Toxicogenomics

Our Genomes: The Important 0.1%

An important finding that emerged from the Human Genome Project is that all individuals are at least 99.9% identical at the DNA level. The remaining 0.1%, which represents interindividual differences that are thought to explain why some individuals are more susceptible to specific diseases or adverse effects to medication, is perhaps the most compelling part of the genome. Up to 10 million such interindividual differences, known as single nucleotide polymorphisms (or SNPs), are estimated to exist among the approximately 3.2 billion base pairs comprising the human genome, and this corresponds to approximately one SNP for every 100 to 1,000 base pairs.

An individual SNP can lead to several potential outcomes. Sometimes, it might not have an impact at all. On other occasions, it may introduce a mutation and generate a less functional protein. If the protein participates in the metabolic degradation of a drug, its decreased activity could result in the delayed inactivation and increased circulatory concentration of the drug and can be responsible for adverse effects during treatment. Alternatively, a SNP may generate a protein with increased activity that subsequently will metabolize a therapeutic compound at higher rates, leading to its shorter persistence in the organism and, possibly, failure to achieve the expected therapeutic effect.

Interindividual genomic variations are increasingly linked to differences in the response to medications and chemicals. For example, specific SNPs are associated with an increased likelihood of diarrhea among patients administered irinotecan, a chemotherapy drug mainly used to treat colon cancer. Similarly, differences in DNA repair genes were linked to benzene-induced toxicity and could become important predictive tools while monitoring exposure. Another occupational disorder, chronic beryllium disease, develops in certain individuals exposed to this metal but not in others and was also documented as a result of secondary exposure in some family members who come in contact with beryllium dust from clothing. Several polymorphisms appear to influence susceptibility to this chronic condition, which causes scarring in the lungs and can lead to several complications, including lung cancer and heart disease.

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