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  Biallelic markers related to genes involved in drug metabolismUSPTO Application #: 20060040304Title: Biallelic markers related to genes involved in drug metabolism Abstract: The invention provides polynucleotides including biallelic markers derived from genes involved in the biotransformation of xenobiotics such as drugs and from genomic regions flanking those genes. Primers hybridizing to regions flanking these biallelic markers are also provided. This invention also provides polynucleotides and methods suitable for genotyping a nucleic acid containing sample for one or more biallelic markers of the invention. Further, the invention provides methods to detect a statistical correlation between a biallelic marker allele and a phenotype and/or between a biallelic marker haplotype and a phenotype. (end of abstract) Agent: Saliwanchik Lloyd & Saliwanchik A Professional Association - Gainesville, FL, US Inventors: Marta Blumenfeld, Ilya Chumakov, Lydie Bougueleret, Annick Cohen-Akenine USPTO Applicaton #: 20060040304 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20060040304. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10/294,934, filed Nov. 14, 2002, which is a divisional of U.S. application Ser. No. 09/671,317, filed Sep. 27, 2000, now U.S. Pat. No. 6,528,260, which is a continuation-in-part of U.S. patent application Ser. No. 09/536,178, filed Mar. 23, 2000 and a continuation-in-part of International Patent Application No. PCT/IB00/00403, filed Mar. 24, 2000, both of which claim priority to U.S. Provisional Patent Application Ser. No. 60/126,269, filed Mar. 25, 1999 and U.S. Provisional Patent Application Ser. No. 60/131,961, filed Apr. 30, 1999. All of the above applications are hereby incorporated herein in their entirety including any figures, tables, or drawings. [0002] The Sequence Listing for this application is on duplicate compact discs labeled "Copy 1" and "Copy 2." Copy 1 and Copy 2 each contain only one file named "SEQLIST4filing.TXT" which was created on Nov. 6, 2002, and is 990 KB. The entire contents of each of the computer discs are incorporated herein by reference in their entireties. FIELD OF THE INVENTION [0003] The present invention is in the field of pharmacogenomics, and is primarily directed to biallelic markers that are located in or in the vicinity of genes, which have an impact on the metabolism of xenobiotics such as drugs and the uses of these markers. The present invention encompasses methods of establishing associations between these markers and a phenotype such as drug response, toxicity and susceptibility to disease. The present invention also provides means to determine the genetic predisposition of individuals to such drug responses, toxicity and diseases. BACKGROUND OF THE INVENTION [0004] To assess the origins of individual variations in drug response, pharmacogenomics uses the genomics technologies to identify polymorphisms within genes associated with drug response. In this respect, there are three main categories of genes that may theoretically be expected to be associated with drug response, namely genes linked with the targeted disease, genes related to the drug's mode of action and genes involved in the drug's metabolism. Among these genes of pharmacogenomic importance, genes coding for drug-metabolizing enzymes have a central role. Drug Metabolism [0005] Drug-metabolizing enzymes are important determinants of drug disposition, safety and efficacy. The enzyme systems involved in the metabolism and the subsequent elimination from the body of environmental chemicals, food toxins and drugs are mainly localized in the liver, although every tissue examined has some metabolic activity. [0006] In order to produce its characteristic effects, a given drug must be present in appropriate concentrations at its sites of action. The absorption, distribution, biotransformation and excretion of a drug all involve its passage across cell membranes. The lipophilic characteristics of drugs that promote their passage through biological membranes and subsequent access to their site of action reduce their elimination from the body. Renal excretion of unchanged drug plays only a modest role in the overall elimination of most therapeutic agents, since lipophilic compounds filtered through the glomerulus are largely reabsorbed through the tubular membranes. Biotransformation of drugs into more hydrophilic metabolites plays a major role in the termination of their biological activity and their elimination from the body. In general, biotransformation