Risk Assessment For Adverse Drug Reactions

Abstract

The present invention provides a method of predicting the risk of a patient for developing adverse drug reactions, particularly SJS or TEN. It was discovered that an HLA-B allele, HLA-B* 1502, is associated with SJS/TEN that is induced by a variety of drugs. The correlation with HLA-B* 1502 is most significant for carbamazepine-induced SJS/TEN, wherein all the patients tested have the HLA-B* 1502 allele. In addition, another HLA-B allele, HLA-B*5801, is particularly associated with SJS/TEN induced by allopurinol. Milder cutaneous reactions, such as maculopapular rash, erythema multiforme (EM), urticaria, and fixed drug eruption, are particularly associated with a third allele, HLA-B *4601. For any of the alleles, genetic markers (e.g., HLA markers, microsatellite, or single nucleotide polymorphism markers) located between DRB1 and HLA-A region of the specific HLA-B haplotype can also be used for the test.

1 - 19 . (canceled) 
     
     
         20 . A method of assessing a risk of a human patient for developing an adverse drug reaction in response to a drug, the method comprising
 detecting the presence of an HLA allele in a sample obtained from the patient, wherein the HLA allele is HLA-B*1502, HLA-B*5801, or HLA-B*4601; and   correlating the presence of the HLA allele in the sample with an increased risk for an adverse drug reaction (ADR) in the patient in response to a drug,   
     
     
         21 . The method of  claim 20 , wherein the drug is selected from the group consisting of carbamazepine, allopurinol, phenyloin, sulfasalazine, amoxicillin, ibuporfen and ketoprofen. 
     
     
         22 . The method of  claim 20 , wherein the adverse drug reaction is Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or a milder cutaneous ADR. 
     
     
         23 . The method of  claim 20 , wherein the drug is carbamazepine, the HLA allele is HLA-B*4601, and the ADR is a milder cutaneous ADR. 
     
     
         24 . The method of  claim 23 , wherein the milder cutaneous ADR is selected from the group consisting of maculopapular rash, erythema multiforme, urticaria and fixed drug eruption. 
     
     
         25 . The method of  claim 20 , wherein the presence of the HLA allele is determined by hybridization with an oligonucleotide that specifically hybridizes to the allele. 
     
     
         26 . The method of  claim 20 , wherein the sample obtained from the patient is a DNA sample. 
     
     
         27 . The method of  claim 26 , wherein the DNA sample is obtained from peripheral blood of the patient. 
     
     
         28 . The method of  claim 20 , wherein the sample obtained from the patient is a RNA sample, a protein sample, a cell sample, or a serum sample. 
     
     
         29 . The method of  claim 20 , wherein the presence of the HLA allele is determined by assaying for an equivalent genetic marker of the HLA allele, wherein the presence of the equivalent genetic marker is indicative of the presence of the HLA allele. 
     
     
         30 . The method of  claim 29 , wherein the equivalent genetic marker is selected from the group consisting of HLA-DRB1*1202, Cw*0801, Cw*0806, A*1101, MICA*019, A*3303, Cw*0302, DRB1*0301, and MICA*00201. 
     
     
         31 . A method for developing a therapy for an adverse reaction induced by a drug, the method comprising screening candidate medicines using an assay in which at least one HLA-B allele is a target, wherein the HLA-B allele is selected from the group consisting of HLA-B*1502, HLA-B*5801, and HLA-B*4601. 
     
     
         32 . The method of  claim 29 , wherein the adverse reaction is SJS, TEN, or a milder cutaneous ADR. 
     
     
         33 . The method of  claim 31 , wherein the drug is selected from the group consisting of carbamazepine, allopurinol, phenyloin, sulfasalazine, amoxicillin, ibuporfen and ketoprofen. 
     
     
         34 . The method of  claim 31 , wherein the assay includes providing a cell that expresses the HLA-B allele and determining whether a candidate drug binds to the HLA-B allele.