A method for differential quantification of hla alleles and uses thereof

Abstract

The present disclosure provides a method for quantifying HLA allele difference and its use. The method for quantifying HLA allele difference comprises the following steps: obtaining the typing results of HLA alleles of a recipient and a donor; combining the typing results of the recipient and the donor in pairs to obtain four sets of combined typing results; decoding the four sets of combined typing results into amino acid sequences respectively; calculating the HED value of each set of combined typing results respectively; calculating the sum of the HED values of the four sets of combined typing results to obtain the HED HLA等位基因 value of the recipient and the donor; and quantifying the difference of the recipient and the donor at the HLA allele according to the HED HLA等位基因 value. The method for quantifying HLA allele difference is used to predict the risk of chronic graft-versus-host disease, the risk of acute graft-versus-host disease, the risk of relapse, the risk of cytomegalovirus infection, etc. of hematopoietic stem cell transplantation, which has important guiding significance for the selection of prognosis treatment plan of the target object.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the technical field of healthcare informatics, and particularly relates to an HLA allele difference quantification method and application thereof. BACKGROUND

[0002] Hematopoietic stem cell transplantation (HSCT) refers to a treatment method of transplanting hematopoietic stem cells to a patient after abnormal (tumor, immune) cells in the patient are cleared by a large dose of radiotherapy and chemotherapy, so as to restore normal hematopoietic function of the patient.

[0003] Among them, the degree of matching of the human leukocyte antigen (HLA) gene determines the success rate of hematopoietic stem cell transplantation and organ survival rate. However, at present, there is still a lack of quantitative description of the physical and chemical property differences between the HLA alleles of the recipient and the donor. Therefore, it is necessary to find an HLA allele difference quantification method. SUMMARY

[0004] In view of this, the present disclosure provides an HLA allele difference quantification method and application thereof.

[0005] In a first aspect of the present disclosure, an HLA allele difference quantification method is provided, which comprises the following steps:

[0006] Step S101, obtaining the typing results of the HLA alleles of the recipient and the donor; wherein the typing result of the recipient is denoted as allele1 / allele2, and the typing result of the donor is denoted as allele3 / allele4;

[0007] Step S102, combining the typing result allele1 / allele2 of the recipient and the typing result allele3 / allele4 of the donor two by two to obtain four groups of combined typing results and denote them as allele1 / allele3, allele1 / allele4, allele2 / allele3, and allele2 / allele4, respectively;

[0008] Step S103, decoding the four groups of combined typing results allele1 / allele3, allele1 / allele4, allele2 / allele3, and allele2 / allele4 into amino acid sequences, respectively;

[0009] Step S104, according to the decoded amino acid sequences of the four sets of combined typing results, respectively calculate the HED value of the typing results of each set of combination in the exon region corresponding to the HLA allele;

[0010] The HED value of the combined typing result allele1 / allele3 is denoted as HED 1 / 3 value;

[0011] The HED value of the combined typing result allele1 / allele4 is denoted as HED 1 / 4 value;

[0012] The HED value of the combined typing result allele2 / allele3 is denoted as HED 2 / 3 value;

[0013] The HED value of the combined typing result allele2 / allele4 is denoted as HED 2 / 4 value;

[0014] Step S105, calculate the sum of the HED values of the four sets of combined typing results in the third exon region of the HLA allele, obtain the HED HLA等位基因 value of the recipient and the donor in the exon region corresponding to the HLA allele;

[0015] HED HLA等位基因 = HED 1 / 3 + HED 1 / 4 + HED 2 / 3 + HED 2 / 4

[0016] Step S106, according to the HED HLA等位基因 value, quantify the difference between the recipient and the donor in the HLA allele; wherein, the greater the HED HLA等位基因 value, the greater the difference between the recipient and the donor in the HLA allele; the smaller the HED HLA等位基因 value, the smaller the difference between the recipient and the donor in the HLA allele.

[0017] In some optional embodiments of the present disclosure, in step S104, the calculation formula of the HED value is:

[0018] HED = ∑D ij = ∑ [α (c i -c j ) 2 + β (p i -p j ) 2 + γ (v i -v j ) 2 ] 1 / 2

[0019] wherein a, b, g represent inverse mean weight factors;

[0020] i and j represent two amino acids at the same position in the HLA allele for the recipient and the donor, respectively;

[0021] c represents the amino acid composition;

[0022] p represents the amino acid polarity;

[0023] v represents the amino acid molecular volume.

[0024] In some optional embodiments of the present disclosure, the calculation formulas of a, b, g are as follows, respectively:

[0025]

[0026] wherein n represents the number of amino acid types in the encoded amino acid sequence;

[0027] |c g -c h | represents the difference between the two amino acid compositions after two-by-two combination of n kinds of amino acids;

[0028] |p g -p h | represents the difference between the two amino acid polarities after two-by-two combination of n kinds of amino acids;

[0029] |v g -v h | represents the difference between the two amino acid molecular volumes after two-by-two combination of n kinds of amino acids.