reactions generate more polar, inactive metabolites that are readily excreted from the body. However in some cases, metabolites with potent biological activity or toxic properties are generated and may result in adverse side effects. Metabolic biotransformation of drugs can be classified as either Phase I functionalization reactions or Phase II biosynthetic reactions. Phase I reactions introduce or expose a functional group on the parent compound, and generally result in the loss of pharmacological activity although there are some examples of retention or enhancement of activity. Phase II conjugation reactions lead to the formation of a covalent linkage between a functional group on the parent compound with glucuronic acid, sulfate, glutathione, amino acids or acetate. These highly polar conjugates are generally inactive and are excreted rapidly in the urine and feces. Within a given cell, most drug metabolizing Phase I enzymes are located primarily in the endoplasmic reticulum, while the Phase II conjugation enzyme systems are mainly cytosolic. In some cases, drugs biotransformed through a Phase I reaction in the endoplasmic reticulum are further metabolized by conjugation in the cytosolic fraction of the same cell (Hardman J. G., Goodman, Gilman A., Limbird L. E.; Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9.sup.th edition, McGraw-Hill, N.Y., 1996). Enzymes Involved in the Biotransformation of Xenobiotics [0007] Besides being involved in the biotransformation of drugs, drug-metabolizing enzymes are also involved in the metabolism of xenobiotics (foreign compounds) as well as in the metabolism of endogenous compounds including steroids, vitamins and fatty acids. Foreign compounds include therapeutic agents, carcinogens, plant metabolites, environmental pollutants, foodstuffs and other dietary components as well as industrial chemicals. The biotransformation of foreign compounds (xenobiotics) is often regarded as detoxification because it usually converts compounds into more water-soluble, readily excreted substances. This tends to decrease the exposure of the organism to the compound and therefore tends to decrease toxicity. However, in some cases the reverse occurs and a metabolite is produced which is more toxic than the parent compound. For example, drug-metabolizing enzymes may activate some carcinogens, and interindividual differences in cancer susceptibilities, have been linked to polymorphisms in drug-metabolizing enzymes. There are many factors, which affect biotransformation and toxicity, such as the dose, availability of cofactors and the relative activity of the various drug-metabolizing enzymes. There may also be several competing pathways of metabolism--some leading to detoxification others to toxicity. Factors, such as genetic factors or environmental factors, which influence the balance between these competing pathways, will also determine the eventual toxicity. [0008] As mentioned above, the metabolic conversion of drugs and other xenobiotics is enzymatic in nature. The enzyme systems involved in the biotransformation of drugs are localized in the liver, although every tissue examined has some metabolic activity. Other organs with significant metabolic capacity include the kidneys, gastrointestinal tract, skin and lungs. Following non-parenteral administration of a drug, a significant portion of the dose may be metabolically inactivated in either the liver or intestines before it reaches the systemic circulation. This first-pass metabolism significantly limits the oral availability of highly metabolized drugs. Cytochrome P450 [0009] The cytochrome P450 enzyme family is the major catalyst of biotransformation reactions. Since its origin, the cytochrome P450 gene family has diversified to accommodate the metabolism of a growing number of environmental chemicals, food toxins and drugs. The resulting superfamily of enzymes catalyzes a wide variety of oxidative and reductive reactions and has activity towards a chemically diverse group of substrates. Cytochrome P450 enzymes are heme-containing membrane proteins localized in the smooth endoplasmic reticulum of numerous tissues. Oxidative reactions catalyzed by the microsomal monooxygenase system require the cytochrome P450 hemoprotein, NADPH-cytochrome P450 reductase, NADPH, and molecular oxygen. Oxidative biotransformations catalyzed by cytochrome P450 monooxygenases include aromatic and side chain hydroxylation, N-, O-, S-dealkylation, N-oxidation, sulfoxidation, N-hydroxylation, deamination, dehalogenation, and desulfuration. Cytochrome