Search

JP-7856987-B2 - SNP for diagnosing drug hypersensitivity reactions and diagnostic methods using the same

JP7856987B2JP 7856987 B2JP7856987 B2JP 7856987B2JP-7856987-B2

Inventors

  • キム、テ－ボム

Assignees

  • ジ アサン ファウンデーション
  • ユニバーシティー オブ ウルサン ファウンデーション フォー インダストリー コーオペレイション

Dates

Publication Date
20260512
Application Date
20220812
Priority Date
20210813

Claims (11)

  1. A composition for determining or predicting drug hypersensitivity reactions, comprising a detection formulation for SNP rs35372932 in the dbSNP database, SNP rs35372932 is a variant in which the 3,259,7208th base on chromosome 6 is substituted from cytosine (C) to thymine (T). The detection formulation is a composition, which is a probe or a primer set.
  2. The composition for determining or predicting drug hypersensitivity reactions according to claim 1, characterized in that the drug hypersensitivity reaction is either an immediate-type or delayed-type drug hypersensitivity reaction.
  3. A composition for determining or predicting the onset of a drug hypersensitivity reaction according to claim 1, The composition further includes rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, rs206887084, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, rs3924164, rs11206477, rs62225078 selected from the dbSNP database. The formulation comprises one or more SNP detection formulations selected from the group consisting of rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, rs144130219, rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, wherein, rs79736818 is a variant in which the 148357581st base of chromosome 5 is substituted from adenine (A) to guanine (G). rs3129871 is a variant in which the 32438565th base on chromosome 6 is substituted from cytosine (C) to adenine (A) . rs9557291 is a variant in which the 99761210th base on chromosome 13 is substituted from guanine (G) to adenine (A). rs11724428 is a variant in which the 112598451st base of chromosome 4 is substituted from guanine (G) to adenine (A) . r s11123552 is a variant in which the 120454245th base of chromosome 2 is substituted from cytosine (C) to guanine (G). rs62124613 is a variant in which the 20386466th base on chromosome 2 is substituted from cytosine (C) to thymine (T). rs77389536 is a variant in which the 102408368th base on chromosome 10 is substituted from thymine (T) to cytosine (C) . rs206887084 is a variant in which the 94620980th base on chromosome 12 is substituted from guanine (G) to adenine (A). rs372025 is a variant in which the 107077214th base on chromosome 4 is substituted from thymine (T) to cytosine (C) . r s8058114 is a variant in which the 12603772nd base of chromosome 16 is substituted from guanine (G) to adenine (A). rs143395859 is a variant in which the 27293404th base on chromosome 7 is substituted from guanine (G) to adenine (A). rs57833801 is a variant in which the 121777405th base on chromosome 2 is substituted from guanine (G) to adenine (A) . rs139830888 is a variant in which the 147872742nd base on chromosome 7 is substituted from guanine (G) to adenine (A). rs9384423 is a variant in which the 156089071st base on chromosome 6 is substituted from adenine (A) to guanine (G) . r s6097064 is a variant in which the 37952348th base on chromosome 20 is substituted from adenine (A) to cytosine (C). rs2175562 is a variant in which the 140398639th base on chromosome 4 is substituted from adenine (A) to guanine (G) . r s3924164 is a variant in which the 76737927th base on chromosome 18 is substituted from cytosine (C) to thymine (T). rs11206477 is a variant in which the base at position 54941621 on chromosome 1 is substituted from cytosine (C) to adenine (A). rs62225078 is a variant in which the 47740975th base on chromosome 22 is substituted from thymine (T) to adenine (A) . r s73202933 is a variant in which the 89819306th base on chromosome 12 is substituted from thymine (T) to cytosine (C). rs72622187 is a variant in which the 6078051st base on chromosome 3 is substituted from guanine (G) to adenine (A) . r s139141104 is a variant in which the 31021244th base on chromosome 6 is substituted from adenine (A) to guanine (G). rs9994092 is a variant in which the 65570396th base on chromosome 4 is substituted from cytosine (C) to adenine (A) . r s1762852884 is a variant in which the 30994936th base on chromosome 6 is substituted from adenine (A) to cytosine (C) . r s2335545 is a substitution of cytosine (C) to thymine (T) at base position 2916111 of chromosome 16. rs9688895 is a variant in which the 38465523rd base on chromosome 16 is substituted from cytosine (C) to adenine (A) . r s144130219 is a variant in which the 98725782nd base on chromosome 13 