# US 2020/0399702 A1 · Methods of predicting predisposition to or risk of kidney disease

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- Number: US 2020/0399702 A1
- Document ID: US20200399702A1
- Status: Published application
- Kind: A1
- Application number: 16/921,287
- Filed: 2020-07-06
- Published: 2020-12-24
- Earliest claimed: 2010-04-18
- Assignees: Beth Israel Deaconess Medical Center, Inc.; Wake Forest University Health Sciences
- Applicants: Beth Israel Deaconess Medical Center, Inc.; Wake Forest University Health Sciences
- Inventors: Giulio Genovese; David J. Friedman; Martin R. Pollak; Barry I. Freedman
- Web page: https://patentgrep.com/patent/US20200399702A1

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- C12Q 2600/172: Haplotypes
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## 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.

## Claims

### Claim at position 1

1-88. (canceled)

### Claim 89

A method for selecting a human subject for treatment to reduce the risk of developing renal failure or delay the development of renal failure, the method comprising:
determining the presence of at least one apolipoprotein L1 (APOL1) gene risk allele in the subject.

### Claim 90 (depends on 89)

The method of claim 89, 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.

### Claim 91 (depends on 90)

The method of claim 90, 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.

### Claim 92 (depends on 91)

The method of claim 91, wherein the at least one SNP produces an APOL1 polypeptide having a S342G and an I384M mutation.

### Claim 93 (depends on 90)

The method of claim 90, 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.

### Claim 94 (depends on 89)

The method of claim 89, wherein the renal disease is focal segmental glomerulosclerosis (FSGS) or hypertensive end-stage kidney disease, or both.

### Claim 95 (depends on 89)

The method of claim 89, wherein the subject is of African or Hispanic ancestry.

### Claim 96 (depends on 90)

The method of claim 90, comprising determining the presence of the at least SNP and the at least one inversion in the human APOL1 gene.

### Claim 97 (depends on 90)

The method of claim 90, wherein the inversion comprises recombination between said human APOL1 gene and a human apolipoprotein 4 (APOL4) gene or the inversion comprises substitution of the 5′ region of said APOL1 gene with the 5′ region of an APOL4 gene

### Claim 98 (depends on 90)

The method of claim 90, wherein said inversion occurs in a coding region of said APOL1 gene, a non-coding region of said APOL1 gene, or in both regions.

### Claim 99 (depends on 89)

The method of claim 89, wherein the nucleic acid molecule having the sequence of at least one APOL1 gene risk allele or a complement thereof has a nucleotide sequence of SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3 or a complement thereof, or the nucleic acid primer capable of amplifying the nucleic acid molecule or complement thereof has a nucleotide sequence of SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3.

### Claim 100 (depends on 99)

The method of claim 99, wherein the determining further comprises determining the presence or absence of a G allele at single nucleotide polymorphism (SNP) rs73885319 in the nucleotide sequence of SEQ ID NO:1, the presence or absence of a G allele at SNP rs60910145 in the nucleotide sequence of SEQ ID NO:2, and the presence or absence of a six base pair deletion at SNP rs71785313 in the nucleotide sequence of SEQ ID NO:3.

### Claim 101 (depends on 89)

The method of claim 89, wherein the biological 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.

### Claim 102 (depends on 89)

The method of claim 89, wherein testing the subject for the presence of at least one APOL1 gene risk allele comprises:
i) contacting a biological sample from the 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;
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; and
iii) selecting the human subject for treatment to reduce the risk of developing renal failure renal failure or delay the development of renal failure in which the formation of a hybridization complex or an amplification product is detected.

### Claim 103

A method for selecting a human subject in need of screening for renal disease and/or for the risk of developing renal disease, the method comprising:
determining the presence of an apolipoprotein L1 (APOL1) gene risk allele in a biological sample of the subject; and
selecting the subject in which the APOL1 gene risk allele is present in the biological sample for screening for renal disease and/or for the risk of developing renal injury/disease.

### Claim 104 (depends on 103)

The method of claim 103, wherein the screening of the subject is an annual or biannual screening for renal disease and/or for risk of developing renal injury/disease.

### Claim 105 (depends on 103)

The method of claim 103, wherein the APOL1 gene risk allele comprises at least one SNP and/or at least one inversion in a human APOL1 gene.

### Claim 106 (depends on 105)

The method of claim 105, 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.

### Claim 107 (depends on 106)

The method of claim 106, wherein the at least one SNP produces an APOL1 polypeptide having a S342G and an I384M mutation.

### Claim 108 (depends on 105)

The method of claim 105, 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.

### Claim 109 (depends on 103)

The method of claim 103, wherein the renal disease is focal segmental glomerulosclerosis (FSGS) or hypertensive end-stage kidney disease, or both.

### Claim 110 (depends on 103)

The method of claim 103, wherein the subject is of African or Hispanic ancestry.

### Claim 111 (depends on 105)

The method of claim 105, comprising determining the presence of the at least SNP and the at least one inversion in the human APOL1 gene.

### Claim 112 (depends on 105)

The method of claim 105, wherein the inversion occurs in a coding region of said APOL1 gene, a non-coding region of said APOL1 gene, or in both regions.

### Claim 113 (depends on 105)

The method of claim 105, wherein the inversion comprises recombination between said human APOL1 gene and a human apolipoprotein 4 (APOL4) gene or the inversion comprises substitution of the 5′ region of said APOL1 gene with the 5′ region of an APOL4 gene.

### Claim 114 (depends on 103)

The method of claim 103, wherein the at least one APOL1 gene risk allele comprises a nucleotide sequence of SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3 or a complement thereof.

### Claim 115 (depends on 114)

The method of claim 114, wherein the determining further comprises determining the presence or absence of a G allele at single nucleotide polymorphism (SNP) rs73885319 in the nucleotide sequence of SEQ ID NO:1, the presence or absence of a G allele at SNP rs60910145 in the nucleotide sequence of SEQ ID NO:2, and the presence or absence of a six base pair deletion at SNP rs71785313 in the nucleotide sequence of SEQ ID NO:3.

### Claim 116 (depends on 103)

The method of claim 103, wherein the determining further comprises
a) contacting the biological sample from the 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;
b) determining 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; and
c) selecting the human subject for screening for renal disease and/or risk of developing renal disease in which the formation of a hybridization complex or an amplification product is detected.

### Claim 117 (depends on 116)

The method of claim 116, wherein the nucleic acid molecule having the sequence of at least one APOL1 gene risk allele or a complement thereof has a nucleotide sequence of SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3 or a complement thereof, or the nucleic acid primer capable of amplifying the nucleic acid molecule or complement thereof has a nucleotide sequence of SEQ ID NO:1, SEQ ID NO:2 and/or SEQ ID NO:3.

### Claim 118 (depends on 117)

The method of claim 117, wherein the determining further comprises determining the presence or absence of a G allele at single nucleotide polymorphism (SNP) rs73885319 in the nucleotide sequence of SEQ ID NO:1, the presence or absence of a G allele at SNP rs60910145 in the nucleotide sequence of SEQ ID NO:2, and the presence or absence of a six base pair deletion at SNP rs71785313 in the nucleotide sequence of SEQ ID NO:3

### Claim 119 (depends on 103)

The method of claim 103, wherein the biological 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.