[0030] In some optional embodiments of the present disclosure, the HLA allele is selected from at least one of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1.

[0031] In some specific embodiments of the present disclosure, the HLA allele comprises HLA-A and HLA-B.

[0032] In the second aspect of the present disclosure, the present disclosure provides a use of the HLA allele difference quantification method as described in the first aspect of the present disclosure for predicting the risk of chronic graft-versus-host disease, or the risk of acute graft-versus-host disease, or the risk of relapse, or the risk of cytomegalovirus infection. Illustratively, by quantifying the difference between HLA-A allele and HLA-B allele, the risk of haploidentical hematopoietic stem cell transplantation for chronic graft-versus-host disease can be predicted.

[0033] In a third aspect of the present disclosure, the present disclosure provides a method for predicting the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation, comprising the following steps:

[0034] In step S201, the HED HLA-A等位基因 value of the third exon region of HLA-A allele of the recipient and the donor is calculated based on the HLA allele difference quantification method according to the first aspect of the present disclosure.

[0035] In step S202, the HED HLA-B等位基因 value of the third exon region of HLA-B allele of the recipient and the donor is calculated based on the HLA allele difference quantification method according to the first aspect of the present disclosure.

[0036] In step S203, the HED HLA-A等位基因 value of the third exon region of HLA-A allele and the HED HLA-B等位基因 value of the third exon region of HLA-B allele of the recipient and the donor are calculated according to the HED 受者 / 供者 value.

[0037] HED HLA-A等位基因 + HED HLA-B等位基因 = HED 受者 / 供者

[0038] In step S204, the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation of the recipient is predicted according to the HED 受者 / 供者 value; wherein the greater the HED 受者 / 供者 value, the lower the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation of the recipient is predicted; and the smaller the HED 受者 / 供者 value, the higher the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation of the recipient is predicted.

[0039] In some optional embodiments of the present disclosure, in step S204, the HED 受者 / 供者 value is compared with a preset threshold value, and the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation of the recipient is predicted.

[0040] If the HED 受者 / 供者 value is greater than or equal to the preset threshold value, the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation of the recipient is low risk.

[0041] If the HED 受者 / 供者 value is less than the preset threshold value, the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation of the recipient is high risk.

[0042] In some optional embodiments of this disclosure, the preset threshold is selected from any number from 60 to 70; for example, 60, 61, 62, 63, 63.10, 63.20, 63.30, 63.31, 63.32, 63.33, 63.34, 63.35, 63.36, 63.37, 63.38, 63.39, 63.40, 63.50, 63.60, 63.70, 63.80, 63.90, 64, 65, 66, 67, 68, 69, or 70, etc.

[0043] In some alternative embodiments of this disclosure, the preset threshold is selected from 63.36.

[0044] In a fourth aspect, this disclosure provides a prediction system for the risk of chronic graft-versus-host disease in haploidentical hematopoietic stem cell transplantation, the prediction system being based on the prediction method described in the third aspect of this disclosure; the prediction system includes:

[0045] HED HLA-A等位基因 The value calculation module is used to calculate the HED in the third exon region of the HLA-A allele for both the recipient and donor. HLA-A等位基因 value;

[0046] HED HLA-B等位基因 The value calculation module is used to calculate the HED in the third exon region of the HLA-B allele for both the recipient and the donor. HLA-A等位基因 value;

[0047] HED 受者 / 供者 Value calculation module, used to calculate values ​​based on HED HLA-A等位基因 Values ​​and HED HLA-B等位基因 Values ​​were calculated for the HED values ​​of the recipient and donor in the third exon regions corresponding to the HLA-A and HLA-B alleles. 受者 / 供者 value;

[0048] Prediction module, used to predict based on HED 受者 / 供者 The value predicts the risk of chronic graft-versus-host disease in recipients undergoing haploidentical hematopoietic stem cell transplantation.

[0049] In some alternative embodiments of this disclosure, the HED HLA-A等位基因 The value calculation module includes:

[0050] The first module for obtaining genotyping results is used to obtain the genotyping results of the HLA-A alleles of the recipient and donor.

[0051] The first genotyping result combination module is used to combine the genotyping results of the recipient and donor HLA-A alleles in pairs to obtain four sets of genotyping results.

[0052] The decoding module one is configured to decode the four sets of combined typing results of the HLA-A alleles of the recipient and the donor into amino acid sequences respectively;

[0053] The first calculation module one is configured to calculate the HED values of the third exon region of the HLA-A alleles of the recipient and the donor according to the amino acid sequences decoded from the four sets of combined typing results of the HLA-A alleles of the recipient and the donor.

[0054] The second calculation module one is configured to calculate the HED values of the third exon region of the HLA-A alleles of the recipient and the donor according to the HED values of the third exon region of the HLA-A alleles of the four sets of combined typing results of the recipient and the donor. HLA*A等位基因

[0055] In some optional embodiments of the present disclosure, the HED HLA-B等位基因 value calculation module comprises:

[0056] The typing result acquisition module two is configured to acquire the typing results of the HLA-B alleles of the recipient and the donor.

