Candidate Gene Casecontrol Association Studies

Until recently, genetic polymorphisms in drug metabolism were typically described on the basis of phenotypic differences among individuals in a population. With recent advances in molecular sequencing technology, SNPs, especially in the regulatory or coding regions, are being discovered and are followed by biochemical studies assessing the phenotypic effects. Ultimately, clinical studies may allow the elucidation of polymorphisms in DME genes that have important consequences in patients. Such a framework may permit the elucidation of polymorphisms in DME that have more subtle, yet clinically important consequences for interindividual variability in drug response.

Population-based case-control studies with appropriately matched cases and controls are a widely used method for detecting genetic associations. The first step in designing a case-control study is to decide on the candidate gene or genes to be studied. The relevance of the candidate gene in the pathogenesis of the particular disease or ADR, and the functional effects of a particular polymorphism may indicate the importance of the association that is detected (128,129). With the availability of data from the human genome project, many studies now attempt to relate the phenotype to polymorphisms in multiple genes. The study of the genetic susceptibility to diclofenac-induced hepatotoxicity is an example where "both metabolic" and "immune" factors potentially involved in the development of liver injury have been investigated.

Diclofenac is a widely used nonsteroidal anti-inflammatory drug that can rarely cause potentially serious hepatotoxicity. Severe liver injury occurs in 3.6 per 100,000 users, and 8% of those who are jaundiced die of hepatic failure (130). Because of its common use, diclofenac hepatotoxicity has been one of the common causes of hepatic ADRs with 180 confirmed cases reported to Food and Drug Administration during the first three years of marketing in the United States (131). The major pathway of metabolism of diclofenac is through 4'-hydroxylation by CYP2C9 (Fig. 5) (132,133). Minor pathways include the formation of 5-hydroxydiclofenac catalyzed by a number of P450s, including CYP3A4, CYP2C8, CYP2C18, and CYP2C19 (134-136), and 3'-hydroxydiclofenac catalyzed by CYP2C9 (134). Both diclofenac and its metabolites undergo glucuronidation and sulfate conjugation, with acylglucuronide appearing to be the most common glucuronic acid conjugate. Conversion of diclofenac to diclofenac acylglucuronide is mediated by UGT2B7 (137). Diclofenac acylglucuronide can form adducts with hepatocellular proteins (138-140), resulting in immune-mediated destruction of hepatocytes (141). There is some in vitro evidence to suggest that 5-hydroxydiclofenac can also bind covalently, leading to the formation of protein adducts (135).

It has been hypothesized that susceptibility to diclofenac-induced hepatotoxicity may be genetically determined by factors affecting the amount of the reactive metabolite and, therefore, protein adduct formed and factors affecting the immune response to those adducts (142). Impaired 4'-hydroxylation or increased metabolism via the minor pathways of metabolism could lead to increased formation of the diclofenac reactive metabolites and hence, adduct formation. Polymorphisms in the CYP2C9 gene, which is responsible for the 4'-hydroxylation of diclofenac, have not been found to be a risk factor for the development of hepatic injury (143). A recent study has found an association between an upstream (C-161T) UGT2B7 polymorphism and diclofenac-induced liver injury (144). Preliminary results indicate that individuals carrying at least one variant -161T allele, which is associated with increased glucuronidation, are at ninefold increased risk of developing an adverse hepatic reaction to diclofenac (144). Therefore, formation of high levels of

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