Risk assessment for phenytoin-induced adverse drug reactions

Abstract

A method of predicting the risk of a patient for developing phenytoin-induced adverse drug reactions (ADRs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reactions with eosinophilia and systemic symptoms (DRESS) is disclosed. Genetic polymorphisms of CYP2C genes (including rs1057910 (CYP2C9*3) and rs3758581 on CYP2C19), and HLA alleles (including HLA-B*1502, HLA-B*1301, and HLA-B*5101) can predict adverse reactions caused by phenytoin or fosphenytoin. Accordingly, the present invention provides a kit to assess the risk of a patient for developing adverse reactions in response to phenytoin-related drugs, which comprises the determination of the presence of a specific allele selected from the group consisting of rs1057910 (CYP2C9*3), rs3758581 on CYP2C19, HLA-B*1502, HLA-B*1301, and HLA-B*5101, wherein the presence of at least one allele is indicative of a risk for the adverse drug reactions.

What is claimed is: 
     
         1 . A method of assessing a risk of a human patient for developing an adverse reaction in response to a drug, comprising
 detecting the presence of a specific allele selected from a panel of CYP2C and HLA-B variants in a sample obtained from the patient, and   correlating the presence of the specific allele in the sample with an increased risk for an adverse reaction in the patient in response to the drugs, wherein the adverse reaction is Stevens-Johnson syndrome, toxic epidermal necrolysis or drug reactions with eosinophilia and systemic symptoms, and wherein the drug is selected from a group consisting of phenytoin or fosphenytoin.   
     
     
         2 . The method of  claim 1 , wherein detecting the presence of the specific allele is selected from a panel of variants comprising rs1057910 (CYP2C9*3), rs3758581, HLA-B*1301, and HLA-B*5101. 
     
     
         3 . The method of  claim 1 , wherein the specific allele is the equal variant of haplotypes or biological function of the rs1057910 (CYP2C9*3) or rs3758581 or HLA-B*1301 or HLA-B*5101. 
     
     
         4 . The method of  claim 1 , wherein either one, two, three, four variants or the combination proves the presence of a specific allele. 
     
     
         5 . The method of  claim 1 , wherein the presence of the allele is determined by using oligonucleotides that specifically hybridizes to the allele. 
     
     
         6 . The method of  claim 1 , wherein the sample obtained from the patient is a DNA sample or RNA or protein or cells or sera from peripheral blood or saliva or urine or hair of the patient. 
     
     
         7 . The method of  claim 1 , wherein the adverse drug reaction is Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reactions with eosinophilia and systemic symptoms. 
     
     
         8 . A kit of detecting a risk of a human patient for developing an adverse reaction in response to phenytoin or fosphenytoin, comprising:
 at least one oligonucleotide primer that hybridize to the risk genes and relevant regions and use of polymerase chain reaction(PCR) to amplify the specific fragment, an oligonucleotide probe that binds specifically to the allele.   
     
     
         9 . The kit of  claim 8 , wherein the kit preferably contains reagents for detecting the probe. 
     
     
         10 . The kit of  claim 8 , wherein there are two to eight oligonucleotide primers. 
     
     
         11 . The kit of  claim 8 , wherein the kits further comprise the PCR primers suitable for each and every allele. 
     
     
         12 . The kit of  claim 8 , wherein the kits further comprise tools and reagents for collecting biological samples from patients, as well as those for preparing genomic DNA, cDNA, RNA or the allele protein from the samples. 
     
     
         13 . The kit of  claim 8 , wherein the kits include PCR primers for amplifying the relevant regions and risk genes of the genomic DNA. 
     
     
         14 . The kit of  claim 8 , wherein detecting the presence of the specific allele selected from a panel of variants comprising CYP2C and HLA-B variants in a sample obtained from the patient, and correlating the presence of the specific allele in the sample with an increased risk for an adverse reaction in the patient in response to the drugs, wherein the adverse reaction is Stevens-Johnson syndrome, toxic epidermal necrolysis or drug reactions with eosinophilia and systemic symptoms. 
     
     
         15 . The kit of  claim 8 , wherein detecting the presence of the specific allele selected from a panel of variants comprising rs1057910 (CYP2C9*3), rs3758581, HLA-B*1301, and HLA-B*5101. 
     
     
         16 . The kit of  claim 8 , wherein the specific allele is the equal variant of haplotypes or biological function of the rs1057910 (CYP2C9*3) or rs3758581 or HLA-B*1301 or HLA-B*5101. 
     
     
         17 . The kit of  claim 8 , wherein either one, two, three, four variants or the combination proves the presence of a specific allele. 
     
     
         18 . The kit of  claim 8 , wherein the presence of the allele is determined by using oligonucleotides that specifically hybridizes to the allele. 
     
     
         19 . The kit of  claim 8 , wherein the sample obtained from the patient is a DNA sample or RNA or protein or cells or sera from peripheral blood or saliva or urine or hair of the patient. 
     
     
         20 . The kit of  claim 8 , wherein the adverse drug reaction is Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reactions with eosinophilia and systemic symptoms.