US2010240541A1PendingUtilityA1

Genetic markers for prognosis of antifolate treatment efficacy

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Assignee: ACADEMISCH ZEIKENHUIS LEIDEN HPriority: Apr 10, 2006Filed: Mar 29, 2010Published: Sep 23, 2010
Est. expiryApr 10, 2026(expired)· nominal 20-yr term from priority
Inventors:Hendrik Jan GuchelaarTom Willem Johannes Huizinga
C12Q 2600/156C12Q 2600/106C12Q 1/6883
46
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Claims

Abstract

Methods and kits for predicting the efficacy of antifolate (e.g., methotrexate) treatment of rheumatoid arthritis by detecting polymorphisms, particularly single nucleotide polymorphisms, in adenosine pathway genes.

Claims

exact text as granted — not AI-modified
1 . A method for determining clinical responsiveness to antifolate therapy in a mammal afflicted with, or at risk of developing, rheumatoid arthritis comprising detecting the presence of a polymorphism in the adenosine monophosphate deaminase (AMPD1) gene, wherein the presence of said polymorphism is indicative of clinical responsiveness to said antifolate therapy. 
     
     
         2 . A method for determining clinical responsiveness to antifolate therapy in a mammal afflicted with, or at risk of developing, rheumatoid arthritis comprising detecting the presence of a polymorphism in the inosine triphosphate pyrophosphatase (ITPA) gene, wherein the presence of said polymorphism is indicative of clinical responsiveness to said antifolate therapy. 
     
     
         3 . The method according to  claim 1  or  2 , wherein said antifolate is methotrexate. 
     
     
         4 . The method according to  claim 1  or  2 , wherein said polymorphism is a single nucleotide polymorphism. 
     
     
         5 . The method according to  claim 4 , wherein said single nucleotide polymorphism is 34C>T. 
     
     
         6 . The method according to  claim 4 , wherein said single nucleotide polymorphism is 94A>C. 
     
     
         7 . A method for determining clinical responsiveness to antifolate therapy in a mammal at risk of developing, or suffering from, rheumatoid arthritis comprising determining a polymorphism in at least two genes selected from the group consisting of adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), inosine triphosphate pyrophosphatase (ITPA), methionine synthase (MTR) and methionine synthase reductase (MTRR), wherein the presence of said polymorphism is indicative of clinical responsiveness to said antifolate therapy. 
     
     
         8 . The method according to  claim 7 , wherein said antifolate is methotrexate. 
     
     
         9 . The method according to  claim 7 , wherein said polymorphism is a single nucleotide polymorphism. 
     
     
         10 . The method according to  claim 7 , wherein the gene is selected from the group consisting of AMPD1, ATIC and ITPA. 
     
     
         11 . The method according to  claim 9 , wherein the single nucleotide polymorphism is selected from the group consisting of AMPD1 34C>T, ATIC 347 C>G and ITPA 94 A>C. 
     
     
         12 . The method according to  claim 9 , wherein the single nucleotide polymorphisms are AMPD1 34C>T and ATIC 347CC. 
     
     
         13 . The method according to  claim 9 , wherein the single nucleotide polymorphisms are AMPD1 34C>T and ITPA 94CC. 
     
     
         14 . The method according to  claim 9 , wherein the single nucleotide polymorphisms are ATIC 347CC and ITPA 94CC. 
     
     
         15 . The method according to  claim 9 , wherein the single nucleotide polymorphisms are AMPD1 34C>T, ATIC 347 C>G and ITPA 94 A>C. 
     
     
         16 . The method according to  claim 1  or  7 , wherein said antifolate responsiveness is measured as a disease activity score (DAS) #2.4. 
     
     
         17 . The method according to  claim 1  or  7 , wherein the mammal is a human. 
     
     
         18 . The method according to any of the preceding claims, wherein the polymorphism is detected by microarray analysis, DNA sequencing or allele specific PCR techniques. 
     
     
         19 . A kit of parts comprising at least one oligonucleotide capable of hybridizing to, or adjacent to, a polymorphic site in a DNA sequence present in the AMPD1 gene. 
     
     
         20 . A kit of parts comprising at least one oligonucleotide capable of hybridizing to, or adjacent to, a polymorphic site in a DNA sequence present in the ITPA gene. 
     
     
         21 . A kit of parts comprising at least two oligonucleotides capable of hybridizing to, or adjacent to, a polymorphic site in a DNA sequence present in at least two genes selected from the group consisting of adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), inosine triphosphate pyrophosphatase (ITPA), methionine synthase (MTR) and methionine synthase reductase (MTRR). 
     
     
         22 . The kit according to any one of  claims 19 - 21 , wherein the oligonucleotides are provided on a solid carrier.

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