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US-20260125758-A1 - MAJOR HISTOCOMPATIBILITY COMPLEX SINGLE NUCLEOTIDE POLYMORPHISMS

US20260125758A1US 20260125758 A1US20260125758 A1US 20260125758A1US-20260125758-A1

Abstract

The present disclosure relates to the identification of single nucleotide polymorphisms (SNPs) in the Gamma genomic block in the central region of the major histocompatibility complex (MHC) that can be used for matching transplant donors and recipients and determining disease susceptibility.

Inventors

  • David Charles Sayer
  • Hayley Marianne Hogan
  • Karolina Mercoulia

Assignees

  • ILLUMINA, INC.

Dates

Publication Date
20260507
Application Date
20251013
Priority Date
20131015

Claims (20)

  1. 1 . A method of reducing the likelihood of graft versus host disease in a transplant recipient, the method comprising: (a) determining the presence or absence of one or more single nucleotide polymorphism alleles in a Major Histocompatibility Complex (MHC) gamma block of a recipient in need of a transplant; (b) determining the presence or absence of one or more single nucleotide polymorphism alleles in the MHC gamma block of one or more potential transplant donors; and (c) selecting a transplant donor from the one or more potential transplant donors based on a match in the presence or absence of the one or more single nucleotide polymorphism alleles in the MHC gamma block of both the selected transplant donor and the recipient, wherein said match is indicative of a reduced likelihood of the transplant recipient developing graft versus host disease following transplantation of a graft from the selected transplant donor.
  2. 2 . The method of claim 1 , wherein the one or more single nucleotide polymorphism alleles are located in a C4 gene.
  3. 3 . The method of claim 1 , wherein the graft versus host disease is severe graft versus host disease.
  4. 4 . The method of claim 1 , wherein determining the presence or absence of one or more single nucleotide polymorphism alleles comprises performing a technique selected from the group consisting of PCR-SSP assay, allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5′ nuclease digestion, a molecular beacon assay, an oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct nucleotide sequencing.
  5. 5 . The method of claim 1 , wherein the one or more single nucleotide polymorphism alleles are selected from the group consisting of C2321, T9763, C9796, T9819, T9881, T10289, T10309, C10676, A11437, A11483, G12071, A12152, A12568, A12837, G12749, A12877, A13189, C13193, A13950, A14483, T14563, T14757, A14831, T14952, G15108, C16954, T17316, T19588, and A20170.
  6. 6 . The method of claim 1 , wherein at least 2 single nucleotide polymorphism alleles are determined.
  7. 7 . The method of claim 6 , wherein at least 10 single nucleotide polymorphism alleles are determined.
  8. 8 . The method of claim 1 , further comprising matching the transplant donor and the recipient at 9/10 HLA alleles.
  9. 9 . A method of increasing the duration of survival of a transplant recipient, the method comprising: (a) determining the presence or absence of one or more single nucleotide polymorphism alleles in a Major Histocompatibility Complex (MHC) gamma block of a recipient in need of a transplant; (b) determining the presence or absence of one or more single nucleotide polymorphism alleles in the MHC gamma block of one or more potential transplant donors; and (c) selecting a transplant donor from the one or more potential transplant donors based on a match in the presence or absence of the one or more single nucleotide polymorphism alleles in the MHC gamma block of both the selected transplant donor and the recipient, wherein said match is indicative that the transplant recipient will experience an increased duration of survival following a transplant of a tissue or organ from the selected transplant donor.
  10. 10 . The method of claim 9 , wherein the one or more single nucleotide polymorphism alleles are located in a C4 gene.
  11. 11 . The method of claim 9 , wherein determining the presence or absence of one or more single nucleotide polymorphism alleles comprises performing a technique selected from the group consisting of PCR-SSP assay, allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, nucleic acid sequencing, 5′ nuclease digestion, a molecular beacon assay, an oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct nucleotide sequencing.
  12. 12 . The method of claim 9 , wherein the one or more single nucleotide polymorphism alleles are selected from the group consisting of C2321, T9763, C9796, T9819, T9881, T10289, T10309, C10676, A11437, A11483, G12071, A12152, A12568, A12837, G12749, A12877, A13189, C13193, A13950, A14483, T14563, T14757, A14831, T14952, G15108, C16954, T17316, T19588, and A20170.
  13. 13 . The method of claim 9 , further comprising matching the transplant donor and the recipient at 9/10 HLA alleles or 10/10 HLA alleles.
  14. 14 . A kit for reducing the likelihood of graft versus host disease in a transplant recipient, the kit comprising: (a) a nucleic acid reagent configured for detecting one or more single nucleotide polymorphism alleles in a Major Histocompatibility Complex (MHC) gamma block; and (b) instructions for identifying a transplant donor based on the detection of the one or more single nucleotide polymorphism alleles, wherein a match in the presence or absence of the one or more single nucleotide polymorphism alleles between a potential transplant donor and the recipient is indicative of a reduced likelihood of the transplant recipient developing graft versus host disease following transplantation.
  15. 15 . The kit of claim 14 , wherein the nucleic acid reagent comprises one or more oligonucleotide probes.
  16. 16 . The kit of claim 14 , wherein the nucleic acid reagent comprises one or more oligonucleotide primers.
  17. 17 . The kit of claim 14 , wherein the nucleic acid reagent is specific for one or more single nucleotide polymorphism alleles in a C4 gene.
  18. 18 . The kit of claim 14 , wherein the one or more single nucleotide polymorphism alleles are selected from the group consisting of C2321, T9763, C9796, T9819, T9881, T10289, T10309, C10676, A11437, A11483, G12071, A12152, A12568, A12837, G12749, A12877, A13189, C13193, A13950, A14483, T14563, T14757, A14831, T14952, G15108, C16954, T17316, T19588, and A20170.
  19. 19 . The kit of claim 14 , further comprising DNA polymerase.
  20. 20 . The kit of claim 14 , wherein the kit is suitable for performing one or more PCR-SSP assays.

