Genetic factors associated with inhibitor development in hemophilia a

Abstract

The present invention provides methods for predicting the risk of an individual developing antibodies to factor VIII by identifying a single nucleotide polymorphism of an immune response or immune modifier gene. The invention further provides oligonucleotides, diagnostic kits, microarrays, and isolated nucleic acids comprising single nucleotide polymorphisms of immune response or immune modifier genes.

1 .- 88 . (canceled) 
     
     
         89 . A method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the method comprising the steps of:
 (a) detecting the identity of the nucleotide(s) corresponding to the genomic position(s) of one or more SNPs selected from the group consisting of rs12368829, rs4147385, and rs927335 in a biological sample from the individual; and   (b) predicting a decreased risk of the individual of developing antibodies to FVIII, if SNP rs12368829 is detected, or
 predicting an increased risk of the individual of developing antibodies to FVIII, if SNP rs4147385 or rs927335 is detected. 
   
     
     
         90 . The method of  claim 89 , wherein the individual is being treated by administration of FVIII. 
     
     
         91 . The method of  claim 89 , wherein the individual has received therapy comprising administration of FVIII. 
     
     
         92 . The method of  claim 89 , wherein the individual has not received therapy comprising administration of FVIII. 
     
     
         93 . The method of  claim 89 , wherein the individual has been diagnosed with mild Hemophilia. 
     
     
         94 . The method of  claim 89 , wherein the individual has been diagnosed with moderate Hemophilia. 
     
     
         95 . The method of  claim 89 , wherein the individual has been diagnosed with severe Hemophilia. 
     
     
         96 . The method of  claim 89 , further comprising assigning a therapy comprising administration of FVIII to said individual with the predicted decreased risk of developing antibodies against FVIII. 
     
     
         97 . The method of  claim 89 , further comprising not assigning a therapy comprising administration of FVIII to said individual with the predicted increased risk of developing antibodies against FVIII. 
     
     
         98 . The method of  claim 97 , further comprising assigning a therapy comprising administration of FVIII bypass therapy to said individual. 
     
     
         99 . The method of  claim 89 , wherein further comprising predicting an increased risk of the individual of developing antibodies to FVIII, if SNPs rs4147385 and r927335 are detected. 
     
     
         100 . The method of  claim 89 , wherein the step a) of detecting the identity comprises amplifying a nucleic acid present in the biological sample. 
     
     
         101 . The method of  claim 89 , wherein the step a) of detecting the identity comprises a method selected from the group consisting of a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay. 
     
     
         102 . The method of  claim 89 , wherein the step a) of detecting the identity comprises microarray hybridization. 
     
     
         103 . The method of  claim 89 , further comprising assigning a therapy comprising administration of a non-Factor VIII hemostatic agent to said individual with the predicted increased risk of developing antibodies against FVIII. 
     
     
         104 . The method of  claim 89 , further comprising assigning a therapy comprising adjusting a dosage and/or frequency of FVIII administration based on the predicted risk of developing antibodies against FVIII. 
     
     
         105 . The method of  claim 104 , wherein adjusting the dosage of FVIII comprises increasing the dosage and/or frequency of FVIII administered to said individual with the predicted decreased risk of developing antibodies against FVIII. 
     
     
         106 . The method of  claim 104 , wherein adjusting the dosage of FVIII comprises decreasing the dosage and/or frequency of FVIII administered to said individual with the predicted increased risk of developing antibodies against FVIII. 
     
     
         107 . The method of  claim 89 , further comprising assigning a therapy comprising adjusting a dosage and/or frequency of a non-Factor VIII hemostatic agent administration based on the predicted risk of developing antibodies against FVIII. 
     
     
         108 . The method of  claim 107 , wherein adjusting the dosage and/or frequency of a non-Factor VIII hemostatic agent comprises decreasing the dosage and/or frequency of a non-Factor VIII hemostatic agent administered to said individual with the predicted decreased risk of developing antibodies against FVIII. 
     
     
         109 . The method of  claim 107 , wherein adjusting the dosage and/or frequency of a non-Factor VIII hemostatic agent comprises increasing the dosage and/or frequency of a non-Factor VIII hemostatic agent administered to said individual with the predicted increased risk of developing antibodies against FVIII. 
     
     
         110 . A method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, wherein the individual is being treated by FVIII bypass therapy, the method comprising the steps of:
 (a) detecting the identity of the nucleotide(s) corresponding to the genomic position(s) of one or more SNPs selected from the group consisting of rs12368829, rs4147385, and rs927335 in a biological sample from the individual; and   (b) predicting a decreased risk of the individual of developing antibodies to FVIII, if SNP rs12368829 is detected, or
 predicting an increased risk of the individual of developing antibodies to FVIII, if SNP rs4147385 or rs927335 is detected. 
   
     
     
         111 . The method of  claim 110 , wherein further comprising predicting an increased risk of the individual of developing antibodies to FVIII, if SNPs rs4147385 and r927335 are detected. 
     
     
         112 . The method of  claim 110 , further comprising the step of assigning a therapy comprising FVIII therapy to said individual with the predicted decreased risk of developing antibodies against FVIII. 
     
     
         113 . The method of  claim 110 , further comprising the step of assigning a therapy comprising FVIII bypass therapy to said individual with the predicted increased risk of developing antibodies against FVIII. 
     
     
         114 . A method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, wherein the individual is being treated by administration of FVIII, the method comprising the steps of:
 (a) detecting the identity of the nucleotide(s) corresponding to the genomic position(s) of one or more SNPs selected from the group consisting of rs12368829, rs4147385, and rs927335 in a biological sample from the individual; and   (b) predicting a decreased risk of the individual of developing antibodies to FVIII, if SNP rs12368829 is detected, or
 predicting an increased risk of the individual of developing antibodies to FVIII, if SNP rs4147385 or rs927335 is detected. 
   
     
     
         115 . The method of  claim 114 , wherein further comprising predicting an increased risk of the individual of developing antibodies to FVIII, if SNPs rs4147385 and rs927335 are detected. 
     
     
         116 . The method of  claim 114 , further comprising the step of assigning a therapy comprising FVIII therapy to said individual with the predicted decreased risk of developing antibodies against FVIII. 
     
     
         117 . The method of  claim 114 , further comprising the step of assigning a therapy comprising FVIII bypass therapy to said individual with the predicted increased risk of developing antibodies against FVIII. 
     
     
         118 . A diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the kit comprising oligonucleotides capable being used to detect one or more SNPs selected from the group consisting of rs12368829, rs4147385, and rs927335. 
     
     
         119 . The diagnostic kit of  claim 118 , wherein the kit comprises at least one oligonucleotide capable of being used to detect SNP rs12368829. 
     
     
         120 . The diagnostic kit of  claim 118 , wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs4147385. 
     
     
         121 . The diagnostic kit of  claim 118 , wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs927335. 
     
     
         122 . The diagnostic kit of  claim 118 , wherein oligonucleotide flanks the position of the SNP in the genome. 
     
     
         123 . The diagnostic kit of  claim 118 , wherein oligonucleotide overlaps the position of the SNP in the genome. 
     
     
         124 . A microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the microarray comprising a support having a plurality of discrete regions each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of rs12368829, rs4147385, and rs927335. 
     
     
         125 . The microarray of  claim 124 , wherein the SNP is rs12368829. 
     
     
         126 . The microarray of  claim 124 , wherein the SNP is rs4147385. 
     
     
         127 . The microarray of according to  claim 124 , wherein the SNP is rs927335. 
     
     
         128 . The microarray according to  claim 124 , wherein the sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) includes a nucleotide corresponding to the position of the SNP in the genome.