Annual Meeting of the North American Society for Pediatric Gastroenterology and Nutrition; Orlando, October 22-24, 1998
NAT-1 GENE POLYMORPHISMS ARE FREQUENT AND ARE ASSOCIATED WITH VARIATION IN RESPONSE TO AMINOSALICYLATE THERAPY IN CHILDHOOD IBD
The N-acetyltransferase enzymes (NAT1 and NAT2) acetylate a variety of arylamine and hydrazine substrates, including xenobiotics which are believed to play a role in colon carcinogenesis. NAT1 is also responsible for the acetylation of 5-aminosalicylates (ASA) thus potentially affecting the therapeutic outcome and toxicity of these agents. Significant NAT1 activity has been identified in the mucosa of the ileum and colon. The NAT1 gene is polymorphic (more than 15 alleles identified) and individual NAT1 alleles are associated in vivo with both higher and lower NAT1 enzymatic activities. We hypothesized that NAT1 allelic variants would be associated with variability in the clinical response and adverse effects to ASA in patients with IBD. Buccal brushings were obtained from 25 pediatric and adolescent IBD patients (12 U.C.; 13 Crohns). NAT1 genotyping was performed by bi-directional cycle sequencing of PCR-amplified DNA from 2 highly polymorphic regions of the NAT1 gene: a 394 bp sequence in the 3′-UTR and a 380 bp sequence in the coding region, allowing identification of 11 of the reported alleles. Seven of the 25 patients sequenced (28%) were shown to carry NAT1 polymorphisms. Five (2 Crohns; 3 U.C.) were shown to have the NAT1 *4/*10 genotype, which is associated with increased NAT1 activity. Two patients carried the NAT1 *4/*11 genotype (both Crohns), associated with reduced NAT1 enzyme activity. Of the 5 patients who carried the NAT1 *4/*10 genotype, one was intolerant of ASA and one developed pancreatitis on ASA and 6-MP therapy. Of the 2 patients with the NAT1 *4/*11 genotype, both required aggressive immune suppression and surgery for control of disease. We conclude that variant NAT1 polymorphisms are common in the pediatric IBD population and may be associated with variation in clinical response to ASA therapy. Sequencing of a larger group of pediatric and adolescent IBD patients is in progress to further evaluate the effect of NAT1 polymorphic variation on clinical outcome. (Supported by the Nemours Foundation).
Abdominal Pain/IBD/Outcomes© 1998 Lippincott Williams & Wilkins, Inc.