Genetic Basis for Adverse Drug Effects: Calcineurin Inhibitors
The calcineurin inhibitors—cyclosporine and tacrolimus—are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor–induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor–induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7–like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator–activated receptor γ gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate–binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor–induced diabetes. The genes encoding for the angiotensinconverting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor–induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor–related ADEs as well as for developing preventive strategies.
The United States Food and Drug Administration (FDA) is responsible for evaluating the safety profiles of drugs available to the American public. To achieve this goal, the FDA uses a variety of tools, processes, and disciplines. In relation to this mission, the FDA's Critical Path Initiative has a major focus on development and qualification of biomarkers that can predict both the benefits and risks of drug treatments.
Personalized medicine tailored to the genetic traits of individual patients and/or subgroups of patients offers the potential of stratifying a disease and/or optimizing the benefit:risk ratio of drug treatment by using biomarkers as diagnostic tests. A focus of personalized medicine is targeting patients who are most likely to benefit from a treatment regimen while avoiding those at risk for adverse drug effects (ADEs) by using DNA-based genomic biomarkers. To achieve the goal of reducing risk, genomic medicine must clarify the genetic association between drug use and serious or fatal ADEs. Some genetic risk factors associated with ADEs have been reported previously. Examples of drugs and genes for which this association has been made include diclofenac (uridine diphosphate glucuronosyltransferase gene, UGT1A6; cytochrome P450 [CYP] gene, CYP2C8; adenosine 5'-triphosphate [ATP]-binding cassette gene, ABCC2), tranilast (UGT1A1), isoniazid (CYP2E1; N-acetyltransferase 2 gene, NAT2), cerivastatin (CYP2C8; solute carrier organic anion transporter family member 1B1 gene, SLCO1B1), simvastatin (ABCB1), and atorvastatin (CYP3A5). These genes are involved in the pharmacokinetics of their respective drugs and are then logically related to dose- and/or concentration-related ADEs. Many other severe ADEs (e.g., hypersensitivity) are not related to the concentration of drug or metabolite, and the association of an ADE with a gene polymorphism in those cases may provide valuable insight into the prediction and prevention of ADEs.
Several drugs have been withdrawn from the market in the past due to severe or fatal ADEs that were not detected during clinical trials but that surfaced only after the drugs were used widely. The success of personalized medicine in drug development requires a more complete understanding of the pharmacogenomics of ADEs. Recently, technologies for candidate gene identification and genomewide scanning not only have identified some genes involved in ADEs, but also have mapped out possible gene-gene interactions contributing to ADEs. For example, the metabolic complications of hypertriglyceridemia caused by long-term β-blocker treatment are greater in those patients homozygous for the β2-adrenergic receptor gene ADRB2 Glu27 variant than those with the ADRB2 Gln27 allele (rs1799889). The former allele was previously associated with hypertriglyceridemia, which suggests that some common genes involved in the disease development may also be responsible for ADEs.
Our understanding of the genetic basis of ADEs is limited because the pathogenesis of ADEs is poorly understood and DNA samples are generally not available in large enough numbers. A good example of this situation is with the calcineurin inhibitors used as immunosuppressants in organ transplantation. Cyclosporine and tacrolimus bind to cyclophilin and FK-binding protein 12, respectively, resulting in inhibition of the phosphatase activity of calcineurin and preventing T-cell activation. The actions of these drugs unrelated to T cells produce acute and chronic nephrotoxicity, hypertension, and diabetes mellitus. Although these ADEs are shared by both agents, cyclosporine is prominently recognized for producing nephrotoxicity and hypertension, whereas tacrolimus clearly has a diabetogenic effect.
In this review, we compare examples of the genes involved in the development of renal failure, diabetes mellitus, and hypertension with the genetic risk factors for the ADEs of calcineurin inhibitors, thereby exploring the concept of deriving an understanding of genetic associations with ADEs from the genetic basis of disease development. In addition, we postulate how understanding the genetic basis of ADEs can optimize the success of drug development and personalized medicine, although this review is not meant to be an exhaustive list of all genes associated with these diseases.
