Biomarker for predicting prognosis effect of ursodesoxycholic acid medication for primary biliary cholangitis and application of biomarker

Abstract

The invention provides a biomarker for predicting the prognosis effect of ursodesoxycholic acid for primary biliary cholangitis and application of the biomarker, and belongs to the technical field of biomarkers. The biomarker disclosed by the invention comprises an activating agent AHSA1 of a 90 kDa heat shock protein ATPase homolog 1 and a glycosylated form C4BN226HexNAc (2) Hex( 7) of a complement C4-B. The invention further discloses a preparation method of the biomarker. According to the method, the improvement of the PBC medication efficiency is taken as a starting point, the serum protein and the N-glycopeptide are taken as screening templates, a more accurate non-invasive prediction means for the curative effect of the PBC medication UDCA is provided, and a theoretical basis is provided for personalized treatment of PBC.

Description

Technical Field

[0001] This invention relates to the field of biomarker technology, and in particular to a biomarker for predicting the prognostic effect of ursodeoxycholic acid, a drug used in primary biliary cholangitis, and its application. Background Technology

[0002] Autoimmune liver diseases (AILD) include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Among these, PBC is a cholestatic autoimmune disease primarily affecting bile duct cells. It is a chronic, progressive disease that can eventually lead to cirrhosis and liver failure; for patients in the late stages, liver transplantation is the only treatment option. Therefore, slowing disease progression in its early stages is a key clinical focus.

[0003] Ursodeoxycholic acid (UDCA) is currently a first-line drug for the treatment of polycystic purpura (PBC). It can slow disease progression at the histological level, prolong the survival rate of patients without liver transplantation, and has few adverse reactions, good patient tolerance, and wide clinical application. However, approximately 40% of patients do not achieve a complete biological response when treated with UDCA monotherapy, significantly reducing clinical benefits. Therefore, predicting the prognostic effect of UDCA in PBC patients before using it for treatment is of great significance.

[0004] Currently, standards for assessing the efficacy of UDCA include the Paris criteria (Paris-I, Paris-II), the Barcelona criteria, the GLOBE score, and the UK-PBC score. However, different standards have varying sensitivity and specificity, which may lead to differences in prognostic assessment results for the same patient. The challenges in UDCA prognosis assessment are mainly reflected in the lack of standardized criteria, significant individual variability, missing histological data, and the complexity of dynamic monitoring. Therefore, providing a biomarker that can accurately and non-invasively predict the prognostic effect of ursodeoxycholic acid (UDCA) in primary biliary cholangitis represents an important unmet medical need.

[0005] Glycosylation is one of the most common types of protein modification, and N-linked glycoproteins (N-glycoproteins) are particularly abundant in eukaryotes, especially in immune-related proteins. Many glycoproteins are associated with the development and progression of chronic diseases, including liver diseases, and some have been used as biomarkers for cancer diagnosis. However, whether serum proteins and N-glycoproteins can serve as non-invasive diagnostic biomarkers for predicting the prognostic effect of ursodeoxycholic acid in primary biliary cholangitis remains to be determined. Summary of the Invention

[0006] The purpose of this invention is to provide a biomarker for predicting the prognostic effect of ursodeoxycholic acid, a drug used in primary biliary cholangitis, and its application.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a biomarker for predicting the prognostic effect of ursodeoxycholic acid, a drug for primary biliary cholangitis. The biomarker includes AHSA1, an activator of 90 kDa heat shock protein ATPase homolog 1, and the glycosylated form of complement C4-B, C4B_N226_HexNAc(2)Hex(7).

[0008] Preferably, the biomarkers also include clinical variables such as body mass index, albumin, globulin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, direct bilirubin, total bile acids, and immunoglobulin M.

[0009] Preferably, the prognostic effect prediction of the drug ursodeoxycholic acid for primary biliary cholangitis is to distinguish between ursodeoxycholic acid response and non-response.

[0010] This invention provides the application of a biomarker in the preparation of a product for predicting the prognostic effect of ursodeoxycholic acid, a drug for primary biliary cholangitis. The biomarker includes AHSA1, an activator of 90 kDa heat shock protein ATPase homolog 1, and the glycosylated form of complement C4-B, C4B_N226_HexNAc(2)Hex(7).

[0011] Preferably, the biomarkers also include clinical variables such as body mass index, albumin, globulin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, direct bilirubin, total bile acids, and immunoglobulin M.

[0012] Preferably, the prognostic effect prediction of the drug ursodeoxycholic acid for primary biliary cholangitis is to distinguish between ursodeoxycholic acid response and non-response.

[0013] This invention provides a product for predicting the prognostic effect of ursodeoxycholic acid, a drug used in primary biliary cholangitis, wherein the product contains a reagent for detecting the biomarker.

[0014] Preferably, the product includes a reagent kit.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention provides an application of non-invasive biomarkers in predicting UDCA response to PBC medication, wherein the biomarkers include AHSA1 and C4B_N226_HexNAc(2)Hex(7). This invention solves the problem of difficult prediction of UDCA response to PBC medication and provides a foundation for the diagnosis and treatment of PBC.