is substituted from thymine (T) to cytosine (C). rs78831487 is a variant in which the base at position 6537140 on chromosome 19 is substituted from thymine (T) to cytosine (C) . r s456449 is a variant in which the 38851003rd base on chromosome 21 is substituted from guanine (G) to adenine (A). rs13250548 is a variant in which the 35650882nd base on chromosome 8 is substituted from adenine (A) to guanine (G). rs77068773 is a variant in which the 23204196th base on chromosome 21 is substituted from adenine (A) to thymine (T) . rs3025035 is a variant in which the 43783622nd base on chromosome 6 is substituted from cytosine (C) to thymine (T). rs2088142 is a variant in which the base at position 33691285 on chromosome 15 is substituted from guanine (G) to adenine (A) . r s1276175 is a variant in which the 30945691st base of chromosome 5 is substituted from guanine (G) to adenine (A). rs144157017 is a variant in which the base at position 50740465 on chromosome 6 is substituted from adenine (A) to guanine (G) . r s59594955 is a variant in which the base at position 38443346 on chromosome 6 is substituted from adenine (A) to cytosine (C). rs28717999 is a composition in which the 65571223rd base of chromosome 4 is substituted from adenine (A) to guanine (G).
  4. If the SNP is one or more selected from the group consisting of rs35372932, rs79736818, rs3129871, rs9557291, rs11724428, rs11123552, rs62124613, rs77389536, and rs206887084, then the composition is for determining drug hypersensitivity reactions or predicting the onset of illness in healthy individuals. If the SNP is one or more selected from the group consisting of rs9557291, rs372025, rs8058114, rs143395859, rs57833801, rs139830888, rs9384423, rs6097064, rs2175562, and rs3924164, then the composition is for determining immediate-type drug hypersensitivity reactions or predicting the onset of illness in healthy individuals. If the SNP is one or more selected from the group consisting of 3) rs11206477, rs62225078, rs73202933, rs72622187, rs139141104, rs9994092, rs1762852884, rs2335545, rs9688895, and rs144130219, then the composition is for determining delayed-type drug hypersensitivity reactions or predicting the onset of illness in healthy individuals. The composition for determining drug hypersensitivity reactions or predicting the onset of a drug hypersensitivity reaction according to claim 3, characterized in that the SNP is one or more selected from the group consisting of 4) rs78831487, rs456449, rs13250548, rs77068773, rs3025035, rs2088142, rs1276175, rs144157017, rs59594955, and rs28717999, wherein the composition is for distinguishing between immediate-type and delayed-type drug hypersensitivity reactions.
  5. The composition for determining or predicting drug hypersensitivity reactions according to claim 1, characterized in that the drug hypersensitivity reaction occurred in a Korean person.
  6. A kit for determining drug hypersensitivity reactions, comprising the composition described in claim 1.
  7. The kit according to claim 6 , characterized in that the kit is an RT-PCR kit or a microarray chip kit.
  8. A method for providing information necessary for determining drug hypersensitivity reactions, which includes the step of determining that a subject has developed a drug hypersensitivity reaction if the single nucleotide polymorphism rs35372932 in dbSNPs is present in the base sequence of an SNP site in a sample obtained from a subject, SNP rs35372932 is a cytosine (C) to thymine (T) substitution at base 32597208 on chromosome 6.
  9. A method for providing information necessary for predicting the onset of a drug hypersensitivity reaction, which includes the step of determining that a subject is at high risk of developing a drug hypersensitivity reaction if the SNP described in claim 8 is present in the base sequence of the SNP site in a sample obtained from a subject, SNP rs35372932 is a variant in which the 3,2597,208th base on chromosome 6 is substituted from cytosine (C) to thymine (T).
  10. The method according to 9, characterized in that the method is performed by one or more methods selected from the group consisting of sequencing, exome sequencing, microarray hybridization, allele-specific PCR, dynamic allele-specific hybridization, PCR extension analysis, and the Taqman method.
  11. The use of a formulation for detecting SNP rs35372932 in dbSNP database for manufacturing a formulation for determining drug hypersensitivity reactions or predicting the onset of disease, SNP rs35372932 is a variant in which the 3,2597,208th base on chromosome 6 is substituted from cytosine (C) to thymine (T). The detection formulation is a probe or primer set, used.

