Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis

Aleixo M. Muise*, Thomas Walters, Wei Xu, Grace Shentu, Conghui Guo, Ramzi Fattouh, Grace Y. Lam, Victorien M. Wolters, Joshua Bennitz, Johan Van Limbergen, Paul Renbaum, Yair Kasirer, Boyee 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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: 1.261.63]) and rs4720672 (Pcombined UC = 4.7 × 10-6, odds ratio = 1.36 [95% confidence interval: 1.191.58]). 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 sodiuminduced 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 languageAmerican English
Pages (from-to)633-641
Number of pages9
JournalGastroenterology
Volume141
Issue number2
DOIs
StatePublished - Aug 2011

Bibliographical note

Funding Information:
Funding A.M.M. is supported by a transition award from the Crohn's and Colitis Foundation of Canada (CCFC)/Canadian Association of Gastroenterology (CAG)/Canadian Institute for Health Research (CIHR), a Canadian Child Health Clinician Scientist Program (Strategic Training Initiatives in Health Research Program—CIHR) award and an Early Researcher Award from the Ontario Ministry of Research and Innovation. J.B. is supported by a CCFC/CAG summer studentship. T.W. is supported by CCFC and AstraZeneca Partnered fellowships from the CAG/CIHR. P.M.S. is a recipient of Canada Research Chair in Gastrointestinal Disease. D.C.W. is the holder of a Medical Research Council Patient Cohorts Research Initiative award (G0800675). Financial assistance was also provided by the Wellcome Trust Programme Grant ( 072789/Z/03/Z ), Action Medical Research, the Chief Scientist Office of the Scottish Government Health Department, and the GI/Nutrition Research Fund, Child Life and Health, University of Edinburgh. R.H.D. is supported by NIH/NIDDK grant ( DK062420 ). M.S.S. is supported by the Gale and Graham Wright Research Chair in Digestive Diseases at Mount Sinai Hospital and funding from CCFC and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK-06-2423). J.H.B., PhD, holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. Funding was provided by a CIHR operating grant ( MOP97756 ) to A.M.M. and J.H.B.

Keywords

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

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