Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population

So Yamada; Mila Tang; Kathryn Richardson; Julius Halaschek-Wiener; Matthew Chan; Victoria J. Cook; J. Mark Fitzgerald; R. Kevin Elwood; Angela Brooks-Wilson; Fawziah Marra

doi:10.2217/pgs.09.66

Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population

So Yamada, Mila Tang, Kathryn Richardson, Julius Halaschek-Wiener, Matthew Chan, Victoria J. Cook, J. Mark Fitzgerald, R. Kevin Elwood, Angela Brooks-Wilson, Fawziah Marra

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

Abstract

Aims: 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. Materials & 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. Conclusion: 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).

Original language	English
Pages (from-to)	1433-1445
Number of pages	13
Journal	Pharmacogenomics
Volume	10
Issue number	9
DOIs	https://doi.org/10.2217/pgs.09.66
Publication status	Published - 2009

Access to Document

10.2217/pgs.09.66

Cite this

@article{5ac336e57b714c19bbc69663e4a38dbf,

title = "Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population",

abstract = "Aims: 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. Materials & 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. Conclusion: 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).",

author = "So Yamada and Mila Tang and Kathryn Richardson and Julius Halaschek-Wiener and Matthew Chan and Cook, {Victoria J.} and Fitzgerald, {J. Mark} and Elwood, {R. Kevin} and Angela Brooks-Wilson and Fawziah Marra",

note = "A Corrigendum has been published for this article:: The CYP2E1 polymorphism studied was erroneously identified as CYP2E1*1C. This variant was actually the CYP2E1*5 polymorphism (rs2031920) that is detected by means of an RsaI PCR-RFLP. The authors would like to sincerely apologize for any inconvenience caused. [Corrigendum. (2010). Pharmacogenomics, 11(9), 1343. https://doi.org/10.2217/pgs.10.114].",

year = "2009",

doi = "10.2217/pgs.09.66",

language = "English",

volume = "10",

pages = "1433--1445",

journal = "Pharmacogenomics",

issn = "1744-8042",

publisher = "Future Medicine Ltd.",

number = "9",

}

TY - JOUR

T1 - Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population

AU - Yamada, So

AU - Tang, Mila

AU - Richardson, Kathryn

AU - Halaschek-Wiener, Julius

AU - Chan, Matthew

AU - Cook, Victoria J.

AU - Fitzgerald, J. Mark

AU - Elwood, R. Kevin

AU - Brooks-Wilson, Angela

AU - Marra, Fawziah

N1 - A Corrigendum has been published for this article:: The CYP2E1 polymorphism studied was erroneously identified as CYP2E1*1C. This variant was actually the CYP2E1*5 polymorphism (rs2031920) that is detected by means of an RsaI PCR-RFLP. The authors would like to sincerely apologize for any inconvenience caused. [Corrigendum. (2010). Pharmacogenomics, 11(9), 1343. https://doi.org/10.2217/pgs.10.114].

PY - 2009

Y1 - 2009

N2 - Aims: 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. Materials & 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. Conclusion: 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).

AB - Aims: 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. Materials & 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. Conclusion: 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).

U2 - 10.2217/pgs.09.66

DO - 10.2217/pgs.09.66

M3 - Article

SN - 1744-8042

VL - 10

SP - 1433

EP - 1445

JO - Pharmacogenomics

JF - Pharmacogenomics

IS - 9

ER -