P450 enzymes also catalyze a number of reductive reactions, generally under conditions of low oxygen tension. The only common structural feature of the diverse group of xenobiotics oxidized by cytochrome P450 enzymes is their high lipid solubility. [0010] Twelve cytochrome P450 gene families have been identified in human beings, and a number of distinct cytochrome P450 enzymes often exist within a single cell. The cytochrome P450 1, 2 and 3 families (CYP1, CYP2, CYP3) encode the enzymes involved in the majority of all drug biotransformations, while the gene products of the remaining cytochrome P450 families are important in the metabolism of endogenous compounds such as steroids and fatty acids. CYP1 A2 gene expression may play an important role in individual risk of environmental toxicity or cancer. CYP1A2 substrates include clinically important drugs such as imipramine, propranolol, paracetamol, clozapine, theophyline, caffeine and acetaminophen. CYP1A2 is also involved in the conversion of heterocyclic amines and arylamines to their proximal carcinogenic and mutagenic forms, as well as in the metabolism of endogenous substances including estradiol and uroporphyrinogen III. Interindividual differences in susceptibility to arylamine- and heterocyclicamine-induced cancers have been linked to CYP1A2 polymorphism. CYP2C8 appears to be responsible for retinol and retinoic acid metabolism and actively catalyzes benzphetamine N-demethylation. CYP2C9 catalyzes the hydroxylation of tolbutamide, a hypoglycemic agent used in the treatment of type II diabetes mellitus, and one allelic variant of CYP2C9 accounts for the occurrence of poor metabolizers of tolbutamide. CYP2C9 may also have an important role in terminating the anti-coagulant activity of warfarin. Widespread interindividual differences in the response to warfarin have been recognized. Such variability is particularly important for drugs such as warfarin which have narrow therapeutic indices (Steward D. J. et al., Pharmacogenetics, 7:361-367, 1997). CYP2C9 is further involved in the oxidation of tielinic acid and several non-steroidal anti-inflammatory agents. The oxidative metabolism through CYP2C9 of tilenic acid can result in the emergence of a drug induced autoimmune hepatitis. CYP3A4 is involved in the biotransformation of a majority of drugs and is expressed at significant levels extrahepatically. It is now recognized that extensive metabolism by CYP3A4 in the gastrointestinal tract is a significant factor contributing to the poor oral availability of many drugs (first-pass metabolism). Barbiturates, certain steroids and macrolide antibiotics can induce this enzyme. It appears to play a central role in the metabolism of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin. Flavin-Containing Monooxygenases (FMOS) [0011] The mammalian flavin-containing monooxygenases (FMOs) are microsomal enzymes that catalyze the NADPH-dependent oxygenation of a wide variety of drugs and other xenobiotics that possess a soft nucleophilic heteroatom, typically a nitrogen, sulfur, phosphorus or selenium atom. Of special clinical interest is the oxidation of trimethylamine in the liver by the FMO, because its deficiency causes the "Fish Odor Syndrome." Drugs oxidized by FMOs include, among others, antidepressant, antipsychotic-neuroleptic, antihypertensive drugs. FMOs have been implicated in the detoxification but also in the metabolic activation of several different environmental toxins and carcinogens. [0012] Unlike all other known oxidases and monooxygenases, among which the well-studied cytochrome P450 monooxygenases, FMOs have the unique property of forming a stable enzyme intermediate in the absence of an oxygenatable substrate. Because the energy for catalysis is already present in the FMO enzyme before contact with the potential substrate, the fit of the substrate does not need to be as stringent as with the other enzymes. This feature, unique to FMOs among monooxygenases, is responsible for the wide range of substrates accepted by FMOs (including tertiary and secondary alkyl- and arylamines, many hydrazines, thiocarbamides, thioamides, sulfides, disulfides, thiols, among others), and determines that any soft nucleophilic xenobiotic accessible to the active enzyme will probably be oxidized by FMO in vivo. Although some FMO substrates are oxidized to less active derivatives, several soft nucleophiles are metabolized to highly reactive and potentially toxic intermediates. [0013] The FMOs represent a multigene family. Five distinct mammalian FMO isoenzymes have been