Methods of predicting predisposition to or risk of kidney disease

Abstract

Methods are disclosed herein for detecting a genetic predisposition to focal segmental glomerulosclerosis (FSGS) or hypertensive end-stage kidney disease (ESKD) or both in a human subject. The methods include detecting the presence of at least one single nucleotide polymorphism (SNP) in an APOL1 gene, such as the C-terminal exon of an APOL1 gene. In a further embodiment, methods are disclosed for detecting resistance of a subject to a disease associated with Trypanosoma infection. The methods include detecting the presence of at least one single nucleotide polymorphism (SNP) in an APOL1 gene, such as the C-terminal exon of an APOL1 gene. Also disclosed are methods for treating a subject infected with T. brucei (such as T. brucei brucei, T. b. rhodesiense , or T. b. gambiense ). The methods include administering a therapeutically effective amount of an APOL1 protein including a S342G substitution, an I384M substitution, and/or a deletion of N388 and Y389 to the subject.

1 . A method for identifying a genetic predisposition to renal disease comprising:
 i) contacting a sample from a human subject with a nucleic acid probe capable of hybridizing to a nucleic acid molecule having the sequence of at least one apolipoprotein L1 (APOL1) gene risk allele or a complement thereof, or a nucleic acid primer capable of amplifying the nucleic acid molecule or complement thereof; and   ii) detecting formation of a hybridization complex between the nucleic acid probe and the nucleic acid molecule or complement thereof or an amplification product corresponding to the nucleic acid molecule or complement thereof,   wherein formation of the hybridization complex or the presence of the at least one human APOL1 gene risk allele in the amplification product indicates the human subject has an increased risk of developing said renal disease, relative to a human subject that lacks the APOL1 gene risk allele.   
     
     
         2 . The method of  claim 1 , wherein the at least one human APOL1 gene risk allele comprises at least one single nucleotide polymorphism (SNP) and/or at least one inversion in a human APOL1 gene. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 2 , wherein the at least one SNP produces an APOL1 polypeptide having a serine to glycine mutation at position 342 (S342G), an isoleucine to methionine mutation at position 384 (I384M), a deletion of amino acids N388 and Y389, or a combination thereof. 
     
     
         5 . The method of  claim 4 , wherein the at least one SNP produces an APOL1 polypeptide having a S342G and an I384M mutation. 
     
     
         6 . The method of  claim 2 , wherein the method comprises determining the presence of the at least one SNP and/or the at least one inversion on both chromosomes of the subject. 
     
     
         7 . The method of  claim 1 , wherein the renal disease is focal segmental glomerulosclerosis (FSGS) or hypertensive end-stage kidney disease, or both. 
     
     
         8 . The method of  claim 7 , wherein the method is for detecting a genetic predisposition to focal segmental glomerulosclerosis, and wherein the human subject is infected with human immunodeficiency virus (HIV). 
     
     
         9 . The method of  claim 1 , wherein the subject is of African or Hispanic ancestry. 
     
     
         10 . The method of  claim 9 , wherein the subject is an African-American subject. 
     
     
         11 . The method of  claim 2 , comprising detecting the presence of the at least SNP and the at least one inversion in the human APOL1 gene. 
     
     
         12 . The method of  claim 2 , wherein said inversion comprises recombination between said human APOL1 gene and a human apolipoprotein 4 (APOL4) gene. 
     
     
         13 . The method of  claim 2 , wherein said inversion occurs in a coding region of said APOL1 gene, a non-coding region of said APOL1 gene, or in both regions. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 2 , wherein detection of at least two SNPs in said human subject indicates an increased likelihood said human subject will develop said renal disease relative to a subject having one or no APOL1 gene risk allele. 
     
     
         16 . The method of  claim 2 , comprising determining whether said human subject is homozygous or heterozygous for said at least one SNP or said inversion, wherein a determination that the human subject is homozygous for the at least one SNP or the at least one inversion indicates an increased likelihood the human subject will develop said renal disease relative to a human subject that is heterozygous for the at least one SNP or the at least one inversion. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 2 , wherein said inversion comprises substitution of the 5′ region of said APOL1 gene with the 5′ region of an APOL4 gene. 
     
     
         19 - 36 . (canceled) 
     
     
         37 . The method of  claim 2 , wherein the presence of said at least one SNP or said inversion indicates said human subject has an increased risk of renal damage following treatment with a therapeutic. 
     
     
         38 . The method of  claim 37 , wherein said therapeutic is selected from a blood pressure medication, a steroid, and/or an immunosuppressive agent. 
     
     
         39 - 54 . (canceled) 
     
     
         55 . The method of  claim 2 , wherein the presence of said at least one SNP or said at least one inversion indicates said human subject has an increased risk of kidney failure relative to a human subject lacking said at least one SNP or said at least one inversion. 
     
     
         56 . The method of  claim 55 , wherein said human subject has a greater need for a kidney transplant relative to a human subject lacking said at least one SNP or said at least one inversion. 
     
     
         57 - 88 . (canceled) 
     
     
         89 . The method of  claim 2 , wherein the sample is selected from the group consisting or whole blood, serum, buccal cells, extracted galls, biopsied or surgically removed tissue, tears, milk, a skin scrape, a surface washing, urine, sputum, cerebrospinal fluid, prostate fluid, pus, and a bone marrow aspirate.