Pharmacogenetics has without doubt become a primary field of research, with extensive involvement of both academic labs and industry. Pharmaceutical companies have invested heavily in genomics-era technologies, and many routinely include pharmacogenetics in their clinical studies (64). Some companies make strategic decisions to investigate pharmacogenetics in specific phases of drug development, but increasingly companies are electing to include pharmacogenetics in all phases of their clinical programs. In a typical clinical study conducted to support the development of a new drug, patients are asked if they would like to consent to participation in an exploratory pharmacogenetic substudy. Consent by patients to be included in this type of investigation is independent from their consent to participate in the trial overall. This is a critical point, as there is considerable unease in the general population about genetics and genetic discrimination (65-67). Following isolation of the subjects' DNA, associations are made between polymorphisms, which are usually SNPs but can be other types of variation as well, and clinical outcomes. The outcomes investigated could be a pharmacokinetic parameter (blood level of the drug), an efficacy measure, or the occurrence of an adverse event.
There are two general approaches to conducting a pharma-cogenetics study. The most common is the candidate gene approach, in which specific SNPs in specific genes are geno-typed and associated with clinical outcomes. Genes that are considered likely to have an impact on drug response are selected for genotyping of their polymorphic loci. Selection of genes is based on existing knowledge of the mechanism of action of the medication (the drug target as well as other genes in the target pathway) and genes that are known to determine the metabolism and distribution of the drug. Selection of SNPs is based on the impact of the polymorphism on gene function and the frequency of the SNP in the population of interest. There is an ever-expanding body of literature reporting associations between specific polymorphisms and drug response; these can guide the selection of polymorphisms to examine.
The advantage of the candidate gene approach is that it is cost-effective and amenable to high throughput. Analysis of associations between the clinical parameter of interest and the genotypes is manageable as well. The disadvantage is that it is somewhat of a "needle in a haystack" approach. When studying complex diseases in which many genes could influence drug response, it is easy to select the wrong candidate genes for study. The alternative approach is a whole-genome scan, in which SNPs are assayed systematically across the entire genome. There are significant disadvantages associated with this approach as well. Analysis of this data is much more laborintensive and most companies lack software to automate the process or reduce its complexity. In addition, whole-genome scans are very expensive. Because costs are prohibitive, whole-genome scans are the exception, not the rule, in drug development programs.
Another critical reason why a pharmacogenetic study might fail to find a genetic explanation for a clinical parameter is that alteration in the gene product (e.g., posttranslational modifications) might not be reflected at the gene level. Gene expression arrays (so-called "transcriptomics") and proteomics approaches are also being developed. Conventionally, studies of the entire transcriptome or proteome as they relate to drug effects are referred to as "pharmacogenomics" because they investigate drug effects in the context of the entire genome. "Pharmacogenetics," on the other hand, considers the effects of only a subset of genes on drug action. (Whole-genome scans can also be considered pharmacogenomics.) Application of techniques to profile the entire proteome or transcriptome in clinical drug development is limited by the fact that sample procurement must be minimally invasive. Usually, it is only reasonable to collect blood from study participants. Unless the drug target is a blood cell, gene expression in the blood is often not informative of events occurring in other tissues. Oncology studies are an important exception, because biopsies can be obtained and profiled more readily.
Was this article helpful?
Are You Prepared For Your First Baby? Endlessly Searching For Advice and Tips On What To Expect? Then You've Landed At The Right Place With All The Answers! Are you expecting? Is the time getting closer to giving birth to your first baby? So many mothers to be are completely unprepared for motherhood and the arrival of a little one, but stress not, we have all the answers you need!