Single Nucleotide Polymorphisms That Increase Expression of the Guanosine Triphosphatase RAC1 Are Associated With Ulcerative Colitis

Aleixo M Muise, Thomas Walters, Wei Xu, Grace Shen-Tu, Cong-Hui Guo, Ramzi Fattouh, Grace Y Lam, Victorien M Wolters, Joshua Bennitz, Johan van Limbergen, Paul Renbaum, Yair Kasirer, Bo-Yee Ngan, Dan Turner, Lee A Denson, Philip M Sherman, Richard H Duerr, Judy Cho, Charlie W Lees, Jack SatsangiDavid C Wilson, Andrew D Paterson, Anne M Griffiths, Michael Glogauer, Mark S Silverberg, John H Brumell

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims
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 (Pcombined UC = 3.3 × 10−8, odds ratio = 1.43 [95% confidence interval: 1.26–1.63]) and rs4720672 (Pcombined 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.
Original languageEnglish
Pages (from-to)633-641
Number of pages9
JournalGastroenterology
Volume141
Issue number2
DOIs
Publication statusPublished - Aug 2011

Keywords

  • Innate Immunity
  • Ulcerative Colitis
  • CD
  • Rac-1 Knockout

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