Methods and kits for determining predisposition to develop kidney diseases

Abstract

Provided are methods and kits for determining predisposition of a subject to develop a kidney disease, by identifying in a sample of the subject at least one APOL1 polypeptide variant which is characterized by a higher trypanolytic activity on Trypanosoma brucei rhodesiense as compared to the trypanolytic activity of wild type APOL1 polypeptide as set forth in SEQ ID NO:1 on the Trypanosoma brucei rhodesiense under identical assay conditions; or at least one APOL1 nucleotide mutation in the APLO1 genomic sequence set forth in SEQ ID NO:3, wherein the at least one nucleotide mutation or polypeptide variant being in linkage disequlibrium (LD) with the S342G mutation in the APOL1 polypeptide set forth in SEQ ID NO:1, wherein presence of the APOL1 polypeptide variant indicates increased predisposition of the subject to develop the kidney disease.

1 . A method of determining predisposition of a subject to develop a kidney disease, comprising:
 identifying in a sample of the subject at least one APOL1 polypeptide variant which is characterized by a higher trypanolytic activity on  Trypanosoma brucei rhodesiense  as compared to the trypanolytic activity of wild type APOL1 polypeptide as set forth in SEQ ID NO:1 on said  Trypanosoma brucei rhodesiense  under identical assay conditions,   wherein presence of said APOL1 polypeptide variant indicates increased predisposition of the subject to develop the kidney disease,   thereby determining the predisposition of the subject to develop the kidney disease.   
     
     
         2 . A method of determining predisposition of a subject to develop a kidney disease, comprising:
 identifying in a sample of the subject at least one APOL1 nucleotide mutation in the APLO1 genomic sequence set forth in SEQ ID NO:3 or at least one APOL1 polypeptide variant, wherein said at least one nucleotide mutation or polypeptide variant being in linkage disequlibrium (LD) with the S342G mutation in the APOL1 polypeptide set forth in SEQ ID NO:1,   wherein presence of said APOL1 nucleotide mutation or said APOL1 polypeptide variant indicates increased predisposition of the subject to develop the kidney disease,   thereby determining the predisposition of the subject to develop the kidney disease.   
     
     
         3 . The method of  claim 1 , wherein said APOL1 polypeptide variant comprises a mutation in the C-terminal helix of said APOL1 polypeptide. 
     
     
         4 . The method of  claim 1 , wherein said APOL1 polypeptide variant has a reduced binding ability to serum resistance-associated protein (SRA) expressed by  Trypanosoma brucei rhodesiense  as compared to the binding ability of said APOL1 wild type polypeptide under identical assay conditions. 
     
     
         5 . The method of  claim 1 , wherein said APOL1 polypeptide variant comprises the amino acid sequence set forth in SEQ ID NO:1 with a mutation selected from the group consisting of G342, M384, N388-del and Y389-del. 
     
     
         6 . The method of  claim 2 , wherein said LD between said APOL1 nucleotide mutation and said S342G mutation is characterized by a Lewontin correlation coefficient (D′) higher than 0.5. 
     
     
         7 . The method of  claim 6 , wherein a significance of said LD is characterized by LOD≧2. 
     
     
         8 . The method of  claim 2 , wherein said APOL1 nucleotide mutation is selected from the group consisting of the guanine-containing allele of single nucleotide polymorphism (SNP) rs73885319 (SEQ ID NO:6), the guanine-containing allele of SNP rs60910145 (SEQ ID NO:7), the guanine-containing allele of SNP rs9622363 (SEQ ID NO:8), the adenine-containing allele of SNP rs60295735 (SEQ ID NO:9) and the cytosine-containing allele of SNP rs58384577 (SEQ ID NO:10). 
     
     
         9 . The method of  claim 1 , wherein said kidney disease comprises end stage kidney disease. 
     
     
         10 . The method of  claim 1 , wherein said kidney disease comprises HIV-associated nephropathy (HIVAN). 
     
     
         11 . A method of designing a life style change to a subject with the risk of kidney disease, comprising:
 (a) identifying in a sample of the subject at least one APOL1 polypeptide variant or at least one APOL1 nucleotide mutation,   (i) wherein said variant is characterized by a higher trypanolytic activity on  Trypanosoma brucei rhodesiense  as compared to the trypanolytic activity of wild type APOL1 polypeptide as set forth in SEQ ID NO:1 on said  Trypanosoma brucei rhodesiense  under identical assay conditions;   (ii) wherein said APOL1 nucleotide mutation is included in the APLO1 genomic sequence set forth in SEQ ID NO:3, and wherein said at least one nucleotide mutation being in linkage disequlibrium (LD) with the S342G mutation in the APOL1 polypeptide set forth in SEQ ID NO:1,   wherein presence of said APOL1 polypeptide variant or said APOL1 nucleotide mutation indicates increased predisposition of the subject to develop the kidney disease, and;   (b) designing the life style change based on presence or absence of said APOL1 polypeptide variant or said APOL1 nucleotide mutation,   thereby designing life style change to a subject with the risk of kidney disease.   
     
