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Could a gene mutation target drug dose?

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A tiny gene mutation in human liver cells could one day influence the dose of a drug needed by an individual patient, according to new research published in The Pharmacogenomics Journal (advance online publication, 13 April 2010).

Researchers from Ohio State University have identified the mutation and have shown that it alters the level of a protein in the liver responsible for processing between 45 and 60 per cent of drugs used to treat a variety of conditions. Each gene contains two alternative forms, or alleles, which in most people are identical.

However, in this study, the researchers found that expression of one allele differed from its partner allele in a single gene, a small difference known as a single nucleotide polymorphism (SNP). This particular SNP (intron 6 SNP rs35599367) affects the gene’s protein-producing process and reduces the level of one of the cytochrome P450 drug metabolising enzymes, CYP3A4.

Reduction in the level of this enzyme means that patients are likely to require smaller doses of the medicines metabolised by CYP3A4. However, higher doses of the same drugs could, of course, lead to toxicity in patients with this gene mutation.

In this study, 235 patients who were taking stable doses of various statins (atorvastatin, simvastatin or lovastatin) and who were carriers of the T allele required significantly lower statin doses than non-T carriers for optimal lipid control.

The researchers suggest their results indicate that intron 6 SNP rs35599367 markedly affects expression of CYP3A4 and could serve as a biomarker for predicting response to CYP3A4-metabolised drugs. Although previous research has shown that the levels of CYP3A4 in humans can vary widely and that those varying levels influence individual drug response and toxicity, studies to date on why this happens have been inconclusive.

The researchers note that using this SNP as a biomarker could eventually take the guesswork out of prescribing. This biomarker could also be applied to clinical trials for new drugs, they add.

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