OBJECTIVE: The inflammasome-related protein NLRP1/NALP1 has been implicated in the onset and progression of some autoimmune diseases. This study was undertaken to determine whether a polymorphism in the NLRP1 gene is associated with susceptibility to rheumatoid arthritis (RA) in Han Chinese and to assess the functional implications of this association. METHODS: RA patients (n = 190) and matched healthy controls (n = 190) residing in the city of Chengdu were genotyped for the NLRP1 promoter polymorphisms rs6502867 and rs878329. Genotyping for rs878329 was performed in a second set of subjects (n = 1,514) residing in the city of Chongqing. The effect of each polymorphism on NLRP1 transcription was evaluated by dual-luciferase assay, while the effect on DNA protein interaction was determined by electrophoretic mobility shift assay. Differential expression of NLRP1 in individuals with different genotypes was investigated by real-time quantitative polymerase chain reaction. RESULTS: The polymorphism rs878329, but not rs6502867, was associated with RA (odds ratio [OR] 0.83, P = 0.02 for the C allele; OR 0.42, P = 0.01 for the CC genotype). The GG genotype of rs878329 was the risk genotype for RA (OR 2.38) and had a runt-related transcription factor 1 binding site that up-regulated NLRP1 transcription. Individuals with the RA risk genotype GG had significantly higher NLRP1 messenger RNA levels than those with the CC genotype among the Han Chinese population. CONCLUSION: Our findings indicate that NLRP1 is associated with RA in Han Chinese. The G allele of rs878329 in the NLRP1 promoter up-regulates gene transcription and confers the risk of RA.
OBJECTIVE: The inflammasome-related protein NLRP1/NALP1 has been implicated in the onset and progression of some autoimmune diseases. This study was undertaken to determine whether a polymorphism in the NLRP1 gene is associated with susceptibility to rheumatoid arthritis (RA) in Han Chinese and to assess the functional implications of this association. METHODS:RApatients (n = 190) and matched healthy controls (n = 190) residing in the city of Chengdu were genotyped for the NLRP1 promoter polymorphisms rs6502867 and rs878329. Genotyping for rs878329 was performed in a second set of subjects (n = 1,514) residing in the city of Chongqing. The effect of each polymorphism on NLRP1 transcription was evaluated by dual-luciferase assay, while the effect on DNA protein interaction was determined by electrophoretic mobility shift assay. Differential expression of NLRP1 in individuals with different genotypes was investigated by real-time quantitative polymerase chain reaction. RESULTS: The polymorphism rs878329, but not rs6502867, was associated with RA (odds ratio [OR] 0.83, P = 0.02 for the C allele; OR 0.42, P = 0.01 for the CC genotype). The GG genotype of rs878329 was the risk genotype for RA (OR 2.38) and had a runt-related transcription factor 1 binding site that up-regulated NLRP1 transcription. Individuals with the RA risk genotype GG had significantly higher NLRP1 messenger RNA levels than those with the CC genotype among the Han Chinese population. CONCLUSION: Our findings indicate that NLRP1 is associated with RA in Han Chinese. The G allele of rs878329 in the NLRP1 promoter up-regulates gene transcription and confers the risk of RA.
Authors: Joshua N Finger; John D Lich; Lauren C Dare; Michael N Cook; Kristin K Brown; Chaya Duraiswami; John Bertin; John J Bertin; Peter J Gough Journal: J Biol Chem Date: 2012-06-04 Impact factor: 5.157
Authors: Alan R Sanders; Harald H H Göring; Jubao Duan; Eugene I Drigalenko; Winton Moy; Jessica Freda; Deli He; Jianxin Shi; Pablo V Gejman Journal: Hum Mol Genet Date: 2013-07-30 Impact factor: 6.150
Authors: Cecilia B Levandowski; Christina M Mailloux; Tracey M Ferrara; Katherine Gowan; Songtao Ben; Ying Jin; Kimberly K McFann; Paulene J Holland; Pamela R Fain; Charles A Dinarello; Richard A Spritz Journal: Proc Natl Acad Sci U S A Date: 2013-02-04 Impact factor: 11.205