[0057] The typing result combination module two is configured to combine the typing results of the recipient and the donor two by two to obtain four sets of combined typing results.

[0058] The decoding module two is configured to decode the four sets of combined typing results of the HLA-B alleles of the recipient and the donor into amino acid sequences respectively.

[0059] The first calculation module two is configured to calculate the HED values of the third exon region of the HLA-B alleles of the recipient and the donor according to the amino acid sequences decoded from the four sets of combined typing results of the HLA-B alleles of the recipient and the donor.

[0060] The second calculation module two is configured to calculate the HED values of the third exon region of the HLA-B alleles of the recipient and the donor according to the HED values of the third exon region of the HLA-B alleles of the four sets of combined typing results of the recipient and the donor. HLA-B等位基因

[0061] In the five aspects of the present disclosure, the present disclosure provides a device for predicting the risk of chronic graft-versus-host disease of haploid hematopoietic stem cell transplantation, which comprises a memory and a processor; wherein the memory is configured to store program instructions; and the processor is configured to invoke the program instructions, and when the program instructions are executed, the steps of the prediction method according to the third aspect of the present disclosure are implemented.

[0062] ​​In the six aspects of the present disclosure, the present disclosure provides a computer readable storage medium, which stores a computer program, and the computer program is executed by a processor to perform the steps of the prediction method of the third aspect of the present disclosure.

[0063] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the present disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0064] The accompanying drawings, which are incorporated into and form part of the specification, illustrate embodiments consistent with the present disclosure and, together with the description, serve to explain the principles of the present disclosure.

[0065] Figure 1 is a flow chart of an HLA allele difference quantification method according to an example embodiment.

[0066] Figure 2 According to an example embodiment, the combination method of the recipient's typing result allele1 / allele2 and the donor's typing result allele3 / allele4 is shown

[0067] Figure 3 is a flow chart of a haploidentical hematopoietic stem cell transplantation chronic graft versus host disease risk prediction method according to an example embodiment.

[0068] Figure 4 is a cGVHD cumulative incidence curve of the low risk and high risk groups of the risk of chronic graft versus host disease in the target object receiving haploidentical hematopoietic stem cell transplantation and not receiving MSC treatment when the preset threshold is 63.36.

[0069] Figure 5 is a flow chart of a haploidentical hematopoietic stem cell transplantation chronic graft versus host disease risk prediction system according to an example embodiment. DETAILED DESCRIPTION

[0070] The present disclosure discloses a HLA allele difference quantification method and its use, and those skilled in the art can refer to the content herein and appropriately improve the process parameters. It should be particularly pointed out that all similar substitutions and changes are obvious to those skilled in the art, and they are all considered to be included in the present disclosure. The method and application of the present disclosure have been described by the preferred embodiments, and the relevant personnel can obviously modify or appropriately change and combine the method and application described herein without departing from the content, spirit and scope of the present disclosure, to realize and apply the present disclosure technology.

[0071] Terminology:

[0072] The term "hematopoietic stem cell transplantation" used in the present disclosure can be divided into autologous transplantation, allogeneic transplantation and syngeneic transplantation according to the source of the donor. The allogeneic transplantation is further divided into sibling donor transplantation and non-blood-related donor transplantation. The syngeneic transplantation is the transplantation between identical twins.

[0073] The term "allogeneic hematopoietic stem cell transplantation" used in the present disclosure is divided into full match and mismatch according to the degree of match of ten loci of Human Leukocyte Antigen (HLA) genes. The full match means that the ten loci of HLA genes of the recipient and the donor are the same, and the mismatch means that at least one locus of HLA genes of the recipient and the donor is different. The haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is one of the allogeneic hematopoietic stem cell transplantation.

[0074] The term "chronic graft-versus-host disease (cGVHD)" used in the present disclosure is a clinical and pathological syndrome caused by the attack of lymphocytes from the donor on the organs of the recipient in the process of reconstituting the immune system of the donor (including classic cGVHD and overlap syndrome), which is one of the main complications after transplantation.

[0075] The term "risk" used in the present disclosure refers to the possibility of occurrence of a certain event within a certain period of time, such as the onset of non-relapse mortality after mismatched allogeneic hematopoietic stem cell transplantation.

[0076] The term "risk prediction" used in the present disclosure includes the probability, odds ratio or likelihood risk prediction of predicting the occurrence of an event.

[0077] The term "threshold" used in the present disclosure is used to evaluate the sensitivity of the effect response of a certain influencing factor on an organism. In the prediction of the risk of haploidentical hematopoietic stem cell transplantation chronic graft-versus-host disease, the reasonable setting of the threshold has important guiding significance for the prognosis evaluation of the target object receiving haploidentical hematopoietic stem cell transplantation and the selection of the prognosis treatment scheme of the target object.

