Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population.
OBJECTIVE
TB is a serious global public health problem. Isoniazid, a key drug used to treat latent TB, can cause hepatotoxicity in some patients. This pilot study investigated the effects of genetic variation in NAT2 and CYP2E1 on isoniazid-induced hepatotoxicity in TB contacts in British Columbia, Canada.


METHODS
DNA re-sequencing was used to establish the spectrum of genetic variation in the exons, promoter and conserved regions of NAT2 in all subjects. For CYP2E1, the CYP2E1*1C polymorphism was genotyped by PCR-RFLP. Association tests of NAT2 variants and haplotypes, as well acetylator types were performed.


RESULTS
We enrolled 170 subjects on isoniazid treatment (23 cases and 147 controls). Systematic re-sequencing of NAT2 revealed 18 known and 10 novel variants.


CONCLUSIONS
No single genetic variant of NAT2 and CYP2E1 showed a significant association with isoniazid-induced hepatotoxicity in this highly heterogeneous population. There was evidence of a trend for increasing hepatotoxicity risk across the rapid, intermediate and slow acetylator groups (p = 0.08).
Yamada
So
S
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
Tang
Mila
M
Richardson
Kathryn
K
Halaschek-Wiener
Julius
J
Chan
Matthew
M
Cook
Victoria J
VJ
Fitzgerald
J Mark
JM
Elwood
R Kevin
RK
Brooks-Wilson
Angela
A
Marra
Fawziah
F
D000107:Acetylation; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001955:British Columbia / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010865:Pilot Projects; D012907:Smoking; D055815:Young Adult
D000995:Antitubercular Agents; D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid