Download genetic variation in isoniazid metabolism genes

PHARMACOGENETIC ANALYSIS OF AN ISONIAZID METABOLISM GENE,
N-ACETYLTRANSFERASE 2
So Yamada1, Mila Tang2, Suzanne Moadebi2, Julius Halaschek-Wiener1, J. Mark
Fitzgerald2, Kevin Elwood2, Fawziah Marra2* and Angela Brooks-Wilson1*
1
Genome Sciences Centre, British Columbia Cancer Agency and 2BC Centre for Disease
Control; Vancouver, BC, Canada; *These authors co-led the study
BACKGROUND: Pulmonary tuberculosis (TB) is among the most serious public
health problems in both developing and developed countries. Incidence rates are
increasing in high-risk populations within Canada. The current treatment of latent TB
generally includes the administration of isoniazid (INH), a drug known to cause
hepatotoxicity as a potentially serious side effect. INH-induced hepatotoxicity derives
from toxic metabolites produced during INH breakdown. Genetic polymorphisms in Nacetyltransferase 2 (NAT2), a core enzyme in INH metabolism, have been previously
established to play a significant role in the development of hepatotoxicity. The
phenotypic response to INH is partly but not entirely determined by the NAT2 genotype.
This investigation of the pharmacogenetic effect of NAT2 variants is part of a larger
study that will also address novel candidate genes for INH-induced hepatotoxicity.
OBJECTIVE: In this pilot study we analyze a group of 67 cases (who developed
hepatotoxicity upon INH treatment) and 111 controls (who did not develop
hepatotoxicity) to test for strong genetic effects of NAT2 genotype on the development of
toxicity in the Vancouver TB-exposed population. The specific aims of the study were to:
1) determine the spectrum of genetic variation in the NAT2 gene in cases and controls
and, 2) to determine whether genetic variants in NAT2 gene correlate with development
of hepatotoxicity in the local population.
METHODS: 178 patients treated for latent TB at the BC Centre for Disease Control TB
Clinic in 2004-05 were enrolled with informed consent. Drug-induced hepatotoxicity was
defined by standard criteria. Genomic DNA was isolated from patients’ peripheral
lymphocytes. All coding and non-coding exons as well as putative regulatory regions of
NAT2 were PCR amplified and bi-directionally sequenced in all participants.
RESULTS: To date, 5 of 8 amplicons of the NAT2 gene have been sequenced and 13
variants detected, 5 of which are exonic. Four of the 5 variants in the coding region
correspond to amino-acid substitutions and include variants known to encode slow
acetylator forms of NAT2. Four of the 8 variants in non-coding exons and putative
regulatory regions were previously unreported. Results of the association tests of these
variants and their haplotypes, with INH-induced hepatotoxicity, will be presented.