[0078] HLA allele difference quantification method:

[0079] In one embodiment, an HLA allele difference quantification method is provided. Figure 1 A flowchart of an HLA allele difference quantification method according to an example embodiment is shown, which includes the following steps:

[0080] In step S101, the typing results of the HLA alleles of the recipient and the donor are obtained; wherein the typing result of the recipient is denoted as allele1 / allele2, and the typing result of the donor is denoted as allele3 / allele4.

[0081] In step S102, the typing result allele1 / allele2 of the recipient and the typing result allele3 / allele4 of the donor are combined in pairs to obtain four sets of combined typing results, denoted as allele1 / allele3, allele1 / allele4, allele2 / allele3, and allele2 / allele4, respectively. Figure 2 is a combination method of the typing result allele1 / allele2 of the recipient and the typing result allele3 / allele4 of the donor according to an example embodiment.

[0082] In step S103, the four sets of combined typing results allele1 / allele3, allele1 / allele4, allele2 / allele3, and allele2 / allele4 are respectively decoded into amino acid sequences.

[0083] In step S104, according to the amino acid sequences decoded from the four sets of combined typing results, the HED value of each set of combined typing results in the exon region corresponding to the HLA allele is calculated.

[0084] The calculation formula of the HED value is:

[0085] HED =∑D ij =∑[α(c i -c j ) 2 +β(p i -p j ) 2 +γ(v i -v j ) 2 ] 1 / 2

[0086] In the formula, i and j respectively represent two amino acids of the alleles at the same position; c represents the amino acid composition; p represents the amino acid polarity; and v represents the amino acid molecular volume.

[0087] The amino acid composition is represented by GRAR740101 in the Amino acid index database, the amino acid polarity is represented by GRAR740102 in the Amino acid index database, and the amino acid molecular volume is represented by GRAR740103 in the Amino acid index database. The HED D1 / A1 value, the HED D1 / A2 value, the HED D2 / A1 value, and the HED D2 / A2 value are calculated based on the physicochemical distance between amino acids according to Grantham, and quantify the differences in the physicochemical properties of the amino acid sequences between the HLA alleles.

[0088] In the formula, α, β, and γ represent inverse mean weight factors.

[0089] The calculation formulas of α, β, and γ are as follows:

[0090]

[0091] In the formula, n represents the number of types of amino acids in the encoded amino acid sequence.

[0092] |c g -c h represents the difference in the composition of two types of amino acids after the two-by-two combination of n types of amino acids.

[0093] |p g -p h represents the difference in the polarity of two types of amino acids after the two-by-two combination of n types of amino acids.

[0094] |v g -v h represents the difference in the molecular volume of two types of amino acids after the two-by-two combination of n types of amino acids.

[0095] For example, if n = 20, ∑|c g -c h is the sum of the differences in the composition of two types of amino acids after the two-by-two combination of 20 types of amino acids (380 groups in total without considering self-combination); ∑|p g -p h is the sum of the differences in the polarity of two types of amino acids after the two-by-two combination of 20 types of amino acids (380 groups in total without considering self-combination); and ∑|v g -v h is the sum of the differences in the molecular volume of two types of amino acids after the two-by-two combination of 20 types of amino acids (380 groups in total without considering self-combination).

[0096] wherein the HED value of the combined typing result allele1 / allele3 is denoted as HED 1 / 3 value; the HED value of the combined typing result allele1 / allele4 is denoted as HED 1 / 4 value; the HED value of the combined typing result allele2 / allele3 is denoted as HED 2 / 3 value; the HED value of the combined typing result allele2 / allele4 is denoted as HED 2 / 4 value.

[0097] In step S105, the sum of the HED values of the four sets of combined typing results in the exon region corresponding to the HLA allele is calculated to obtain the HED HLA等位基因 value of the recipient and the donor in the exon region corresponding to the HLA allele.

[0098] wherein HED HLA等位基因 = HED 1 / 3 + HED 1 / 4 + HED 2 / 3 + HED 2 / 4 .

[0099] In step S106, the difference between the recipient and the donor in the HLA allele is quantified according to the HED HLA等位基因 value; wherein the greater the HED HLA等位基因 value, the greater the difference between the recipient and the donor in the HLA allele; and the smaller the HED HLA等位基因 value, the smaller the difference between the recipient and the donor in the HLA allele.

[0100] The HLA allele difference visualization and quantification method provided by the present disclosure can be used to predict the risk of chronic graft-versus-host disease, or the risk of acute graft-versus-host disease, or the risk of relapse, or the risk of cytomegalovirus infection in hematopoietic stem cell transplantation. Illustratively, by quantifying the difference between HLA-A alleles and HLA-B alleles, the risk of chronic graft-versus-host disease in haploid hematopoietic stem cell transplantation can be predicted.

