Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma

Abstract

BackgroundN-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD.MethodsA case control study was performed with 729 Caucasian participants, 123 CRC, 201 CD, 167 UC, 15 IBD dysplasia/cancer and 223 controls. NAT1 and NAT2 genotyping were performed using Taqman based techniques. Eight single nucleotide polymorphisms (SNPs) were characterized for NAT1 and 7 SNPs for NAT2. Haplotype frequencies were estimated using an Expectation-Maximization (EM) method. Disease groups were compared to a control group for the frequencies at each individual SNP separately. The same groups were compared for the frequencies of NAT1 and NAT2 haplotypes and deduced NAT2 phenotypes.ResultsNo statistically significant differences were found for any comparison. Strong linkage disequilibrium was present among both the NAT1 SNPs and the NAT2 SNPs.ConclusionThis study did not demonstrate an association between NAT1 and NAT2 polymorphisms and IBD or sporadic CRC, although power calculations indicate this study had sufficient sample size to detect differences in frequency as small as 0.05 to 0.15 depending on SNP or haplotype.

Common polymorphisms in the microsomal epoxide hydrolase and N-acetyltransferase 2 genes in association with inflammatory bowel disease in the Danish population

“…and either UC or CD. The NAT2 slow frequency was approximately 55% in all groups of UC, CD and healthy controls, which is in agreement with another Caucasian study [28]. A study of a Japanese population showed an association between the NAT2*7B slow acetylator haplotype and CD, but no association was found between all NAT2 slow acetylator phenotypes and CD or UC [22].…”

Genetic Polymorphisms of CYP2D6 Oxidation in Patients with Inflammatory Bowel Disease

“…Patients with IBD have a higher risk of colorectal cancer than general population and are predisposed to this complication. This risk is related to the extent and duration of disease, but not disease activity [29,37,38]. The risk of malignant transformation is particularly high for patients having the disease for longer than 8 years for patients with UC affecting the entire colon.…”

“…The present results suggested that CYP2D6*1 allele and EM genotype may be involved in risk of inflammatory bowel disease. Mahid et al [38] reported that the continuous state of inflammation and repair in IBD may increase both the frequency and propagation of genetic mutations.…”

Influence of Polymorphic N-Acetyltransferases on Non-Malignant Spontaneous Disorders and on Response to Drugs

“…Ricart et al [41] reported 54.7% of rapid acetylators among 64 UC patients treated with sulphasalazine, a proportion similar to that found in the American population. A Chinese study [42] did not disclose any relationship of NAT2 genotype with susceptibility of IBD (mainly UC), neither did Mahid et al [43] in a study that included 167 UC, 201 CD patients and 223 controls. Two of these studies [41,43] also identified the NAT1 genotype, without finding any difference with controls.…”