amoura Z Avouac J Meyer O Kahan A Boileau C Allanore Y Riemekasten G Melchers I Hunzelmann N Distler J Tarner I Airo P Matucci Cerinic M Caramaschi, Paola Riccieri V. mostra contributor esterni nascondi contributor esterni
Data di pubblicazione:	2011
Rivista:	ANNALS OF THE RHEUMATIC DISEASES
Abstract:	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.
Handle:	http://hdl.handle.net/11562/492951
Appare nelle tipologie:	01.01 Articolo in Rivista

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