[0101] Method for predicting risk of chronic graft-versus-host disease for haploidentical hematopoietic stem cell transplantation:

[0102] In one embodiment, a method for predicting the risk of chronic graft-versus-host disease in haploid hematopoietic stem cell transplantation is provided. Figure 3 is a flowchart of a method for predicting the risk of chronic graft-versus-host disease in haploid hematopoietic stem cell transplantation according to an example embodiment, which comprises the following steps:

[0103] In step S201, based on the HLA allele difference quantification method provided in the embodiments of the present disclosure, the HED value of the recipient and the donor in the third exon region of HLA-A allele is calculated. HLA-A等位基因

[0104] In step S202, based on the HLA allele difference quantification method provided in the embodiments of the present disclosure, the HED value of the recipient and the donor in the third exon region of HLA-B allele is calculated. HLA-B等位基因

[0105] In step S203, the sum of the HED HLA-A等位基因 value and the HED HLA-B等位基因 value is calculated, to obtain the HED 受者 / 供者 value of the recipient and the donor in the third exon region corresponding to HLA-A allele and HLA-B allele.

[0106] In step S203, the sum of the HED HLA-A等位基因 value and the HED HLA-B等位基因 value is calculated, to obtain the HED 受者 / 供者 value of the recipient and the donor in the third exon region corresponding to HLA-A allele and HLA-B allele. HLA-A等位基因 HLA-B等位基因 受者 / 供者

[0107] In step S204, according to the HED 受者 / 供者 value, the risk of the haploid hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted. The greater the HED 受者 / 供者 value is, the lower the risk of the haploid hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted; the smaller the HED 受者 / 供者 value is, the higher the risk of the haploid hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted.

[0108] In one embodiment, the HED 受者 / 供者 value is compared with a preset threshold value, to predict the risk of the haploid hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease; if the HED 受者 / 供者 value is greater than or equal to the preset threshold value, the risk of the haploid hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is low risk; if the HED 受者 / 供者 value is less than the preset threshold value, the risk of the haploid hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is high risk.

[0109] Exemplarily, the preset threshold value is 63.36. Figure 4is a cGVHD cumulative incidence curve of the target object predicted to accept haploidentical hematopoietic stem cell transplantation and not to accept MSC treatment in the risk of developing chronic graft versus host disease, when the preset threshold is selected as 63.36. Among them, the incidence of chronic graft versus host disease in the predicted low-risk group is 17% within 18 months after haploidentical hematopoietic stem cell transplantation; the incidence of chronic graft versus host disease in the predicted high-risk group is 37% within 18 months after haploidentical hematopoietic stem cell transplantation. There is a significant difference in the incidence of cGVHD between the low-risk group and the high-risk group, and the p value is 0.0041.

[0110] The prediction method of the haploidentical hematopoietic stem cell transplantation chronic graft versus host disease risk of the present disclosure has important guiding significance for the selection of the prognosis treatment scheme of the target object.

[0111] System for predicting risk of chronic graft-versus-host disease for haploidentical hematopoietic stem cell transplantation:

[0112] In one embodiment, a prediction system of haploidentical hematopoietic stem cell transplantation chronic graft versus host disease risk is provided, which is based on the prediction method of haploidentical hematopoietic stem cell transplantation chronic graft versus host disease risk provided by the embodiments of the present disclosure. Figure 5 is a flowchart of a prediction system of haploidentical hematopoietic stem cell transplantation chronic graft versus host disease risk according to an example embodiment, which includes a HED HLA-A等位基因 value calculation module, a HED HLA-B等位基因 value calculation module, a HED 受者 / 供者 value calculation module and a prediction module.

[0113] HED HLA-A等位基因 value calculation module, configured to calculate the HED HLA*A等位基因 value of the HLA-A allele of the recipient and the donor in the third exon region of HLA-A allele. The HED HLA-A等位基因 value calculation module includes a typing result acquisition module one, a typing result combination module one, a decoding module one, a first-level calculation module one and a second-level calculation module one.

[0114] The typing result acquisition module one is configured to acquire the typing result of the HLA-A allele of the recipient and the donor.

[0115] The typing result combination module one is configured to combine the typing result of the HLA-A allele of the recipient and the donor two by two and obtain four groups of combined typing results.

[0116] The decoding module one is configured to decode the four groups of combined typing results of the HLA-A allele of the recipient and the donor into amino acid sequences respectively.

[0117] The first-level calculation module one is configured to calculate the HED value of each of the four sets of combined typing results in the third exon region of the HLA-A allele according to the amino acid sequence decoded from the four sets of combined typing results of the HLA-A alleles of the recipient and the donor.

[0118] The second-level calculation module one is configured to calculate the HED value of the recipient and the donor in the third exon region of the HLA-A allele according to the HED values of the four sets of combined typing results of the HLA-A alleles of the recipient and the donor in the third exon region of the HLA-A allele. HLA-A等位基因

[0119] The HED HLA-B等位基因 value calculation module is configured to calculate the HED value of the recipient and the donor in the third exon region of the HLA-B allele. HLA-A等位基因 The HED HLA-B等位基因 value calculation module includes the HED HLA-B等位基因 value calculation module includes the typing result acquisition module two, the typing result combination module two, the decoding module two, the first-level calculation module two and the second-level calculation module two.

[0120] The typing result acquisition module two is configured to acquire the typing results of the HLA-B alleles of the recipient and the donor.

