TY - JOUR
T1 - NLRP1 influences the systemic sclerosis phenotype: A new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis
AU - Dieudé, P.
AU - Guedj, M.
AU - Wipff, J.
AU - Ruiz, B.
AU - Riemekasten, G.
AU - Airo, P.
AU - Melchers, I.
AU - Hachulla, E.
AU - Matucci Cerinic, M.
AU - Diot, E.
AU - Hunzelmann, N.
AU - Caramaschi, P.
AU - Sibilia, J.
AU - Tiev, K.
AU - Mouthon, L.
AU - Riccieri, V.
AU - Cracowski, J. L.
AU - Carpentier, P. H.
AU - Distler, J.
AU - Amoura, Z.
AU - Tarner, I.
AU - Avouac, J.
AU - Meyer, O.
AU - Kahan, A.
AU - Boileau, C.
AU - Allanore, Y.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952362007&partnerID=8YFLogxK
U2 - 10.1136/ard.2010.131243
DO - 10.1136/ard.2010.131243
M3 - Journal articles
AN - SCOPUS:79952362007
SN - 0003-4967
VL - 70
SP - 668
EP - 674
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 4
ER -
