BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.
BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.
Authors: Laura M Hodges; Svetlana M Markova; Leslie W Chinn; Jason M Gow; Deanna L Kroetz; Teri E Klein; Russ B Altman Journal: Pharmacogenet Genomics Date: 2011-03 Impact factor: 2.089