Pharmacogenetic Testing in Drug-Induced Liver Injury
In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug-induced liver injury (DILI). In addition, a relatively small number of human leukocyte antigen (HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI.
Inter-individual variation in the human genome has long been considered to contribute to the differences in response to a medication and susceptibility to adverse drug reactions. During what is described as a 'candidate gene era', spanning the period of a decade from the early 1990s, many genes encoding functionally polymorphic drug metabolizing enzymes and drug transporters were first cloned. These advances triggered a number of carefully designed candidate gene studies including well characterized patients with hepatotoxicity and drug-exposed controls; these investigations in turn improved our understanding of pathogenic processes involved in the development of idiosyncratic drug-induced liver injury (DILI). As a result of the 'Human Genome Project', positions of millions of nucleotides that differ most commonly between individuals are now known. Genome-wide association studies (GWAS) have undoubtedly brought about a major step change in the methodological rigour of pharmacogenetic studies; although nearly 2000 GWAS have been listed currently by the National Human Genome Research Institute, a very small proportion of these have explored drug response and even fewer have investigated adverse drug reactions. In contrast to GWAS that have explored genetic variants in relation with complex traits, those investigating genetic susceptibility to hepatotoxicity have identified risk alleles with substantially stronger associations with DILI and higher risk ratios for susceptibility. Therefore, it is time to consider whether knowledge of one's genotype could be useful in stratifying patients to appropriate treatment ensuring optimal benefit-risk ratio and whether genetic tests can be used to improve the accuracy of clinical diagnosis, hence, facilitate management of individual patients care.
Abstract and Introduction
Abstract
In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug-induced liver injury (DILI). In addition, a relatively small number of human leukocyte antigen (HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI.
Introduction
Inter-individual variation in the human genome has long been considered to contribute to the differences in response to a medication and susceptibility to adverse drug reactions. During what is described as a 'candidate gene era', spanning the period of a decade from the early 1990s, many genes encoding functionally polymorphic drug metabolizing enzymes and drug transporters were first cloned. These advances triggered a number of carefully designed candidate gene studies including well characterized patients with hepatotoxicity and drug-exposed controls; these investigations in turn improved our understanding of pathogenic processes involved in the development of idiosyncratic drug-induced liver injury (DILI). As a result of the 'Human Genome Project', positions of millions of nucleotides that differ most commonly between individuals are now known. Genome-wide association studies (GWAS) have undoubtedly brought about a major step change in the methodological rigour of pharmacogenetic studies; although nearly 2000 GWAS have been listed currently by the National Human Genome Research Institute, a very small proportion of these have explored drug response and even fewer have investigated adverse drug reactions. In contrast to GWAS that have explored genetic variants in relation with complex traits, those investigating genetic susceptibility to hepatotoxicity have identified risk alleles with substantially stronger associations with DILI and higher risk ratios for susceptibility. Therefore, it is time to consider whether knowledge of one's genotype could be useful in stratifying patients to appropriate treatment ensuring optimal benefit-risk ratio and whether genetic tests can be used to improve the accuracy of clinical diagnosis, hence, facilitate management of individual patients care.
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