NAT1 Genotypes Do not Predict Response to Mesalamine in Patients with Ulcerative Colitis

Zusammenfassung

Hintergrund: Die 5-Aminosalicylsäure (5-ASA) wird in der Darmmukosa von der N-Acetyltransferase 1 (NAT1) metabolisiert. Durch bekannte genetische Polymorphismen in diesem Enzym kommt es zu einer schnellen oder langsamen Acetylierung. Bei etwa 10 % der Patienten mit Colitis ulcerosa (CU) verursacht die Behandlung mit 5-ASA Nebenwirkungen. Wir haben daher die genetischen Variationen bei Patienten mit CU bestimmt und deren mögliche Assoziation mit dem klinischen Ansprechen auf 5-ASA untersucht. Methoden: Von 78 Patienten mit CU wurde DNA gewonnen. 77 % der Patienten befanden sich während der 5-ASA-Behandlung in Remission, 23 % litten an einem akuten Schub. Für 23 bekannte Allele wurde NAT1 mithilfe von RFLP-Untersuchungen und DANN-Sequenzierung genotypisiert. Retrospektiv wurde das dokumentierte klinische Ansprechen auf 5-ASA ermittelt und mit den NAT1-Genotypen korreliert. Ergebnisse: Mithilfe der PCR wurde eine 570-bp umfassende Region aus dem kodierenden Bereich und 240 bp aus der 3′-untranslatierten Region (UTR) des humanen NAT1-Gens amplifiziert. Dabei wurden die 4 bereits bekannten NAT1-Allele NAT1*3, *4, *10 und *11 gefunden. 31 % der Patienten waren heterozygot und 4 % homozygot für das NAT1*10-Allel. 6 % der Patienten waren heterozygot für das NAT1*3-Allel. 6 % waren heterozygot für das NAT1*11-Allel. Zwischen dem NAT1-Genotyp und dem klinischen Ansprechen beziehungsweise den Nebenwirkungen wurden keine Assoziationen gefunden. Schlussfolgerung: Die NAT1-Genotypen erlauben keine Vorhersage für das klinische Ansprechen von Patienten mit CU auf Mesalamin oder zu erwartende Nebenwirkungen. Das Ansprechen auf 5-ASA könnte daher auch durch nicht genomische Effekte beeinflusst werden.

Abstract

Background: 5- Aminosalicylic acid (5-ASA) is metabolised in colonic mucosa by N-acetyltransferase 1 (NAT1). Common genetic polymorphisms in this enzyme result in rapid or slow acetylation. 5-ASA treatment causes side effects in up to 10 % of patients with ulcerative colitis (UC). We therefore determined genetic variations of NAT1 in patients with UC and looked for a possible association with the clinical response to 5-ASA. Methods: DNA was obtained from 78 patients with UC. 77 % of the patients were in remission during 5-ASA treatment, whereas 23 % suffered from active disease. NAT1 genotyping was performed for 23 known alleles using RFLP and sequence analysis. Clinical response to 5-ASA was determined by medical record review and associated with NAT1 genotypes. Results: Utilising PCR we amplified a 570-bp coding region of the human NAT1 gene in addition to 240 bp in the 3′-untranslated region (UTR). 4 NAT1 alleles previously known as NAT1*3, *4, *10 and *11 were recovered. 31 % of the patients were heterozygous and 4 % homozygous for the NAT1*10 allele. 6 % were heterozygous for the NAT1*3 allele. 6 % were heterozygous for the NAT1*11 allele. No association was found between NAT1 genotype and clinical response as well as side effects to 5-ASA in patients with UC. Conclusions: NAT1 genotypes do not predict response or side effects to mesalamine in patients with UC. Variations caused by non-genomic effects may be associated with the clinical response to 5-ASA.

Colitis ulcerosa - Morbus Crohn - intestinale Komplikation

ulcerative colitis - Crohn’s disease - intestinal complications

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