[0121] The typing result combination module two is configured to combine the typing results of the recipient and the donor two by two to obtain four sets of combined typing results.

[0122] The decoding module two is configured to decode the four sets of combined typing results of the HLA-B alleles of the recipient and the donor into amino acid sequences respectively.

[0123] The first-level calculation module two is configured to calculate the HED value of each of the four sets of combined typing results in the third exon region of the HLA-B allele according to the amino acid sequence decoded from the four sets of combined typing results of the HLA-B alleles of the recipient and the donor.

[0124] The second-level calculation module two is configured to calculate the HED value of the recipient and the donor in the third exon region of the HLA-B allele according to the HED values of the four sets of combined typing results of the HLA-B alleles of the recipient and the donor in the third exon region of the HLA-B allele. HLA*B等位基因

[0125] The HED 受者 / 供者 value calculation module is configured to calculate the HED value of the recipient and the donor in the third exon region of the HLA-A allele and the HLA-B allele according to the HED HLA-A等位基因 value and the HED HLA-B等位基因 value. 受者 / 供者 value.​​

[0126] a prediction module configured to predict, according to the HED 受者 / 供者 value, a risk of the haploidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease. In an embodiment, the HED 受者 / 供者 value is greater, the risk of the haploidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease is lower; the HED 受者 / 供者 value is smaller, the risk of the haploidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease is higher. In an embodiment, the HED 受者 / 供者 value is compared with a preset threshold value, and the risk of the haploidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease is predicted; if the HED 受者和供者 value is greater than or equal to the preset threshold value, the risk of the haploidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease is low; if the HED 受者 / 供者 value is smaller than the preset threshold value, the risk of the haploidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease is high.

[0127] Device for predicting risk of chronic graft-versus-host disease for haploidentical hematopoietic stem cell transplantation:

[0128] In an embodiment, a device for predicting a risk of chronic graft-versus-host disease of haploidentical hematopoietic stem cell transplantation is provided, and the device comprises a memory and a processor; the memory is configured to store program instructions; and the processor is configured to invoke the program instructions, and when the program instructions are executed, steps of a method for predicting a risk of chronic graft-versus-host disease of haploidentical hematopoietic stem cell transplantation provided by an embodiment of the present disclosure are implemented.

[0129] Computer-readable storage medium:

[0130] In an embodiment, a computer readable storage medium is provided, and the computer readable storage medium stores a computer program, and when the computer program is executed by a processor, steps of a method for predicting a risk of chronic graft-versus-host disease of haploidentical hematopoietic stem cell transplantation provided by an embodiment of the present disclosure are implemented.

[0131] The above describes in detail a method for quantifying HLA allele difference and use thereof provided by the present disclosure. The principles and implementation manners of the present disclosure are described by using specific examples, and the above description of the embodiments is only used to help understand the method and core idea thereof. It should be noted that, for those skilled in the art, without departing from the principles of the present disclosure, the present disclosure can be improved and modified in several ways, and these improvements and modifications also fall within the protection scope of the claims of the present disclosure.

Claims

1. A method of HLA allele differential quantification, characterized in that, The HLA gene differential quantification method comprises the following steps: Step S101, obtaining the typing results of the HLA alleles of the recipient and the donor; wherein the typing result of the recipient is denoted as allele1 / allele2, and the typing result of the donor is denoted as allele3 / allele4; Step S102, combining the typing result allele1 / allele2 of the recipient and the typing result allele3 / allele4 of the donor in pairs to obtain four groups of combined typing results and denote them as allele1 / allele3, allele1 / allele4, allele2 / allele3 and allele2 / allele4 respectively; Step S103, decoding the four groups of combined typing results allele1 / allele3, allele1 / allele4, allele2 / allele3 and allele2 / allele4 into amino acid sequences respectively; Step S104, calculating the HED value of each group of combined typing results in the exon region corresponding to the HLA allele according to the decoded amino acid sequences of the four groups of combined typing results; wherein the HED value for the combined genotyping result allele1 / allele3 is denoted HED 1 / 3 value; The HED value for the combined genotyping result allele1 / allele4 is noted as HED 1 / 4 value; The HED value for the combined genotyping result allele2 / allele3 is noted as HED 2 / 3 values; The HED value for the combined genotyping result allele2 / allele4 is noted as HED 2 / 4 values; Step S105, calculate the sum of the HED values of the four groups of combined typing results in the exon region HED value corresponding to the allele, and obtain the HED value of the donor and the recipient in the exon region corresponding to the HLA allele HLA等位基因 ; HED HLA等位基因 = HED 1 / 3 + HED 1 / 4 + HED 2 / 3 + HED 2 / 4 ; Step S106, according to the HED HLA等位基因 value, quantifying the difference between the recipient and the donor at the HLA allele; wherein, the HED HLA 等位基因 The greater the HED value, the greater the difference between the recipient and the donor at the HLA allele; and HLA等位基因 The smaller the HED value, the smaller the difference between the recipient and the donor at the HLA allele. In step S104, the calculation formula of the HED value is as follows: HED = ∑D ij = ∑[α(c i -c j ) 2 +β(p i -p j ) 2 +γ(v i -v j ) 2 ] 1 / 2 ; Wherein, α, β, γ represent the inverse mean weight factor; i and j represent two amino acids at the same position in the HLA allele of the recipient and the donor respectively; c represents the amino acid composition; p represents the amino acid polarity; v represents the amino acid molecular volume.

