Polymorphisms clinical relevance

Nebert DW. Polymorphisms in drug-metabolizing enzymes what is their clinical relevance and why do they exist Am J Hum Genet 1997 60 265-271. 

McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukaemia 2000 14 567-572. 

Nebert, D.W., "Polymorphisms in Drug-Metabolizing Enzymes What is Their Clinical Relevance and Why Do They Exist ," Am. J. Hum. Genet., 60, 265-271 (1997). 

Goldstein, J.A. (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. British Journal of Clinical Pharmacology, 52, 349-355. 

Two more recent studies have also addressed SNP polymorphisms and potential links to clinically relevant conditions. " Given the role in inflammation and cytokine expression, one study examined the potential for linkage to autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease in a population of more than 2000 patients. No significant association was found with any of the SNPs. In contrast, a strong association was found between a single polymorphism (G-105A alteration in the promoter) and women with preeclampsia. " Women who had preeclampsia were 1.34 times more likely to carry this mutant allele. The role that this mutant plays in the condition is unknown. 

Uridine diphosphate glucuronosyltransferase, more specifically UGTIAI, is capable of glucuronidating bilirubin. The clinically relevant polymorphisms related to genetic abnormalities in the UGTIAI enzyme are those associated with familial... 

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

The clinical relevance of UGTIA polymorphisms to the anti-tumor activity of irinotecan was investigated in several reports. However, the results provide substantial inconsistencies among the studies performed under a variety of regimens. 

Evans, W.E. and Relling, M.V. (1999) Pharmacogenomics translating functional genomics into rational therapeutics. Science, 286, 487—4-91. Wijnen, P.A. et cd. (2007) Review article. The prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment. Pharmacol. Then, 26 (Suppl 2), 211-219. 

Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, Brockmoller J. Effect of genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs clinical relevance. Clin Pharmacokinet 2005 44(12) 1209-25. 

Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein) recent advances and clinical relevance. Clin Pharm Ther 2004 75 13-33. 

Drugs that are metabolized by polymorphic enzymes are often actively screened out of the drug development process. However, such action may be unnecessary when the clinical relevance of the polymorphism in relation to the drug is assessed more carefully. It is also important to realize that there is wide variation in the abundance of enzymes even within the same genotype, as shown in Fig. 16.3. 

Further in vitro/in vivo investigations are needed to assess the relationship between CYP2C8 (and CYP2C9) polymorphisms and drag metabolic clearance, in order to address the clinical relevance of CYP2C8 genotyping. 

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