Abstract and Introduction
Abstract
The calcineurin inhibitors—cyclosporine and tacrolimus—are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor–induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor–induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7–like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator–activated receptor γ gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate–binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor–induced diabetes. The genes encoding for the angiotensinconverting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor–induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor–related ADEs as well as for developing preventive strategies.
Introduction
The United States Food and Drug Administration (FDA) is responsible for evaluating the safety profiles of drugs available to the American public. To achieve this goal, the FDA uses a variety of tools, processes, and disciplines. In relation to this mission, the FDA's Critical Path Initiative has a major focus on development and qualification of biomarkers that can predict both the benefits and risks of drug treatments.
Personalized medicine tailored to the genetic traits of individual patients and/or subgroups of patients offers the potential of stratifying a disease and/or optimizing the benefit:risk ratio of drug treatment by using biomarkers as diagnostic tests. A focus of personalized medicine is targeting patients who are most likely to benefit from a treatment regimen while avoiding those at risk for adverse drug effects (ADEs) by using DNA-based genomic biomarkers. To achieve the goal of reducing risk, genomic medicine must clarify the genetic association between drug use and serious or fatal ADEs. Some genetic risk factors associated with ADEs have been reported previously. Examples of drugs and genes for which this association has been made include diclofenac (uridine diphosphate glucuronosyltransferase gene, UGT1A6; cytochrome P450 [CYP] gene, CYP2C8; adenosine 5'-triphosphate [ATP]-binding cassette gene, ABCC2), tranilast (UGT1A1), isoniazid (CYP2E1; N-acetyltransferase 2 gene, NAT2), cerivastatin (CYP2C8; solute carrier organic anion transporter family member 1B1 gene, SLCO1B1), simvastatin (ABCB1), and atorvastatin (CYP3A5). These genes are involved in the pharmacokinetics of their respective drugs and are then logically related to dose- and/or concentration-related ADEs. Many other severe ADEs (e.g., hypersensitivity) are not related to the concentration of drug or metabolite, and the association of an ADE with a gene polymorphism in those cases may provide valuable insight into the prediction and prevention of ADEs.
Several drugs have been withdrawn from the market in the past due to severe or fatal ADEs that were not detected during clinical trials but that surfaced only after the drugs were used widely. The success of personalized medicine in drug development requires a more complete understanding of the pharmacogenomics of ADEs. Recently, technologies for candidate gene identification and genomewide scanning not only have identified some genes involved in ADEs, but also have mapped out possible gene-gene interactions contributing to ADEs. For example, the metabolic complications of hypertriglyceridemia caused by long-term β-blocker treatment are greater in those patients homozygous for the β2-adrenergic receptor gene ADRB2 Glu27 variant than those with the ADRB2 Gln27 allele (rs1799889). The former allele was previously associated with hypertriglyceridemia, which suggests that some common genes involved in the disease development may also be responsible for ADEs.
Our understanding of the genetic basis of ADEs is limited because the pathogenesis of ADEs is poorly understood and DNA samples are generally not available in large enough numbers. A good example of this situation is with the calcineurin inhibitors used as immunosuppressants in organ transplantation. Cyclosporine and tacrolimus bind to cyclophilin and FK-binding protein 12, respectively, resulting in inhibition of the phosphatase activity of calcineurin and preventing T-cell activation. The actions of these drugs unrelated to T cells produce acute and chronic nephrotoxicity, hypertension, and diabetes mellitus. Although these ADEs are shared by both agents, cyclosporine is prominently recognized for producing nephrotoxicity and hypertension, whereas tacrolimus clearly has a diabetogenic effect.
In this review, we compare examples of the genes involved in the development of renal failure, diabetes mellitus, and hypertension with the genetic risk factors for the ADEs of calcineurin inhibitors, thereby exploring the concept of deriving an understanding of genetic associations with ADEs from the genetic basis of disease development. In addition, we postulate how understanding the genetic basis of ADEs can optimize the success of drug development and personalized medicine, although this review is not meant to be an exhaustive list of all genes associated with these diseases.
Source...