Cytochrome P450 (CYP450,2D6*A), N-Acetyltransferase-2 (NAT2*7, A) and Multidrug Resistance 1 (MDR1 3435 T) Alleles Collectively Increase Risk of Ulcerative Colitis

Background: Discovering the association between genetic variations of metabolizing enzymes with idiopathic diseases such as ulcerative colitis (UC) may not only be an auxiliary agent in diagnosis but also could be an effective pharmacotherapy for inflammatory bowel disease (IBD). The aim of the present case-control study was to determine the association of cytochrome P450 2D6 (CYP2D6 *4), N-acteyltransferase-2 (NAT2*7) and multidrug resistance 1 (MDR1) 3435 C/T genotypes with UC susceptibility and thiopurine methyltransferase (TPMT) enzyme activity. Methods: TPMT activity was measured by high performance liquid chromatography (HPLC) and genotypes for the 3 mentioned polymorphisms were determined in 215 unrelated UC patients and 212 unrelated healthy controls by polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) in a Kurdish population from Iran. Results: CYP2D6*4 A allele, NAT2*7 A and MDR1 3435 C/T alleles act synergistically to increase the risk of UC by 3.49 times. The frequency of the A allele of CYP2D6*4 was significantly higher in UC patients (12.6%) compared to control subjects (8.5%, P = 0.046) that significantly increased the risk of UC by 1.56-fold (P = 0.047). The frequencies of NAT2*7 genotypes and alleles were similar in both studied groups. Conclusion: The most important outcome of this study is that for the first time we demonstrated the simultaneous presence of TMDR1, A CYP2D6*4 and A NAT2*7 alleles robustly increased the risk of developing UC by 3.49-fold. The current study suggests that CYP2D6*4 and MDR1 3435 C/T gene polymorphisms may be risk factors for UC susceptibility.