Genetic polymorphisms associated with autoinflammatory diseases, methods of detection and uses thereof

Abstract

The present invention provides compositions and methods based on genetic polymorphisms that are associated with autoinflammatory diseases such as psoriasis. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

1 . A method of determining whether a human has an altered risk for autoinflammatory disease, comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307 or its complement, wherein said polymorphism indicates said human has an altered risk for autoinflammatory disease. 
     
     
         2 . The method of  claim 1 , wherein said autoinflammatory disease is psoriasis or Crohn's disease. 
     
     
         3 . The method of  claim 1 , wherein said altered risk is an increased risk. 
     
     
         4 . The method of  claim 1 , wherein said altered risk is a decreased risk. 
     
     
         5 . The method of  claim 1 , wherein said polymorphism comprises a haplotype provided in any of Tables 5-10. 
     
     
         6 . The method of  claim 5 , wherein said haplotype comprises a risk haplotype selected from the group consisting of:
 1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439 (G), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (T) (Table 10; IL12B);   2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439 (T), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (C) (Table 10; IL12B);   3) rs7530511 (C), rs11465804 (T), rs10889671 (G), rs11209026 (G), and rs1857292 (A) (Table 5; IL23R);   4) rs7530511 (C), rs10889671 (G), and rs11209026 (G) (Table 6; IL23R);   5) rs2201841 (G), rs10489628 (G), 10889674 (G), rs12085634 (T), rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (A), rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (A) (Table 8; IL23R); and   6) rs2201841 (A), rs10489628 (G), 10889674 (G), rs12085634 (A), rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (G) (Table 8; IL23R).   
     
     
         7 . The method of  claim 5 , wherein said haplotype comprises a protective haplotype selected from the group consisting of: 1) rs2546892 (G), rs1433048 (A), rs6894567 (G), rs17860508 (C), rs7709212 (C), rs953861 (A), rs6869411 (T), rs1833754 (T), and rs6861600 (G) (Table 9; IL12B);
 2) rs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225 (G), rs1368439 (T), rs3212227 (G), rs3213120 (C), rs3213119 (G), and rs2853696 (C) (Table 10; IL12B);   3) rs7530511 (T), rs11465804 (T), rs10889671 (A), rs11209026 (G), and rs1857292 (T) (Table 5; IL23R);   4) rs7530511 (C), rs11465804 (G), rs10889671 (G), rs11209026 (A), and rs1857292 (A) (Table 5);   5) rs7530511 (T), rs10889671 (A), and rs11209026 (G) (Table 6; IL23R);   6) rs7530511 (C), rs10889671 (G), and rs11209026 (A) (Table 6; IL23R);   7) rs7530511 (T), rs10489629 (T), rs4655692 (A), rs2201841 (A), rs11465804 (T), rs10489628 (G), rs1343152 (A), rs10789229 (C), rs10889671 (A), rs11209026 (G), rs10889674 (T), rs12085634 (T), rs1343151 (G), rs1008193 (C), rs6693831 (T), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs1857292 (T), rs11209031 (A), and rs11209032 (G) (Table 7; IL23R);   8) rs7530511 (C), rs10489629 (C), rs4655692 (G), rs2201841 (A), rs11465804 (G), rs10489628 (G), rs1343152 (C), rs10789229 (T), rs10889671 (G), rs11209026 (A), rs10889674 (T), rs12085634 (T), rs1343151 (A), rs1008193 (C), rs6693831 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs1857292 (A), rs11209031 (A), and rs11209032 (G) (Table 7; IL23R); and   9) rs2201841 (A), rs10489628 (G), 10889674 (T), rs12085634 (T), rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (G) (Table 8; IL23R).   
     
     
         8 . The method of  claim 1 , wherein said nucleic acid is a nucleic acid extract from a biological sample from said human. 
     
     
         9 . The method of  claim 8 , wherein said biological sample is blood, saliva, or buccal cells. 
     
     
         10 . The method of  claim 8 , further comprising preparing said nucleic acid extract from said biological sample prior to said testing step. 
     
     
         11 . The method of  claim 10 , further comprising obtaining said biological sample from said human prior to said preparing step. 
     
     
         12 . The method of  claim 1 , wherein said testing step comprises nucleic acid amplification. 
     
     
         13 . The method of  claim 12 , wherein said nucleic acid amplification is carried out by polymerase chain reaction. 
     