identified and cloned from various animal and human tissues: FMO1, FMO2, FMO3, FMO4 and FMO5. Human FMO2 and human FMOX were cloned and sequenced by the inventors as described in PCT Publication WO 9824914. FMOX represents a new member of the FMO gene family not previously identified in mammals. Tissue specificity and activities of the different FMOs have been thoroughly characterized. FMO1 is known to be expressed in the human kidney but is absent from the liver. In man the enzyme is subject to developmental regulation. FMO2 is predominantly expressed in lung of all mammalian species tested. FMO3 was isolated from human liver, and accounts for the majority of FMO expressed in adult human liver. [0014] Many of the FMO substrates may also be oxidized by the cytochrome P450 monooxygenases. However, the final oxidation products are usually different, and the nitrogen of a specific compound is rarely N-oxygenated by both types of monooxygenases. Today, a large number of drugs in human clinical trials contain a nitrogen, sulfur, phosphorous or some other nucleophilic functionality. Of the two major monooxygenase systems considered to be responsible for heteroatom-containing chemical and drug oxidative metabolism (CYP 450 and FMO), relatively little is known concerning the role of the FMO in human drug metabolism. Yet, given the wide range of substrates potentially oxidized by FMOs, this class of monooxygenases seems to represent a major determinant of drug safety and efficacy. Uridine Diphosphite Glucoronosyl Transferase (UGTS) [0015] Glucoronidation is a major detoxification pathway of Phase II metabolism that is catalyzed by the UDP-glucuronosyl transferase family of enzymes. Glucuronidation is quantitatively the most important conjugation reaction. Members of this enzyme family catalyze the conjugation of numerous endogenous substances of widely differing structures such as bilirubin, steroid hormones and fat-soluble vitamins. In general, xenobiotics become substrates for glucoronidation by first passing through Phase I metabolism, but many compounds do not require this step because they already possess reactive functionalities (e.g. hydroxyl, carboxyl, amino, sulfhydryl etc.) that are direct targets for glucuronosyl transferase. The human UGT genes appear to have evolved by a series of gene-duplication and gene-conversion events resulting in the emergence of a diversity of isoforms. They are divided into two families, UGT1 which is known to have bilirubin and phenol as substrates, and UGT2 which is known to have steroid, bile, and odorant as substrates, with these two families located on different chromosomes. The UGT2 family is divided into subfamilies UGT2A and UGT2B. The UGTs have different but sometimes overlapping substrate specificities. They catalyze the transfer of an activated glucuronic acid molecule to aromatic and aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups of both exogenous and endogenous compounds, to form O-- N-- and S-glucuronide conjugates. The increased water solubility of the glucuronide conjugates promotes their elimination in the urine or bile. In addition to high levels of expression in the liver, UGTs are also found in the kidney, intestine, brain and skin. Glucoronidation constitutes, from a general point of view, a reaction of detoxification and elimination. It generally leads to the formation of inactive metabolites and therefore, glucoronidation can dramatically modify the pharmacological activity of a drug. Moreover, UGTs play a major role in the elimination of nucleophilic metabolites of carcinogens, such as phenols and quinols of polycyclic aromatic hydrocarbons. In this way they prevent their further oxidation to electrophiles, which may react with DNA, RNA or protein. On the other hand, glucoronidation of certain compounds facilitates metabolic activation. Aromatic amines are some of the most studied examples of the role glucoronidation plays in metabolic activation of carcinogens. Glucoronidation has also been implicated in adverse drug reactions of certain carboxylic drugs, which resulted in a toxic immunological response. Glucoronidation although generally a detoxification reaction, may occasionally be involved in increasing toxicity. Glutathione Conjugation and Further Metabolism Continue reading... Full patent description for Biallelic markers related to genes involved in drug metabolism Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Biallelic markers related to genes involved in drug metabolism patent application. 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