[0016] This invention aims to improve the efficacy of PBC medication. Using serum proteins and N-glycopeptides as screening templates, it provides a more accurate, non-invasive method for predicting the efficacy of UDCA in PBC medication, thus providing a theoretical basis for personalized treatment of PBC. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0018] Figure 1 This is the AUC curve of the response of the biomarker UDCA-treat to PBC drug treatment for UDCA in Example 1; Figure 2 This is the AUC curve of the response of PBC drug treatment to UDCA after the biomarker UDCA-treat was combined with clinical variables in Example 1; Figure 3 The results of LC-MS / MS detection of AHSA1 and C4B_N226_HexNAc(2)Hex(7) in the biomarker UDCA-treat in Example 1 in the serum of patients in the UDCA response group and patients in the UDCA non-response group are shown. Detailed Implementation

[0019] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0020] The inventors investigated biomarkers associated with PBC based on a discovery cohort [healthy control group (CTR=138), primary biliary cholangitis (PBC=215), autoimmune hepatitis (AIH=100), and PBC+AIH overlap syndrome (PBC+AIH=119)] and a validation cohort (CTR=32, PBC=61, AIH=31, PBC+AIH=41). The following examples investigated biomarkers predicting the prognostic effect of ursodeoxycholic acid in PBC treatment, using a discovery cohort of PBC=215 and a validation cohort of PBC=61.

[0021] Example 1

[0022] This embodiment aims to explore the role of different serum proteins and N-glycopeptides (IGP) in predicting the prognostic effect of ursodeoxycholic acid in primary biliary cholangitis.

[0023] We included differentially expressed proteins (N=36) and IGP (N=6) (fold change >1.5, P<0.05) between the UDCA non-response and response groups as candidate biomarkers for predicting PBC outcomes after UDCA treatment. Feature selection was evaluated using 2000 combinations with 1 / 2 / 3 / 5 / 7 / 10 features. A random forest model was constructed using the `train()` function of the `caret` package in R, and the hyperparameter `mtry` was optimized based on the Kappa coefficient using 10-fold cross-validation, while other parameters remained at their default settings. The optimal model with 1 / 2 / 3 / 5 / 7 / 10 features was selected. The output represents the patient's probability in both the response and non-response categories; the highest probability indicates the predicted response to UDCA treatment.

[0024] The results showed that the combination of two biomarkers (UDCA-treat), namely the activator of 90 kDa heat shock protein ATPase homology 1 (AHSA1) and the glycosylated form of complement C4-B, C4B_N226_HexNAc(2)Hex(7) (C4B_N226_HexNAc(2)Hex(7)), had ROC-AUC values ​​of 0.74 and 0.9, respectively, in predicting UDCA responses on the training and validation sets. Figure 1 When 10 clinical variables (BMI, ALB, GLO, ALP, ALT, AST, GGT, DBIL, TBA, and IgM) were added to these two proteins, the ROC-AUC values ​​in the training and validation sets for predicting UDCA responses were 0.959 and 0.94, respectively. Figure 2 This indicates that the combination of biomarkers can serve as candidate biomarkers for UDCA response. Compared with the UDCA responder group, patients in the non-responder group had higher abundances of AHSA1 and C4B_N226_HexNAc(2)Hex(7). Figure 3 Although the removal of ASHA1 or C4B_N226_HexNAc(2)Hex(7) alone has little effect on the UDCA treatment model, the removal of both leads to a significant reduction in training and validation metrics (Table 1).

[0025] Table 1 Ablation analysis results of features in the UDCA-treat model

[0026] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A biomarker for predicting the prognostic effect of ursodeoxycholic acid, a drug used in primary biliary cholangitis, characterized in that, The biomarkers include AHSA1, an activator of 90 kDa heat shock protein ATPase homology 1, and the glycosylated form of complement C4-B, C4B_N226_HexNAc(2)Hex(7).

2. The biomarker as described in claim 1, characterized in that, The biomarkers also include clinical variables such as body mass index, albumin, globulin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, direct bilirubin, total bile acids, and immunoglobulin M.

3. The biomarker as described in claim 1 or 2, characterized in that, The prognostic effect prediction of ursodeoxycholic acid in primary biliary cholangitis is to distinguish between ursodeoxycholic acid response and non-response.

4. The application of a biomarker in the preparation of a product for predicting the prognostic effect of ursodeoxycholic acid, a drug for primary biliary cholangitis, characterized in that, The biomarkers include AHSA1, an activator of 90 kDa heat shock protein ATPase homology 1, and the glycosylated form of complement C4-B, C4B_N226_HexNAc(2)Hex(7).

5. The application as described in claim 4, characterized in that, The biomarkers also include clinical variables such as body mass index, albumin, globulin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, direct bilirubin, total bile acids, and immunoglobulin M.

6. The application as described in claim 4 or 5, characterized in that, The prognostic effect prediction of ursodeoxycholic acid in primary biliary cholangitis is to distinguish between ursodeoxycholic acid response and non-response.

7. A product for predicting the prognostic effect of ursodeoxycholic acid, a drug used in primary biliary cholangitis, characterized in that, The product contains a reagent for detecting the biomarker described in claim 1 or 2.

8. The product as described in claim 7, characterized in that, The product includes a reagent kit.

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