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Evidence for a functional genetic polymorphism of the Rho-GTPase Rac1. Implication in azathioprine response?

Bourgine, Joanna; Garat, Anne; Allorge, Delphine; Crunelle-Thibaut, Aurélie; Lo-Guidice, Jean-Marc; Colombel, Jean-Frédéric; Broly, Franck; Billaut-Laden, Ingrid

Pharmacogenetics and Genomics: June 2011 - Volume 21 - Issue 6 - p 313–324
doi: 10.1097/FPC.0b013e3283449200
ORIGINAL ARTICLES
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Background Adverse effects of thiopurine drugs occur in 15–28% of patients and the majority is not explained by thiopurine-S-methyltransferase deficiency. Furthermore, approximately 9% of patients with inflammatory bowel disease are resistant to azathioprine therapy. Recently, the small guanosine triphosphatase, Rac1, was identified as an important molecular target of 6-thioguanine triphosphate, one of the active metabolite of thiopurines such as azathioprine. To date, no functional genetic polymorphism of the human Rac1 gene had been reported.

Objectives Evidence for functional genetic polymorphisms of the human Rac1 gene and to investigate their relative contribution to the development of toxicity induced by azathioprine treatment in patients with inflammatory bowel disease.

Methods We first screened for polymorphisms in the Rac1 gene in genomic DNA samples from 92 unrelated Caucasian individuals. The functional consequences of identified polymorphisms were assessed in vitro using transient transfection assays in Jurkat and A549 cell lines. The relationship between polymorphisms of Rac1 and thiopurine response or hematotoxicity was studied in 128 patients under thiopurine treatment.

Results Three single nucleotide polymorphism and one variable number tandem repeat were identified in the promoter region of Rac1 gene. Interestingly, in Jurkat T cells, the c.-289G>C substitution and c.-283_-297[3] variable number tandem repeat displayed a significantly increased promoter activity (P<0.01) of 150 and 300%, respectively, compared with that of the wild-type sequence. Patients with thiopurine-S-methyltransferase mutations presented a significantly increased probability of developing hematotoxicity (odds ratio=5.68, 95% confidence interval=1.45–22.23, P=0.00625). Moreover, among the 75 patients who did not develop hematotoxicity, there was a marginally overrepresentation of functional genetic polymorphisms of Rac1 (odds ratio=0.18, 95% confidence interval=0.02–1.49, P=0.079).

Conclusion This study constitutes the first report of a functional genetic polymorphism that could affect Rac1 expression and thus modulate the risk of adverse drug reaction in patients under thiopurine treatment. A larger scale (case–control) study should enable us to confirm or cancel these preliminary results.

Supplemental Digital Content is available in the article.

aEA4483, Faculty of Medicine, University Lille Nord de France

bDepartment of Gastroenterology, Hôpital Claude Huriez, CHRU, Lille, France

Correspondence to Dr Ingrid Billaut-Laden, Equipe d'accueil EA4483, Faculté de Médecine, Pôle Recherche, 1 place de Verdun, 59045 Lille Cedex, France Tel: +33 3 20 62 68 18; fax: +33 3 20 62 68 91; e-mail: ingrid.billaut@univ-lille2.fr

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.pharmacogeneticsandgenomics.com).

Received July 5, 2010

Accepted January 10, 2011

Copyright © 2011 Wolters Kluwer Health, Inc. All rights reserved.