Wednesday, December 16, 2009

Drug-induced hearing loss: new SNPs in old genes

Drug-induced ototoxicity is known and well documented. Merck manual  lists several antibiotics (streptomycin, neomycin, vancomycin), chemotherapeutic drugs (such as cisplatin), diuretics (like ethacrynic acid and furosemide), Quinine and Salicylates among the prime suspects.

The impact of these drugs on individuals depends on their genetic makeup.

Here is a new addition to the collection of genes associated with hearing loss caused by gene-environment-interaction:  Genetic variants in TPMT and COMT have been found to affect hearing of children receiving cisplatin chemotherapy (Ross et al., 2009)

220 drug-metabolism genes are suspected to be responsible for genetic susceptibility to cisplatin-induced hearing loss in children. Metabolism genes such as Glutathione S-transferases and megalin were previously studied. Genotyping of 1,949 SNPs in these candidate genes in an initial cohort of 54 children lead to  identification of new genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3–125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9–15.9.

What do we know about these genes?

TPMT is aS-adenosyl methionine-dependent methyltransferase that converts 6TI to 6MMPr. Its sequence is conserved in human, chimpanzee, dog, cow, rat, chicken, and zebrafish.  Hard to say how our ancestors were exposed to this compounds, but as thiopurines are known inhibitors of de novo purine synthesis and cellular proliferation, it makes sense to have ways to deal with this molecule.

The enzyme is mostly known because it metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct. Accordingly, genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to drugs such as 6-mercaptopurine within individuals. A pseudogene for this locus is located on chromosome 18q

COMT is a Catechol-O-methyltransferase that catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines - chemicals produced in the medulla of the adrenal gland. COMT is also known for its role in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease.
Location: 22q11.21-q11.23|22q11.21

Now that we know, what can we do with the new SNP information?

Perhaps, investigate cost-effectiveness of genotyping for ototoxycity implications - clinical trial  NCT00521950 is already doing it for Inflammatory Bowel Diseases. 

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