Common variants in the NLRP3 region contribute to Crohn's disease susceptibility.
We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (P(combined) = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1beta production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.
Villani
Alexandra-Chloé
AC
Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, Montréal, Québec, Canada. alexandra-chloe.villani@mail.mcgill.ca
Lemire
Mathieu
M
Fortin
Geneviève
G
Louis
Edouard
E
Silverberg
Mark S
MS
Collette
Catherine
C
Baba
Nobuyasu
N
Libioulle
Cécile
C
Belaiche
Jacques
J
Bitton
Alain
A
Gaudet
Daniel
D
Cohen
Albert
A
Langelier
Diane
D
Fortin
Paul R
PR
Wither
Joan E
JE
Sarfati
Marika
M
Rutgeerts
Paul
P
Rioux
John D
JD
Vermeire
Severine
S
Hudson
Thomas J
TJ
Franchimont
Denis
D
D020029:Base Pairing; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human