lunes, 11 de marzo de 2013

Genome-wide studies in pharmacogenomics: harnessing the power of extreme phenotypes, Pharmacogenomics, Future Medicine

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Genome-wide studies in pharmacogenomics: harnessing the power of extreme phenotypes, Pharmacogenomics, Future Medicine

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March 2013, Vol. 14, No. 4, Pages 337-339 , DOI 10.2217/pgs.13.35
(doi:10.2217/pgs.13.35)

Genome-wide studies in pharmacogenomics: harnessing the power of extreme phenotypes

David Gurwitz* & Howard L McLeod*
* Author for correspondence
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Four years ago this journal featured a theme issue on genome-wide association studies (GWAS) in pharmacogenomics. In our accompanying editorial we noted that “relatively few GWAS on drug response were so far published compared with the large numbers of disease risk GWAS” and called upon the pharmacogenomics research community to apply this powerful, hypothesis-free research approach for improving knowledge on drug safety and efficacy [1]. Our call seems to have been timely, as the past few years have witnessed an increase in pharmacogenomics-oriented genome-wide studies. Among PubMed-listed pharmacogenomics-related manuscripts, the fraction of those mentioning both ‘pharmacogenomics’ and ‘genome-wide’ as keywords have risen fourfold over the past few years, from 2.1% in 2006 to nearly 9% of total manuscripts published between 2009 and 2012 (Table 1). However, as in past years, only a tiny fraction (under 2%) of published genome-wide studies (in all areas) are concerned with pharmacogenomics (Table 1), a disappointingly low figure considering the huge societal burden of adverse drug events and ineffective therapeutics [2].
Some of the recent pharmacogenomic genome-wide studies yielded novel insights. The genome-wide studies by Ge et al. on IL28B polymorphisms and antihepatitis C drug response [3], Daly et al. on HLA-B*5701 and flucloxacillin-induced liver injury [4], Baldwin et al. on paclitaxel-induced sensory peripheral neuropathy [5], and Brown et al. on temozolomide-associated cytotoxicity [6] have advanced our understanding of DNA sequence variations and drug response, and several pharmacogenomic tests are on their way to clinical practice [7]. The studies on toxic drug reactions in particular have extra power compared with typical GWAS. For example, the study by Daly et al. on flucloxacillin-induced liver injury, an extreme and rare drug response phenotype, included only 51 affected individuals and 282 controls, yet it reported the unprecedented odds risk ratio of 80.6 (p = 8.7 × 10-33 for carriers of HLA-B*5701) [4], while typical GWAS odds risk ratios are below 2.

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