     
         12 . The method of  claim 11 , wherein said subject is infected with HIV. 
     
     
         13 . A method of designing a nephrotoxic anti-retroviral treatment regimen to a subject infected with HIV, comprising:
 (a) identifying in a sample of the subject at least one APOL1 polypeptide variant or at least one APOL1 nucleotide mutation,   (i) wherein said variant is characterized by a higher trypanolytic activity on  Trypanosoma brucei rhodesiense  as compared to the trypanolytic activity of wild type APOL1 polypeptide as set forth in SEQ ID NO:1 on said  Trypanosoma brucei rhodesiense  under identical assay conditions;   (ii) wherein said APOL1 nucleotide mutation is included in the APLO1 genomic sequence set forth in SEQ ID NO:3, and wherein said at least one nucleotide mutation being in linkage disequlibrium (LD) with the S342G mutation in the APOL1 polypeptide set forth in SEQ ID NO:1,   wherein presence of said APOL1 polypeptide variant or said APOL1 nucleotide mutation indicates increased predisposition of the subject to develop the kidney disease, and;   (b) designing the nephrotoxic anti-retroviral treatment regimen based on presence or absence of said APOL1 polypeptide variant or said APOL1 nucleotide mutation,   thereby designing a nephrotoxic anti-retroviral treatment regimen to the subject infected with HIV.   
     
     
         14 . A method of determining if a subject is suitable for donating a kidney for transplantation, comprising:
 (a) identifying in a sample of the subject at least one APOL1 polypeptide variant or at least one APOL1 nucleotide mutation,   (i) wherein said variant is characterized by a higher trypanolytic activity on  Trypanosoma brucei rhodesiense  as compared to the trypanolytic activity of wild type APOL1 polypeptide as set forth in SEQ ID NO:1 on said  Trypanosoma brucei rhodesiense  under identical assay conditions;   (ii) wherein said APOL1 nucleotide mutation is included in the APLO1 genomic sequence set forth in SEQ ID NO:3, and wherein said at least one nucleotide mutation being in linkage disequlibrium (LD) with the S342G mutation in the APOL1 polypeptide set forth in SEQ ID NO:1,   wherein presence of said APOL1 polypeptide variant or said APOL1 nucleotide mutation indicates increased predisposition of the subject to develop a kidney disease, and;   wherein increased predisposition of the subject to develop said kidney disease indicates that the subject is not suitable for donating the kidney for transplantation,   thereby determining if the subject is suitable for donating a kidney for transplantation.   
     
     
         15 . A kit for determining predisposition to a kidney disease, comprising a reagent capable of specifically detecting at least one APOL1 nucleotide mutation in the APLO1 genomic sequence set forth in SEQ ID NO:3, wherein said at least one nucleotide mutation being in linkage disequlibrium (LD) with the S342G mutation in the APOL1 polypeptide set forth in SEQ ID NO:1, and/or a reagent capable of specifically detecting at least one APOL1 polypeptide variant, wherein said APOL1 polypeptide variant is characterized by a higher trypanolytic activity on  Trypanosoma brucei rhodesiense  as compared to the trypanolytic activity of wild type APOL1 polypeptide as set forth in SEQ ID NO:1 on said  Trypanosoma brucei rhodesiense  under identical assay conditions. 
     
     
         16 . The kit of  claim 15 , wherein said APOL1 nucleotide mutation is selected from the group consisting of the guanine-containing allele of single nucleotide polymorphism (SNP) rs73885319 (SEQ ID NO:6), the guanine-containing allele of SNP rs60910145 (SEQ ID NO:7), the guanine-containing allele of SNP rs9622363 (SEQ ID NO:8), the adenine-containing allele of SNP rs60295735 (SEQ ID NO:9) and the cytosine-containing allele of SNP rs58384577 (SEQ ID NO:10). 
     
     
         17 . The kit of  claim 15 , wherein said reagent comprises a polynucleotide capable of specifically detecting said APOL1 nucleotide mutation. 
     
     
         18 . The kit of  claim 15 , wherein said reagent comprises an antibody capable of specifically binding an APOL1 variant comprises said nucleotide mutation and not to said APLO1 wild type polypeptide. 
     
     
         19 . The kit of  claim 15 , wherein said APOL1 polypeptide variant comprises the amino acid sequence set forth in SEQ ID NO:1 with a mutation selected from the group consisting of G342, M384, N388-del and Y389-del. 
     
     
         20 . The method of  claim 1 , further comprising informing the subject on the state of the predisposition to develop the kidney disease. 
     
     
         21 . The method of  claim 2 , further comprising informing the subject on the state of the predisposition to develop the kidney disease. 
     
     
         22 . The method of  claim 2 , wherein said nucleotide mutation creates an APOL1 protein variant. 
     
     
         23 . The method of  claim 2 , wherein said nucleotide mutation is detected by a DNA detection method. 
     
     
         24 . The method of  claim 22 , wherein said APOL1 protein variant is detected by a protein detection method.