title: Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis.
abstract: OBJECTIVE
  RAC1 is a guanosine triphosphatase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases are associated with dysregulation of immune defenses. We studied the role of RAC1 in inflammatory bowel diseases using human genetic and functional studies and animal models of colitis.
  
  
  METHODS
  We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 messenger RNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulfate sodium.
  
  
  RESULTS
  We observed a genetic association between RAC1 with ulcerative colitis in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the single nucleotide polymorphisms rs10951982 (P(combined UC) = 3.3 × 10(-8), odds ratio = 1.43 [95% confidence interval: 1.26-1.63]) and rs4720672 (P(combined UC) = 4.7 × 10(-6), odds ratio = 1.36 [95% confidence interval: 1.19-1.58]). Patients with inflammatory bowel disease who had the rs10951982 risk allele had increased expression of RAC1 compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected against dextran sulfate sodium-induced colitis.
  
  
  CONCLUSIONS
  Human studies and knockout mice demonstrated a role for the guanosine triphosphatase RAC1 in the development of ulcerative colitis; increased expression of RAC1 was associated with susceptibility to colitis.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@sickkids.ca
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.forename: Thomas
authors.initials: T
authors.lastname: Walters
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Grace
authors.initials: G
authors.lastname: Shen-Tu
authors.forename: Cong-Hui
authors.initials: CH
authors.lastname: Guo
authors.forename: Ramzi
authors.initials: R
authors.lastname: Fattouh
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Lam
authors.forename: Victorien M
authors.initials: VM
authors.lastname: Wolters
authors.forename: Joshua
authors.initials: J
authors.lastname: Bennitz
authors.forename: Johan
authors.initials: J
authors.lastname: van Limbergen
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Yair
authors.initials: Y
authors.lastname: Kasirer
authors.forename: Bo-Yee
authors.initials: BY
authors.lastname: Ngan
authors.forename: Dan
authors.initials: D
authors.lastname: Turner
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sherman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.forename: Judy
authors.initials: J
authors.lastname: Cho
authors.forename: Charlie W
authors.initials: CW
authors.lastname: Lees
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.forename: David C
authors.initials: DC
authors.lastname: Wilson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
mesh_terms: D000483:Alleles; D000818:Animals; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism*; D016264:Dextran Sulfate; D056726:Genetic Association Studies; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016017:Odds Ratio; D009195:Peroxidase / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood*; D018709:Statistics, Nonparametric; D044465:White People / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D016264:Dextran Sulfate; D009195:Peroxidase; D020830:rac1 GTP-Binding Protein