Description

RELATED APPLICATIONS This application is a divisional of U.S. application Ser. No. 17/671,951, filed on Feb. 15, 2022, issuing as U.S. Pat. No. 12,442,040 on Oct. 14, 2025, which is a continuation of U.S. patent application Ser. No. 16/362,310, filed on Mar. 22, 2019, now U.S. Pat. No. 11,279,976, which is a continuation of U.S. patent application Ser. No. 15/029,224, filed on Apr. 13, 2016, now U.S. Pat. No. 10,280,461, which is the U.S. National Phase of PCT Application No. PCT/AU2014/000980, filed Oct. 15, 2014 and published in English as WO/2015/054731 on Apr. 23, 2015, which claims priority to Australian Application No. 2013903971, filed on Oct. 15, 2013, which are each incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said. XML copy, created on Dec. 15, 2025, is named “IP-1415C-US.xml” and is 63,555 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety. FIELD The present disclosure relates to the identification of single nucleotide polymorphisms (SNPs) in the Gamma genomic block in the central region of the major histocompatibility complex (MHC) that can be used for matching transplant donors and recipients and determining disease susceptibility. BACKGROUND The Major Histocompatibility Complex (MHC) is a gene dense region of approximately 4 Mb on the short arm of chromosome 6. The MHC contains many immune response genes, including genes encoding the human leukocyte antigens (HLAs). The MHC also contains many genes involved in immunological and inflammatory responses and has been associated with numerous autoimmune and inflammatory disorders. The MHC is usually inherited as a complete block; however, recombination has been shown to occur at frequencies of approximately 1/100 meioses at specific regions within the MHC. Between these recombination hot spots are genomic blocks of DNA up to several hundred kilobases in length. Thus, many unrelated individuals within a population either have a conserved haplotype, or recombined blocks from conserved haplotypes. The conserved haplotypes are referred to as “extended haplotypes” or “ancestral haplotypes”. There are 4 major genomic blocks within the MHC. The precise boundaries of these genomic blocks are unknown and smaller genomic blocks between the major genomic blocks are likely to exist. The major blocks are the alpha block, which includes HLA-A; the beta block, which includes HLA-B and HLA-C; the gamma block, which includes the Bf, C2 and C4 genes; and the delta block, which includes the HLA-DRB, and the DQB1 genes. The HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 genes are presently used to match transplant donors and recipients. HLA-DPB1 is probably in a separate block centromeric of delta block due to the high rate of recombination seen between the genes of the delta block and HLA-DPB1. Nevertheless, HLA-DPB1 is frequently typed for transplantation matching. HLA matching has been shown to be critical for an improved outcome following stem cell transplantation. Furthermore, a study by Petersdorf et al. (2007) showed that the outcome following unrelated stem cell transplant was improved if HLA matched donors and recipients were haplotype-matched compared to donor/recipient pairs that were HLA-matched, but haplotype-mismatched. In this study, genomic DNA from both the donor and recipient was extracted and hybridized to microarrays containing oligonucleotide probes configured to detect physical linkage between the HLA alleles. This approach is not suitable to routine HLA typing and a routine test for assessing or improving the likelihood of haplotype matching has been, hitherto, undescribed. In some aspects of molecular biology, a haplotype is described as the physical linkage that exists between 2 nucleotide polymorphisms. When referring to HLA and MHC, the term haplotype is used to describe the entire MHC, spanning at least HLA-A to HLA-DQB1. This region spans approximately 4 Mb and is usually inherited intact. Some haplotypes remain intact for up to thousands of generations and remain identical in sequence except for a small number of SNPs between unrelated individuals. Different ancestral haplotypes contain unique combinations of HLA alleles and have unique sequence content in many regions throughout the MHC. It is likely that the haplotype/HLA matched individuals with reduced graft-versus-host disease (GVHD) compared with HLA matched but haplotype mismatched individuals is because haplotype matched individuals share a complete or partial ancestral haplotype and therefore also share many unique sequences. The best stem cell donor is an identical twin, followed by an HLA haploidentical sibling. The relatively low probability of identifying an HLA haploidentical si