Molecule associated with onset of gout, and method and kit for evaluating diathesis of uric acid-related diseases and inflammation-related diseases, and inspection object and drug

Abstract

To specify a molecule associated with the onset of gout so as to provide a method for evaluating a diathesis of uric acid-related diseases and a diathesis of inflammation-related diseases, an evaluation kit for carrying out the method, an inspection object, and a drug, on the basis of the molecule specified above, for contributing to the early treatment and prevention of the uric acid-related diseases and inflammation-related diseases. The molecule includes any one protein and cDNA of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D and FAM35A, or proteins of combination thereof with GLUT9, NPT1, URAT1, or NXRN2, and is capable of selectively inducing gout. A molecule includes protein and cDNA of an ABCG2 variant and is capable of selectively and ATP-dependently decreasing urate excretion.

1 . A molecule associated with onset of gout, comprising any one protein or cDNA of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, or a combination thereof with any one protein or cDNA of GLUT9, NPT1, URAT1, and NXRN2, and being capable of relating to the onset of gout; or comprising protein or cDNA of an ABCG2 variant, and being capable of selectively and ATP-dependently decreasing excretion of urate. 
     
     
         2 . A method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis, the method comprising:
 evaluating whether or not a subject has a diathesis capable of inducing urate regulation failure, or a state or a uric acid-related disease attributable to the failure, and the evaluating comprising:   a step of detecting a gene polymorphism of a gene encoding at least any one protein or cDNA of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, or a combination thereof with gene polymorphisms of GLUT9, NPT1, URAT1, and NXRN2, using a test sample containing human genes of the subject.   
     
     
         3 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to  claim 2 ,
 wherein detection of a gene polymorphism of a gene encoding any one protein or cDNA of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, or a combination thereof with GLUT9, NPT1, URAT1, and NXRN2 is detection of a SNP or a polymorphism having a relationship of linkage disequilibrium with the SNP or a polymorphism with a frequency of 1% or less.   
     
     
         4 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to  claim 2  or  3 ,
 wherein the method uses a combination with detection of SNPs of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, in which the SNPs are rs4073582, rs671, rs2188380, rs1260326, rs10791821, rs56027330, rs11758351, rs4496782, and rs7903456, respectively, or a gene polymorphism having a relationship of linkage disequilibrium with the SNPs, or other gene polymorphisms. 
 
     
     
         5 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to any one of  claims 2  to  4 ,
 wherein the method uses detection of gene polymorphisms of G279R of NPT4, and V178I, N299S, E311K, G462R, V508I, V516M, A634V, F489L and D620G of ABCG2, or a gene polymorphism having a relationship of linkage disequilibrium with the polymorphisms, and a combination thereof. 
 
     
     
         6 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to any one of  claims 2  to  5 ,
 wherein the method uses a combination of detection of a SNP of GLUT9 (rs3775948), a gene polymorphism (SNP) of NPT1 (rs1165196, I269T), a SNP of URAT1 (rs505802), a SNP of NXRN2 (rs2285340 or rs506338), or polymorphisms having a relationship of linkage disequilibrium therewith, or W258X and R90H of URAT1, and SNPs (Q126X, Q141K, and V12M) and polymorphisms (R113X, F208S, G268R, P269S, E334X, S441N, L447V, S486N, F506SfsX4, R575X, and C608X) of ABCG2. 
 
     
     
         7 . A method for evaluating whether or not a subject has a diathesis capable of inducing urate regulation failure, or a state or a disease attributable to the failure,
 wherein the method is carried out evaluation using a test sample containing human genes of the subject, based on Q126X and Q141K of two SNPs of genes encoding ABCG2 protein, and   wherein when a gene encoding Q of Q126X is C/C and a gene encoding Q of Q141K is C/C, the function of ABCG2 is evaluated to be normal;   when a gene encoding Q of Q126X is C/C, and a gene encoding Q of Q141K is A/C, the function of ABCG2 is evaluated to be 3/4;   when a gene encoding Q of Q126X is T/C and a gene encoding Q of Q141K is C/C, the function of ABCG2 is evaluated to be 1/2;   when a gene encoding Q of Q126X is C/C and a gene encoding Q of Q141K is A/A, the function of ABCG2 is evaluated to be 1/2;   when a gene encoding Q of Q126X is T/C and a gene encoding Q of Q141K is A/C, the function of ABCG2 is evaluated to be 1/4; and   when a gene encoding Q of Q126X is T/T and a gene encoding Q of Q141K is C/C, ABCG2 is evaluated to have no function, and   wherein the method evaluates that a diathesis capable of inducing urate regulation failure, or a state or a disease attributable to the failure is evaluated to be high depending on a degree of loss of the function of ABCG2.   
     
     
         8 . A method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis, wherein when one polymorphism which produces an amino acid variation of any one of V178I, N299S, E311K, G462R, V508I, V516M, A634V, R113X, F208S, G268R, E334X, S441N, S486N, and F506SfsX4 of ABCG2 is present, it is evaluated that a subject has a diathesis capable of inducing urate regulation failure or a state or a disease attributable to the failure, substantially similar to the case in which one Q126X is present. 
     
