TAILIEUCHUNG - Chapter 005. Principles of Clinical Pharmacology (Part 8)

Principles of Genetic Variation and Human Traits (See also Chaps. 62 and 64) Variants in the human genome resulting in variation in level of expression or function of molecules important for pharmacokinetics and pharmacodynamics are increasingly recognized. These may be mutations (very rare variants, often associated with disease) or polymorphisms, variants that are much more common in a population. Variants may occur at a single nucleotide [known as single nucleotide polymorphism (SNP)] or involve insertion or deletion of one or more nucleotides. They may be in the exons (coding regions) or introns (noncoding intervening sequences). Exonic polymorphisms may or. | Chapter 005. Principles of Clinical Pharmacology Part 8 Principles of Genetic Variation and Human Traits See also Chaps. 62 and 64 Variants in the human genome resulting in variation in level of expression or function of molecules important for pharmacokinetics and pharmacodynamics are increasingly recognized. These may be mutations very rare variants often associated with disease or polymorphisms variants that are much more common in a population. Variants may occur at a single nucleotide known as single nucleotide polymorphism SNP or involve insertion or deletion of one or more nucleotides. They may be in the exons coding regions or introns noncoding intervening sequences . Exonic polymorphisms may or may not alter the encoded protein and variant proteins may or may not display altered function. Similarly polymorphisms in intronic regions may or may not alter gene expression and protein level. As variation in the human genome is increasingly well documented associations are being described between polymorphisms and various traits including response to drug therapy . Some of these rely on well-developed chains of evidence including in vitro studies demonstrating variant protein function familial aggregation of the variant allele with the trait and association studies in large populations. In other cases the associations are less compelling. Identifying real associations is one challenge that must be overcome before the concept of genotyping to identify optimal drugs or dosages in individual patients prior to prescribing can be considered for widespread clinical practice. Nevertheless the appeal of using genomic information to guide therapy is considerable. Rates of drug efficacy and adverse effects often vary among ethnic groups. Many explanations for such differences are plausible genomic approaches have now established that functionally important variants determining differences in drug response often display differing distributions among ethnic groups. This .

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