Seminars in Cerebrovascular Diseasesand Stroke Vol. 3 No. 1 2003 Pharmacogenetics in Cerebrovascular Disease KATRINA GWINN-HARDY Bethesda, Maryland ABSTRACT The principles of pharmacogenetics are a longstanding component of clinical practice, in which the physician chooses therapy based on the profile of the patient's historic and diagnostic features, to maximize benefit and minimize adverse events. However, the tools of modern molecular biology have allowed increased sophistication to be applied to the profiling of patients to optimize treatment. While these tools are not yet available to the practicing clinician, an awareness of the concepts on which they are based is of interest, as they are likely to become available and 'widely used in the future. Keywords: pharmacogenetics, genetics, stroke, risk factors. Although pharmacogenetics is the subject of consid- erable hype, the concepts underlying it are not new. For example, when a clinician considers treatment based on ethnicity or gender, family histo12r and/or allergies (all of which are influenced by genetic factors), he or she is using pharmacogenetic principles. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can lead to adverse drug reactions, has long been known to be more common in African and Mediterranean people than in those of northern European origin.1 Malignant hyperther- mia, 2 long QT syndrome 3 venous thromobembolic dis- ease, 4 and tardive dyskinesia 5 among many other exam- ples, have all been associated with underlying genetic risk factors. New tools such as DNA microarray tech- nology, 6 high-output screening systems, and advanced bioinformatics, when combined with the infrastructures of large simple clinical trials, will lead to a better under- standing of pharmacogenetics. Genetic causes of disease range from classic Mende- lian (a single gene leads to disease) to complex (multiple genes contribute to risk for disease in combination with other genetic and/or environmental factors). While rare, single gene disorders are important, in part because they From the National Institute of Neurological Disorders and Stroke, Bethesda, MD. Address reprint requests to Katrina Gwinn-Hardy, MD, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892. E-mail: gwinnk @ ninds.nih.gov. 9 2003 Elsevier Inc. All rights reserved. 1528-9931/03/0301-0008530.00/0 doi: 10.1053/scds.2003.00014 elucidate pathways leading to disease. 7 Pharmacogenetic studies, however, are based on common genes of lesser influence. One method of identifying genetic risk factors is the candidate gene association study, in which a given polymorphism in a gene of interest is compared between cases or controls; if the polymorphism is more common in affected subjects, a contribution to risk for disease is implied. A candidate gene is usually selected because the gene product is intuitively related to the disease process. Stroke Genetics and Pha rmacogenetics Many genetic influences on stroke and its risk factors have been established. 8 Single gene disorders that cause stroke include hemoglobinopathies, dyslipoproteinemias, and cardioembolic disorders. 9,1~ Family history of isch- emic stroke is a major risk factor for the disease.9,11 Ethnicity is also a risk factor; age-standardized mortality rates for stroke is higher among African Americans than Whites.12 Family history is an independent risk factor for subarachnoid hemorrhage (SAH). 13 Most clinicians sep- arate stroke into ischemic and hemorrhagic types as two broad categories (and those into subcategories), and one might surmise that such stratification would be important for gene discovery. The experience in stroke suggests the opposite; grouping all types of stroke together has been successful. A genome scan of 476 patients (from 179 extended Icelandic pedigrees) considered all types of - 43