     
         9 . A method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis, wherein when one polymorphism which produces an amino acid variation of any one of L447V, R575X, and C608X of ABCG2 is present, it is evaluated that a subject has a diathesis capable of inducing urate regulation failure or a state or a disease attributable to the failure, substantially similar to the case in which one Q126X is present. 
     
     
         10 . A method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis, wherein presence of one polymorphism which produces an amino acid variation of any one of V12M, P269S, F489L, and D620G of ABCG2 is evaluated to be associated with a diathesis capable of inducing urate regulation failure or a state or a disease attributable to the failure. 
     
     
         11 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to any one of  claims 2  to  10 ,
 wherein the method evaluates estimation of clinical disease types or suitable drugs based on the result obtained by the method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis as defined in any one of  claims 2  to  10 . 
 
     
     
         12 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to any one of  claims 2  to  11 ,
 wherein when a serum uric acid level is a predetermined value or more, it is evaluated that a subject has a high diathesis capable of inducing urate regulation failure or a state or a disease attributable to the failure. 
 
     
     
         13 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to  claim 12 ,
 wherein a threshold of the serum uric acid level is in a range from 6.0 to 9.0 mg/dl, and more preferably in a range from 7.0 to 8.0 mg/dl.   
     
     
         14 . The method for evaluating a uric acid-related disease diathesis and an inflammation-related disease diathesis according to any one of  claims 2  to  13 ,
 wherein the uric acid-related disease and the inflammation-related disease include hyperuricemia, gout, rheumatoid arthritis, osteoarthritis, infertility, cerebral stroke, neurodegenerative disease, ischemic heart disease, chronic kidney disease, renal dysfunction, urolithiasis, kidney stone, aneurysm, arrhythmia including atrial fibrillation, inflammatory bowel disease, enteritis, functional dyspepsia, viral intestinal disease, and photosensitivity. 
 
     
     
         15 . An evaluation kit for a uric acid-related disease diathesis and an inflammation-related disease diathesis, the kit evaluating whether or not a subject has a diathesis capable of inducing urate regulation failure, or a state or a disease attributable to the failure, wherein the kit includes means for detecting a SNP of at least any one gene selected from CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A genes, or a gene polymorphism having a relationship of linkage disequilibrium with the SNP, or a polymorphism having a frequency of 1% or less, or a combination thereof with a gene polymorphism of GLUT9, NPT1, URAT1 and NXRN2, using a test sample containing human genes of the subject. 
     
     
         16 . The evaluation kit for a uric acid-related disease diathesis and an inflammation-related disease diathesis according to  claim 15 ,
 wherein each SNP of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D and FAM35A is each of rs4073582, rs671, rs2188380, rs1260326, rs10791821, rs56027330, rs3775948, rs1165196, rs505802, rs2285340 or rs506338, rs11758351, rs4496782, and rs7903456.   
     
     
         17 . The evaluation kit for a uric acid-related disease diathesis and an inflammation-related disease diathesis according to  claim 15  or  16 ,
 wherein detection in an ABCG2 gene is detection in at least any one of V178I, N299S, E311K, G462R, V508I, V516M, A634V, Q126X, Q141K, V12M, R113X, F208S, G268R, P269S, E334X, S441N, L447V, S486N, F506SfsX4, R575X, C608X, F489L, and D620G, or combination thereof. 
 
     
     
         18 . An inspection object, which is a living body in which urate transport kinetics is to be examined, the inspection object comprising:
 a nonhuman animal having a deficiency of at least any one gene selected from CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A; or a nonhuman animal overexpressing or decreased-expressing at least any one gene selected from human CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, or at least any one gene selected from nonhuman CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A; a nonhuman animal overexpressing or decreased-expressing a human ABCG2 gene or nonhuman human ABCG2 gene including at least any one polymorphism selected from V178I, N299S, E311K, G462R, V508I, V516M, A634V, Q126X, Q141K, V12M, R113X, F208S, G268R, P269S, E334X, S441 N, L447V, S486N, F506SfsX4, R575X, C608X, F489L, and D620G of ABCG2, or a combination thereof; a nonhuman cell line or a human cell line having a deficiency of at least any one gene of CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35, a nonhuman cell line or a human cell line overexpressing or decreased-expressing at least any one gene selected from human CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, or nonhuman CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, GLUT9, NPT1, URAT1, NXRN2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, a nonhuman cell line or a human cell line overexpressing or decreased-expressing human ABCG2 gene or a nonhuman ABCG2 gene including at least any one polymorphism selected from V178I, N299S, E311K, G462R, V508I, V516M, A634V, Q126X, Q141K, V12M, P269S, R113X, F208S, G268R, E334X, S441N, L447V, S486N, F506SfsX4, R575X, C608X, F489L, and D620G of ABCG2, or combination thereof; or a cell membrane vesicle prepared from the cell lines.   
     
     
         19 . A drug for uric acid-related diseases and inflammation-related diseases, for reducing a diathesis capable of inducing urate regulation failure, or a state or a disease attributable to the failure,
 the drug including polynucleotide or polypeptide encoding at least any one protein selected from CNIH2-PACS1, ALDH2, MYL2-CUX2, GCKR, MAP3K11, NPT4, ABCG2, HIST1H2BF/HIST1H4E, HIST1H2BE/HIST1H4D, and FAM35A, or combination thereof with GLUT9, NPT1, URAT1, and NXRN2 in a form capable of being introduced into cells.