2. The HLA allele differential quantification method of claim 1, wherein, The calculation formulas of α, β and γ are as follows: Wherein, n represents the number of amino acid types in the encoded amino acid sequence; |c g -c h | represents the difference between the two amino acids resulting from the pairwise combination of n amino acids. |p g -p h | represents the difference in polarity between two amino acids resulting from the pairwise combination of n amino acids; |v g -v h | represents the difference between the volumes of two amino acid molecules after two- by-two combination of n amino acids.

3. The HLA allele differential quantification method of claim 1, wherein, The HLA allele is selected from at least one of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1.

4. A system for predicting the risk of chronic graft-versus-host disease for haploidentical hematopoietic stem cell transplantation, characterized in that, The prediction system is based on a prediction method; the prediction method comprises the following steps: Step S201, based on the HLA allele difference quantification method as claimed in any one of claims 1 to 3, calculate the HED of the third exon region of HLA-A allele of the recipient and the donor HLA-A等位基因 value; Step S202, based on the HLA allele difference quantification method as claimed in any one of claims 1 to 3, calculate the HED of the third exon region of HLA-B allele of the recipient and the donor HLA-B等位基因 value; Step S203, calculating the HED of the recipient and the donor according to the HED HLA-A等位基因 values and the HED HLA-B等位基因 values, the HED of the recipient and the donor at the third exon region corresponding to the HLA-A allele and the HLA-B allele 受者 / 供者 values; HED HLA-A等位基因 +HED HLA-B等位基因 =HED 受者 / 供者 ; Step S204, according to the HED 受者 / 供者 value, the risk of the haplidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease; wherein, the HED 受者 / 供者 The greater the HED value, the lower the risk of the haplidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease; the HED 受者 / 供者 The smaller the HED value, the higher the risk of the haplidentical hematopoietic stem cell transplantation of the predicted recipient developing chronic graft-versus-host disease. The prediction system comprises: HED HLA-A等位基因 a value calculation module for calculating the HED of the recipient and the donor at the third exon region of HLA-A allele HLA-A等位基因 a value; HED HLA-B等位基因 a value calculation module for calculating the HED of the recipient and the donor at the third exon region of HLA-B allele HLA-A等位基因 a value; HED 受者 / 供者 a value calculation module, configured to calculate the HED HLA-A等位基因 value and the HED HLA-B等位基因 value of the third exon region corresponding to the HLA-A allele and the HLA-B allele of the recipient and the donor according to the HED 受者 / 供者 value of the third exon region corresponding to the HLA-A allele and the HLA-B allele of the recipient and the donor. a prediction module for predicting the risk of a recipient haploidentical hematopoietic stem cell transplant developing chronic graft-versus-host disease based on the HED 受者 / 供者 value.

5. The prediction system of claim 4, wherein, In step S204, the HED 受者 / 供者 value is compared with a preset threshold value, and the risk of the recipient developing chronic graft-versus-host disease after haploid hematopoietic stem cell transplantation is predicted. If HED 受者 / 供者 If the value is greater than or equal to the preset threshold, the predicted risk of chronic graft-versus-host disease in recipient haploidentical hematopoietic stem cell transplantation is low. If HED 受者 / 供者 If the value is less than the preset threshold, the risk of chronic graft-versus-host disease in recipient haploidentical hematopoietic stem cell transplantation is predicted to be high.

6. The prediction system of claim 5, wherein, The preset threshold value is selected from any number between 60 and 70.

7. The prediction system according to any one of claims 4 to 6, characterized in that, The HED HLA-A等位基因 The value calculation module comprises: a typing result acquisition module I, configured to acquire the typing results of the HLA-A alleles of the recipient and the donor; The typing result combination module one is used for combining the typing results of the HLA-A alleles of the recipient and the donor in pairs and obtaining four groups of combined typing results; The decoding module one is used for decoding the four groups of combined typing results of the HLA-A alleles of the recipient and the donor into amino acid sequences respectively; The first calculation module one is used for calculating the HED value of each group of combined typing results in the third exon region of the HLA-A allele according to the decoded amino acid sequences of the four groups of combined typing results of the HLA-A alleles of the recipient and the donor; The second calculation module I is used to calculate the HED value of the third exon region of HLA-A allele of the recipient and the donor according to the typing results of the four groups of combinations of the recipient and the donor HLA-A alleles, and the HED value of the third exon region of HLA-A allele of the recipient and the donor HLA-A等位基因 .

