Polymorphism, genetic

Enzyme levels and activities within the human population can vary considerably and many of the enzymes involved in the metabolism of xenobiotics are polymorphicaUy distributed in the human population. Genetic polymorphism (from Greek poly many , morph form ) is defined as the occurrence of at least two different alleles, with allele frequencies exceeding 1% at a particular locus. The allelic variants include point mutations as well as deletions and insertions and genetic polymorphism may cause an increase, a decrease, or no change in enzymatic activity. 

Genetic polymorphism may result in poor metabolizers (i.e., individuals who have only a limited or no capacity to metabolize a given chemical via a specific enzymatic pathway), and extensive metabolizers (i.e., individuals who have a sufficient capacity to metabolize a given chemical via a specific enzymatic pathway) and individuals of a particular group may therefore respond differently to exposure to chemicals. 

It should be noted that a large variation in metabolic capacity not necessarily corresponds to an equal variation in toxicity. 

There are many examples in the literamre showing a more than 10-fold variation in metabolic capacity depending on genetic polymorphism in the involved enzymes (Kalberlah and Schneider 1998). 

The glutathione S-transferases (GST) enzymes are dimeric enzymes that catalyze the conjugation of glutathione (GSH) to electrophilic xenobiotics in order to inactivate them and facilitate their 

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The genes for MHC molecules, unlike immunoglobulin genes, do not undergo rearrangements to create structural diversity. The Pzm light chain is invariant, but the class I MHC heavy chain is the most genetically polymorphic... 

Genetic polymorphism, due to two or more alleles in a gene leading to more than one phenotype with respect to biological target reactivity to drugs. 

Polymorphisms, in pharmacology, these are associated with genetic polymorphisms of biological targets (see Genetic polymorphisms). 

Based on their physiological function it is not surprising that genetic polymorphisms affecting expression and... 

Ikura M, Ames JB (2006) Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily two ways to promote multifunctionality. Proc Natl Acad Sci USA 103 1159-1164... 

As yet, no human diseases have been identified as a result of FATPl mutations. However, genetic polymorphisms in the human FATPl gene have been linked to dyslipidemia. An A/G exchange at position +48 in intron 8 of the FATPl gene has been shown to result in increased TG concentrations in female but not in male subjects. In a second study, the same polymorphism was linked to increased postprandial TG concentrations and smaller low density lipoprotein (LDL) particles. To date, it is still unknown if this polymorphism is associated with altered levels of FATPl expression and/or function. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

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... 

Some authors use the term mutation as a synonym for genetic polymorphism. However, it is recommended to reserve the term mutation for genetic variations acquired within the life span of an organism such as those mutations acquired in tumor tissues during multi-step carcinogenesis. 

There are only very few genes which do not carry any polymorphisms. And there exists even a significant number of polymorphic genes that are not expressed at all in part of the population due to genetic polymorphisms. Table 1 summarizes a few selected polymorphisms with their functional and medical impact. 

Pharmacogenetics. Table 1 Selected genetic polymorphisms and their medical impact... 

General Anaesthetics General Transcription Factors Genetic Polymorphism... 

One fascinating aspect of the effect of the genetic polymorphisms described earlier is that acculturation can partially overcome the protective factor, and Asian groups born in North America may have only partial protection (Goldman 1993 Tu and Israel 1995). In individuals who consume small amounts of alcohol over time, the aversive effects diminish, an effect similar to that described in clinical reports of patients who developed a resistance to the effects of disulfiram. 

Sun F, Tsuritani 1, Yamada Y Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men. Behav Genet 32 229—236, 2002... 

Falck GCM, Hirvonen A, Scarpato R, et al. 1999. Micronuclei in blood lymphocytes and genetic polymorphism for GSTMl, GSTTl and NAT2 in pesticide-exposed greenhouse workers. Mutat Res 441 225-237. 

Many are inhibited by various drugs or their metabolic products, providing another cause of drug interactions Some exhibit genetic polymorphisms, which can result in atypical drug metabolism... 

Singh KK, Hughes MD, Chen J, Spector SA (2005) Genetic polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4-I- lymphocyte count and HIV-1 RNA load. J Infect Dis 191 1971-1980... 

LAMPE J w, PETERSON s (2002) Brassica, biotransformation and cancer risk genetic polymorphisms alter the preventive effects of cruciferous vegetables. J Nutr. 132 2991-4. 

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. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

The basic biology of chemokines and their receptors is well covered in Chapters 2 and 3 of this book, and we will focus hereafter upon the roles of individual chemokines and receptors in atherosclerosis. The largest amount of data on the roles of chemokines in cardiovascular disease (C VD) has been obtained from in vitro studies and murine models, which will be discussed in detail. In man, genetic polymorphisms in chemokine and chemokine-receptor genes have pointed to an important role for specific chemokines in various atherosclerotic diseases including coronary artery disease and carotid artery occlusive disease. For properties see Table 1. 

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