A genetic polymorphism

Essential to the definition of Pharmacogenetics is the term genetic polymorphism. It is extrapolated that there are at least three million genetic polymorphisms in the human genome. Historically, a genetic polymorphism was defined as a genetic variation with a population frequency of 1% and above, but the larger inter-ethnic variation of population frequencies makes a strict definition based on such frequencies impractical. The most common molecular type of polymorphism is the... 

Echeverria D, Woods JS, Heyer NJ, Rohhnan D, Farin FM, Li T, Garabedian CE. 2006. The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans. Neurotoxicol Teratol 28 39-48. 

Todesco, L. etal. (2003). Determination of-3858G->A and-164C->A genetic polymorphisms of CYP1A2 in blood and saliva by rapid allelic discrimination large difference in the prevalence of the -3858G->A mutation between Caucasians and Asians. Eur.. Clin. Pharmacol, 59, 343-6. 

Okuyama, Y., Ishiguro, H., Toru, M., and Aiinami, T. (1999) A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia. Biochem. Biophys. Res. Commun. 258, 292-295. 

Finley JC, O Leary M, Wester D, MacKenzie S, Shepard N, Farrow S, Lockette W. A genetic polymorphism of the alpha2-adrenergic receptor increases autonomic responses to stress. J Appl Physiol 2004 96(6) 2231-9. 

Kotler M, Barak P, Cohen H, et al (1999) Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity. Am J Med Genet 88 628-633... 

The marked interindividual variation in coumarin metabolism to 7-hydroxy-coumarin has led to studies to evaluate whether a genetic polymorphism exists in human CYP2A6. 

In addition to such in vitro studies, the metabolism of the drug can be assessed in individuals who are genetically deficient in a specific CYP enzyme, but this approach is obviously limited to those CYP enzymes that have a genetic polymorphism, such as CYP 2D6 and CYP 2C19 ( 35). Further confirmation can be obtained by coadministering a drug that is a known inhibitor of a specific CYP enzyme to determine whether such coadministration alters the clearance of the drug in question. 

It has been found, however, that the acetylation of certain compounds in man and in the rabbit shows wide interindividual variation. This variation in acetylation is a genetic polymorphism in NAT2 and shows a bimodal distribution with two phenotypes, known as rapid and slow acetylators. The slow acetylator has a mutation, which gives rise to a less active form of the enzyme. This is discussed in more detail in the next chapter. 

Pemble, S., Schroeder, K.R., Spencer, S.R., Meyer, D.J., Hallier, E., Bolt, H.M., Ketterer, B. Taylor, J.B. (1994) Human glutathione S-transferases theta (GSTTI) cDNA cloning and the characterization of a genetic polymorphism. Biochem. J., 300, 271-276... 

Taylor, J.B. (1994) Human glutathione -transferase theta (GSTTl) cDNA cloning and the characterization of a genetic polymorphism. Biochem. J., 300, 271-276... 

D.G. McCarver, R. Byun, R.N. Hines, M. Hicheme, W. Wegenek, A Genetic Polymorphism in the Regulatory Sequences on Human CYP2E1 Association with Increased Chloroxazone Hydroxylation in the Presence of Obesity and Ethanol Intake , Toxicol. Appl. Pharmacol., 152, 276-281 (1998). 

McCarver DG, Byun R, Hines RN, Hichme M, Wegenek W. A genetic polymorphism in the regulatory sequences of human CYP2E1 association with increased chlorzoxazone hydroxylation in the presence of obesity and ethanol intake. Toxicol Appl Pharmacol 1998 152 276-281. 

Meirhaeghe, A., Fajas, L., Helbecque, N., Cottel, D., Lebel, R, Dallongeville, J., Deeb, S., Auwerx, J., and Amouyel, R (1998). A Genetic Polymorphism of the Peroxisome Proliferator-Activated Receptor y Gene Influences Plasma Leptin Levels in Obese Humans. Hum. Mol. Genet. 7, 435-440. 

Femandez-Salguero P, Hoffman SM, Cholerton S, et al. A genetic polymorphism in coumarin 7-hydroxylation sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet 1995 57 651-660. 

This polymorphism, which was not related to the geographical origin of the infected fish hosts, is typical of a genetic polymorphism under the control of two co-dominant alleles. This type of balanced polymorphism indicates that cross-fertilisation must also occur, at least transiently, in L. intestinalis. The use of enzymes as markers in genetic studies in cestodes is clearly an important method for the detection of cross-fertilisation in this group. 

Individuals with the short form of the serotonin transporter have a poorer response to lithium (55). The short form of the serotonin transporter is a genetic polymorphism that increases the risk of depression in the setting of adversity (56,57,58) and reduces the likelihood of a response to antidepressant treatment, and is therefore associated with a poorer outcome (59,60,61,62). Similarly, a single nucleotide polymorphism (SNP) in the gene that encodes brain-derived neurotrophic factor (the val66met SNP of BDNF) has been associated with a poor response to lithium (63). This SNP is over-represented among patients with rapid cycling (64), who are less likely to respond well to lithium. 

ORNL used a factor of 10 for the uncertainty factor to protect susceptible subpopulations (UFh) because some individuals have a genetic polymorphism causing their serum-ChE activity to be abnormally low (Evans et al. 1952 Harris and Whittaker 1962). For homozygous individuals, the activity can be as low as 8-21% of the normal mean (Bonderman and Bonderman 1971). Genetic polymorphisms are also recognized for buty... 

The human paraoxonase-1 (PONl) is a 45kDa calcium-dependent enzyme bound to high-density lipoprotein (HDL) particles, in association with other apolipoproteins. PON 1 shows a genetic polymorphism the most prominent determines the Q192R allozyme, which can have a substantial impact on PONl activity against OPs and arylesters (Smo-len et al, 1991) (Table 70.1). The enzyme was shown to be involved in the protection against atherosclerosis (Shih... 

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