8. The prediction system according to any one of claims 4 to 6, characterized in that, The HED HLA-B等位基因 The value calculation module comprises a typing result acquisition module two, configured to acquire the typing results of the HLA-B alleles of the recipient and the donor. The typing result combination module two is used for combining the typing results of the HLA-B alleles of the recipient and the donor in pairs and obtaining four groups of combined typing results; The decoding module two is used for decoding the four groups of combined typing results of the HLA-B alleles of the recipient and the donor into amino acid sequences respectively; The decoding module II is used for decoding the typing results of the four groups of combinations of the recipient and donor HLA-B alleles into amino acid sequences respectively; the first calculation module II is used for calculating the HED values of the typing results of each group of combinations in the third exon region of the HLA-B alleles according to the amino acid sequences decoded from the typing results of the four groups of combinations of the recipient and donor HLA-B alleles. A second calculation module II is used to calculate the HED value of the third exon region of HLA-B allele of the recipient and the donor according to the typing results of the four groups of combinations HLA-B等位基因 .

9. An apparatus for predicting the risk of chronic graft-versus-host disease for haploidentical hematopoietic stem cell transplantation, characterized by, The prediction device comprises a memory and a processor; wherein the memory is used for storing program instructions; the processor is used for calling the program instructions, and the steps of the prediction method are implemented when the program instructions are executed; The prediction method comprises the following steps: Step S201, based on the HLA allele difference quantification method as claimed in any one of claims 1 to 3, calculating the HED value of the third exon region of HLA-A allele of the recipient and the donor HLA-A等位基因 value; Step S202, based on the HLA allele difference quantification method as claimed in any one of claims 1 to 3, calculate the HED of the recipient and the donor in the third exon region of HLA-B allele HLA-B等位基因 value; Step S203, calculating the HED value of the recipient and the donor according to the HED HLA-A等位基因 value and the HED HLA-B等位基因 value, calculating the HED of the recipient and the donor in the third exon region corresponding to the HLA-A allele and the HLA-B allele 受者 / 供者 value; HED HLA-A等位基因 +HED HLA-B等位基因 =HED 受者 / 供者 ; Step S204, according to the HED 受者 / 供者 value, the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted; wherein, the HED 受者 / 供者 The greater the HED value, the lower the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease; the HED 受者 / 供者 The smaller the HED value, the higher the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease.

10. The prediction device according to claim 9, characterized by In step S204, the HED 受者 / 供者 value is compared with a preset threshold value to predict the risk of the recipient developing chronic graft-versus-host disease after haploidentical hematopoietic stem cell transplantation. If HED 受者 / 供者 If the value is greater than or equal to the preset threshold, the predicted risk of chronic graft-versus-host disease in recipient haploidentical hematopoietic stem cell transplantation is low. If HED 受者 / 供者 If the value is less than the preset threshold, the risk of chronic graft-versus-host disease in recipient haploidentical hematopoietic stem cell transplantation is predicted to be high.

11. The prediction device according to claim 10, characterized by The preset threshold value is selected from any number of 60 to 70.

12. A computer readable storage medium having stored thereon a computer program, characterized in that, The computer program is executed by the processor to implement the steps of the prediction method. The prediction method comprises the following steps: Step S201, based on the HLA allele difference quantification method as claimed in any one of claims 1 to 3, calculating the HED value of the third exon region of HLA-A allele of the recipient and the donor HLA-A等位基因 value; Step S202, based on the HLA allele difference quantification method as claimed in any one of claims 1 to 3, calculate the HED of the third exon region of HLA-B allele of the recipient and the donor HLA-B等位基因 value; Step S203, calculating the HED of the recipient and the donor according to the HED HLA-A等位基因 values and the HED HLA-B等位基因 values, the HED of the third exon region corresponding to the HLA-A allele and the HLA-B allele of the recipient and the donor 受者 / 供者 values; HED HLA-A等位基因 +HED HLA-B等位基因 =HED 受者 / 供者 ; Step S204, according to the HED 受者 / 供者 value, the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted; wherein, the HED 受者 / 供者 The greater the HED value, the lower the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted; and the smaller the HED value, the higher the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted. 受者 / 供者 The smaller the HED value, the higher the risk of the haplidentical hematopoietic stem cell transplantation of the recipient developing chronic graft-versus-host disease is predicted.

13. The computer-readable storage medium of claim 12, wherein, In step S204, the HED 受者 / 供者 value is compared with a preset threshold value, and the risk of the recipient developing chronic graft-versus-host disease after haploid hematopoietic stem cell transplantation is predicted. If HED 受者 / 供者 If the value is greater than or equal to the preset threshold, the predicted risk of chronic graft-versus-host disease in recipient haploidentical hematopoietic stem cell transplantation is low. If HED 受者 / 供者 If the value is less than the preset threshold, the risk of chronic graft-versus-host disease in recipient haploidentical hematopoietic stem cell transplantation is predicted to be high.

14. The computer-readable storage medium of claim 13, wherein, The preset threshold value is selected from any number of 60 to 70. The computer program is executed by the processor to implement the steps of the prediction method. The prediction method comprises the following steps: The preset threshold value is selected from any number of 60 to 70.

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