     
         14 . The method of  claim 1 , further comprising correlating the presence or absence of said polymorphism with an altered risk for autoinflammatory disease. 
     
     
         15 . The method of  claim 14 , wherein said correlating step is performed by computer software. 
     
     
         16 . The method of  claim 1 , wherein said testing is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE). 
     
     
         17 . The method of  claim 1 , wherein said testing is performed using an allele-specific method. 
     
     
         18 . The method of  claim 17 , wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification. 
     
     
         19 . The method of  claim 18 , wherein said method is performed using an allele-specific primer provided in Table 3. 
     
     
         20 . The method of  claim 1  which is an automated method. 
     
     
         21 . The method of  claim 1 , further comprising correlating the presence of said polymorphism with said human's responsiveness to a therapeutic agent. 
     
     
         22 . The method of  claim 21 , wherein said therapeutic agent comprises an anti-IL12 or anti-IL23 antibody. 
     
     
         23 . The method of  claim 21 , wherein said therapeutic agent is evaluated in a clinical trial. 
     
     
         24 . The method of  claim 1 , further comprising the step of selecting said human for inclusion in a clinical trial of a therapeutic agent or assigning said human to a group within a clinical trial. 
     
     
         25 . The method of  claim 24 , wherein said therapeutic agent comprises an anti-IL12 or anti-IL23 antibody. 
     
     
         26 . A method for reducing risk of autoinflammatory disease in a human, comprising administering to said human an effective amount of a therapeutic agent, said human having been identified as having an increased risk for autoinflammatory disease due to the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307 or its complement. 
     
     
         27 . The method of  claim 26 , wherein said method comprises testing nucleic acid from said human for the presence or absence of said polymorphism. 
     
     
         28 . The method of  claim 26 , wherein said autoinflammatory disease is psoriasis or Crohn's disease. 
     
     
         29 . The method of  claim 26 , wherein said polymorphism comprises a haplotype provided in any of Tables 5-10. 
     
     
         30 . The method of  claim 26 , wherein said therapeutic agent targets at least one of IL12 and IL23. 
     
     
         31 . The method of  claim 30 , wherein said therapeutic agent comprises an anti-IL12 or anti-IL23 antibody. 
     
     
         32 . The method of  claim 31 , wherein said therapeutic agent comprises an anti-IL-12p40 antibody selected from the group consisting of ABT-874 and CNTO-1275. 
     
     
         33 . A method of identifying a human having an increased risk for autoinflammatory disease, comprising testing a nucleic acid sample from said human for the presence or absence of a first polymorphism which is in linkage disequilibrium with a second polymorphism, wherein said second polymorphism is a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307 or its complement, and wherein said first polymorphism identifies said human as having an increased risk for autoinflammatory disease. 
     
     
         34 . The method of  claim 33 , wherein said linkage disequilibrium is r 2 =1. 
     
     
         35 . The method of  claim 33 , wherein said autoinflammatory disease is psoriasis or Crohn's disease. 
     
     
         36 . The method of  claim 33 , wherein said first polymorphism is selected from the group consisting of the polymorphisms provided in Table 4. 
     
     
         37 . The method of  claim 33 , further comprising correlating the presence or absence of said first polymorphism with an increased risk for autoinflammatory disease. 
     
     
         38 . The method of  claim 37 , wherein said correlating step is performed by computer software. 
     
     
         39 . A kit for determining whether a human has an altered risk for autoinflammatory disease, wherein said kit comprises at least one container and at least one oligonucleotide stored in said container, wherein said oligonucleotide is capable of detecting the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307 or its complement. 
     
     
         40 . The kit of  claim 39 , wherein said oligonucleotide selectively hybridizes to said nucleic acid in the presence of said polymorphism and does not hybridize to said nucleic acid in the absence of said polymorphism. 
     
     
         41 . A method for determining a human's risk for a disease, the method comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307 or its complement, wherein said polymorphism indicates said human has an altered risk for said disease, and said disease is selected from the group consisting of inflammatory disorders, chronic inflammatory disorders, autoimmune disorders, inflammatory bowel disease, psoriasis, Crohn's disease, pediatric Crohn's disease, ulcerative colitis, atopic dermatitis, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, celiac disease, Graves' disease, Graves' opthalmopathy, Graves' disease without opthalmopathy, Barrett's esophagus, infectious diseases, mycobacterial infections, tuberculosis, leprosy, Chagas' disease cardiomyopathy, fatal cerebral malaria, hypertension, and stroke.