Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity.
Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(-2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.
Yamada
S
S
Cancer Genetics, Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
Richardson
K
K
Tang
M
M
Halaschek-Wiener
J
J
Cook
V J
VJ
Fitzgerald
J M
JM
Elwood
K
K
Marra
F
F
Brooks-Wilson
A
A
D000328:Adult; D000368:Aged; D043182:Carboxylesterase / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects*; D055985:Latent Tuberculosis / Q000188:drug therapy; D015810:Linkage Disequilibrium; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
C121305:CES1P1 protein, human; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase; D007538:Isoniazid