Conference report--genomics: the promise of SNPs and bats highlights of the ABRF 2004--integrating technologies in proteomics and genomics; February 28-March 2, 2004; Portland, Oregon.
Year: 2004
Type: article
Abstract: We are all human, but we are not all identical.
Hardly a surprise to most, if not all, but a somehow puzzling fact when we consider how drugs are administered: In the vast majority of cases, for the same indication, adult patients receive the same doses of the same drug, with the same schedule. Corrections to the posology or the route of administration are undertaken if necessary (and feasible), according to age, concomitant treatments, and weight or in the presence of defects in liver or kidney function. Our genetic diversity, however, although suspected in determining variability in responses to drugs, is not taken into account. Not yet at least.
Things may, however, change in the future if more information is gained on the extent of heterogeneity of drug responses and meaningful correlations are found between specific haplotypes and patterns of response or toxicity. Estimates vary pretty widely, but from 20% up to 90% of the large population, differences seen in drug efficacy are being ascribed to genetic polymorphisms within populations. In other words, the presence of very small amino acid changes in a protein sequence, or changes in its level of expression, may significantly change the outcome of a drug treatment. Depending on which protein is being affected, drug uptake and transport, drug metabolism, or drug interaction(s) with the target may constitute the critical step.
If we recall that there are probably more than 1.4 million single-nucleotide polymorphisms (SNPs) in the human genome (60,000 of which occur in coding sequences), we have a fairly clear view of the extent of genetic variability that our species carries along and its potential effect on individual responses to treatment.
In light of the genetic variability estimated in humans, only very few correlations, although well-known, have been established (so far) between genetic polymorphisms and response to drug treatment. For example, as reviewed by Evans and McLeod,[1] single-nucleotide substitutions in the sequence of the multidrug-resistant-1 (MDR1) gene coding for a transmembrane receptor have been shown to significantly influence response to digoxin by influencing the intracellular concentrations of the available drug. Similarly, genetic variations in target receptors, such as the beta2-adrenergic receptor or the angiotensin-converting enzyme (ACE), have been shown to influence the efficacy of treatment with beta blockers or ACE inhibitors.
Besides interfering with metabolism, transport, or effector activity of a drug, genetic polymorphisms may also influence the occurrence and extent of drug-related toxicities, by preventing action of a protective element or inducing overexpression of a toxicity-enhancing factor. Clinical trials evaluate safety and efficacy in the majority of patients on study, but in a way, they may not capture those few individuals carrying clinically relevant mutations. Even if such patients are randomly included in a study, a lack of efficacy or unexpected toxicities may be recorded, but in most cases go unexplained for lack of biologic and genetic data.
A greater awareness of the potential necessity of more individually targeted therapies is, however, growing. In the oncology field, for example, the introduction of more biologically targeted therapies is mandating accurate and prospective testing of patients (eg, hormone receptors' expression in breast cancer patients or tyrosine kinase expression in solid tumors) as individual patients may differ in the expression of the drug targets. The next step might be the acquisition of more data on drug activity/toxicity and the patients' genetic background as well as better prediction of responder vs nonresponder phenotypes.
Genomics experts addressed these issues and the new discovery strategies being pursued at sessions held during the Association of Biomolecular Resource Facilities (ABRF) 2004 conference on Integrating Technologies in Proteomics and Genomics.
Source: PubMed
Author: Sara M Mariani
Institution: Medscape
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W313536763