Description

This invention relates to SNPs for diagnosing drug hypersensitivity reactions and diagnostic methods using the same. This application claims priority under Korean Patent Application No. 10-2021-0107164, filed on August 13, 2021, and all content disclosed in the specification and drawings of said application is incorporated herein by reference. Medically, drug allergy refers to a reaction mediated by immunological mechanisms in patients sensitized to a drug, and is different from what the general public or patients mean when they say they have a drug side effect or drug allergy. While drug side effects and drug allergies are commonly used, they often refer to adverse drug reactions. Adverse drug reactions encompass the majority of adverse reactions caused by drugs, and the WHO defines them as unintended harmful reactions to the human body that occur in addition to therapeutic effects when a drug is administered in a normal dose via an appropriate route for prevention, diagnosis, and treatment. Adverse drug reactions can be broadly divided into predictable Type A reactions, which are related to the drug dose, and unpredictable Type B reactions, which are independent of the drug dose. Predictable Type A adverse drug reactions account for about 80% of all adverse drug reactions and are mainly caused by the drug's inherent pharmacological effects, and therefore include dose-dependent drug toxicity, side effects, indirect effects, and drug interactions. Unpredictable adverse drug reactions of type B drugs account for approximately 15-20% of the remaining cases and include hypersensitivity, idiosyncrasies, intolerances, and pseudoallergic reactions. The World Allergy Organization (WAO) recommends classifying drug allergies into immediate (within 1 hour) and delayed (more than 1 hour) types based on the time it takes for symptoms to appear after drug exposure. According to the Gell & Coombs classification, hypersensitivity reactions to not only drugs but also other environmental factors are divided into four types. Of these, those related to drug allergies are primarily type I, which involves IgE, and type IV, which involves T-cells. Type I reactions are immediate-type humoral immune responses mediated by IgE, mast cells, basophils, etc., and include anaphylaxis, angioedema, bronchospasm, and urticaria (hives). Representative drugs that elicit this type of reaction include β-antibiotics (penicillins and cephalosporins), quinolone myocardial inhibitory drugs, platinum compounds such as carboplatin and oxaliplatin n, and monoclonal antibodies such as cetuximab and rituximab. Types II to IV are delayed reactions. Type II refers to humoral cytotoxic reactions mediated by IgM or IgG antibodies and complement, including hemolytic anemia, thrombocytopenia, and neutropenia. Representative drugs include β-lactam antibiotics (penicillin and cephalosporins), NSAIDs (non-steroidal antiinflammatory drugs), quinine/quinidine, vancomycin, carbamazepine, propylthiouracil, and flecainide. Thus, drug hypersensitivity reactions are the most serious form of allergic reactions and are considered a medical emergency; therefore, predicting the occurrence of drug hypersensitivity reactions in advance is extremely important. Based on this, the inventors conducted GWAS analysis to predict and diagnose drug hypersensitivity reactions, and as a result, identified SNPs that have a significant correlation with drug hypersensitivity reactions, thus completing the present invention. Figures 1a and 1b are diagrams summarizing the quality control (QC) process flow according to one embodiment of the present invention, where Figure 1a is a quality control process flow diagram for discovery analysis and Figure 1b is a quality control process flow diagram for replication analysis.Figure 2 shows a multidimensional scaling (MDS) plot of the discovery data for the 1000G dataset, where blue, yellow, and gray represent the control group, cases (DHR, immediate + delayed), and the 1000G population, respectively.Figures 3a to 3c show quantile (Q-Q) plots of the analysis data. Figure 3a shows the analysis results for the control group versus DHR, Figure 3b shows the analysis results for the control group versus immediate-type reactions, and Figure 3c shows the analysis results for the control group versus delayed-type reactions.Figure 4 shows the Manhattan plot of the control group versus DHR (immediate + delayed) based on discovery analysis, with the red line indicating the significance level of Bonferroni correction.Figures 5a and 5b show region plots; Figure 5a shows the results of logistic regression analysis for the control group versus DHR, and Figure 5b shows a generalized multinomial logit model for the control group versus delayed response.Figure 6 shows the Miami plot obtained from discovery analysis. The upper panel shows the comparison results between immediate-type responses and the control group, and the lower panel shows the comparison results be