Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. Collectively, these mutations account for 11% of MH cases and identify the gene segment 6400-6700 as a mutation hot spot. Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype.
Drug treatment remains a mainstay of medicine. In some situations a drug unexpectedly has no effect, or unforeseen serious side effects occur. For the patient this represents a dangerous and potentially life-threatening situation. It certainly is a distressing experience for the doctor. At the societal level, adverse drug reactions represent a leading cause of disease and death. Genetic variation often underlies these unexpected situations. Pharmacogenetics is the term used about genetically determined variability in the metabolism of drugs. Pharmacogenomics usually refers to drug discovery based on knowledge of genes, but it is a discipline that offers insight into aetiologic mechanisms, and possible prevention and treatment. There is a trend towards a definition of pharmacogenomics that includes both pharmacogenetics and pharmacogenomics as defined above. Our article is an introduction to pharmacogenomics, using the broader definition. Biotechnological methods cannot be understood without a grasp of basic medical genetics, and we provide a brush-up on the fundamentals. We then outline pharmacogenetics, giving examples of genetically based variation in drug metabolising enzymes, drug receptors and drug transporting proteins. Modern biotechnology would be unthinkable without the aid of computers, and we briefly touch upon the field of bioinformatics. Finally, we give an overview of pharmacogenomics in the narrower sense. The rapidly growing field of pharmacogenomics is going to influence our everyday practice of medicine in the immediate future.
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