One hope for personalized medicine is that individuals would have their major gene variations profiled and that drug interactions with critical genes would also be profiled. Thus, a person with a particular disease could determine whether a particular drug is efficacious given their gene variations, or whether that drug would be likely to produce an adverse reaction. Fulfilling this hope requires both profiling of gene variations present in individuals and pharmacogenetic studies of drugs, that is, analyses and clinical testing of how drugs behave in the presence of genetic variations. I have discussed individual profiling in the blog entry Individual DNA testing. It is starting to get off the ground but has a very long way to go. This blog posting is about progress/lack of progress in pharmacogenetic drug profiling.
My comments are mainly based on a review article that appeared in PloS ONE four days ago Fulfilling the Promise of Personalized Medicine? Systematic Review and Field Synopsis of Pharmacogenetic Studies. The authors looked systematically at the published literature in an attempt to determine the current state of pharmacogenetic knowledge. “From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25:1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40–222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of â‰¥4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.”
The state of progress appears to be underwhelming. The authors conclude “The high expectation but limited translation of the pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines.”
So, more or less the same thing can be said about the pharmacogenetic profiling aspect of the personalized medicine hope: It is starting to get off the ground but has a very long way to go. It is a long long way to Tipperary, to stem cell treatment and to drug-response related personalized medicine. At least, we are on our way.