Biomarker composition for determining exposure to heavy metals in air in people with allergic diseases

Abstract

The present invention relates to: a biomarker composition capable of determining whether an individual having an allergic disease is exposed to heavy metals in the air; a kit comprising an agent capable of detecting the biomarker; and the like. More specifically, the biomarker composition and the like of the invention is achieved by identifying genes of which the expression increases when an individual having an allergic disease is exposed to heavy metals.

Description

Biomarker composition for determining exposure to heavy metals in the air in patients with allergic diseases

[0001] The present invention relates to a biomarker composition capable of determining whether an individual with an allergic disease is exposed to heavy metals in the air, an information providing method including a step of measuring the expression level of the biomarker, and a kit including a preparation capable of detecting the biomarker.

[0002] Allergic reactions are conditions caused by the immune system's hypersensitivity to a specific environment. The number of patients has been steadily increasing over the past 20 to 30 years. The incidence of allergic diseases continues to rise in modern society, yet a complete cure has not yet been developed.

[0003] Common allergens include pollen, certain foods, medications, and metals. While it is well known that some metals trigger allergic reactions, research on the effects of exposure to fine heavy metal particles in the air (i.e., inhalation) on individuals with allergic diseases is limited.

[0004] As a prior art, Amir Zahedi et al., Effect of ambient air PM2.5-bound heavy metals on blood metal(loid)s and children's asthma and allergy pro-inflammatory (IgE, IL-4 and IL-13) biomarkers, Journal of Trace Elements in Medicine and Biology, Volume 68, December 2021, 126826 reported on the effect of heavy metals bound to ambient PM2.5 on inflammatory responses, but failed to suggest heavy metal-specific markers or identify the effects in patients with allergic diseases.

[0005] Regarding the effects on respiratory allergies, it has been reported that exposure to certain heavy metals in the air, such as cadmium, can worsen respiratory allergies such as asthma, and cadmium exposure is known to be associated with increased airway inflammation and worsening asthma symptoms, but there have been no reports on diagnostic technologies or biomarkers that can effectively identify and proactively address these.

[0006] Accordingly, the inventors of the present invention completed the invention of this biomarker by evaluating the effects of exposure to heavy metals in the air on patients with allergic diseases.

[0007] The technical task of the present invention is to provide a biomarker composition for confirming whether a patient with an allergic disease is exposed to heavy metals in the air.

[0008] Another technical task of the present invention is to provide a method for providing information necessary for determining whether an individual suffering from an allergic disease is exposed to heavy metals in the air.

[0009] Another technical task of the present invention is to provide a diagnostic kit for determining whether a patient with an allergic disease is exposed to heavy metals in the air.

[0010] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0011] In order to solve the above problem, the present invention provides a biomarker composition for determining whether a patient with an allergic disease is exposed to heavy metals in the air, comprising at least one gene selected from the group consisting of the following, or an expression product of the corresponding gene: S100A13 (S100 calcium-binding protein A13, Gene ID: 6283), USP9X (Ubiquitin Specific Peptidase 9, X-Linked, Gene ID: 8239), SNORD33 (Small Nucleolar RNA, C / D Box 33, Gene ID: 26818), PDHB (Pyruvate Dehydrogenase E1 Beta Subunit, Gene ID: 5162), EIF4E3 (Eukaryotic Translation Initiation Factor 4E Family Member 3, Gene ID: 317649), EBF1 (Early B Cell Factor 1, Gene ID: 1879), POLR2J3 (RNA Polymerase II Subunit J3, Gene ID: 548644), CPNE5 (Copine 5, Gene ID: 57699), ADD1 (Adducin 1, Gene ID: 118), POLR2J2 (RNA Polymerase II Subunit J2, Gene ID: 246721), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), CAPN10-DT (CAPN10 Divergent Transcript, Gene ID: 101752400), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), RASA4DP (RAS P21 Protein Activator 4, Divergent Pseudogene, Gene ID: 100133005),CCDC138 (Coiled-Coil Domain Containing 138, Gene ID: 165055), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), DLG1 (Discs Large MAGUK Scaffold Protein 1, Gene ID: 1739), LOC105374942 (Gene ID: 105374942), LOC105371573 (Gene ID: 105371573), RPS2P40 (Ribosomal Protein S2 Pseudogene 40, Gene ID: 91561), CLASP2 (CLIP-Associating Protein 2, Gene ID: 23122), SPTAN1 (Spectrin Alpha, Non-Erythrocytic 1, Gene ID: 6709), TNS3 (Tensin 3, Gene ID: 64759), MTCH2 (Mitochondrial Carrier 2, Gene ID: 23788), DOT1L (DOT1 Like Histone Lysine Methyltransferase, Gene ID: 84444), DNM3 (Dynamin 3, Gene ID: 26052), TMEM116 (Transmembrane Protein 116, Gene ID: 89894), MAN2A2 (Mannosidase Alpha Class 2A Member 2, Gene ID: 4126), THUMPD3P1 (THUMP Domain Containing 3 Pseudogene 1, Gene ID: 100419989), ZNF606 (Zinc Finger Protein 606, Gene ID: 80095), CD79A (CD79a Molecule, Immunoglobulin-Associated Alpha, Gene ID: 973), POC1B (POC1 Centriolar Protein B, Gene ID: 282809),LOC101927365 (Gene ID: 101927365), WDFY4 (WD Repeat And FYVE Domain Containing 4, Gene ID: 57705), FAM135A (Family With Sequence Similarity 135 Member A, Gene ID: 57579), LMO7 (LIM Domain 7, Gene ID: 4008), CBWD5 (COBW Domain Containing 5, Gene ID: 220869), LOC107984281 (Gene ID: 107984281), LOC105376624 (Gene ID: 105376624), NAGPA (N-Acetylglucosamine-1-Phosphodiester Alpha-N-Acetylglucosaminidase, Gene ID: 51172), GYG1P3 (Glycogenin 1 Pseudogene 3, Gene ID: 645506), IGLV4-60 (Immunoglobulin Lambda Variable 4-60, Gene ID: 28785), SH2B2 (SH2B Adaptor Protein 2, Gene ID: 10603), WDR7 (WD Repeat Domain 7, Gene ID: 23335), SDCBPP3 (Syndecan Binding Protein Like 3, Gene ID: 100131656), AURKAIP1 (Aurora Kinase A Inhibitory Protein 1, Gene ID: 54998), ZCCHC17 (Zinc Finger CCHC-Type Containing 17, Gene ID: 51538), ENTPD6 (Ectonucleoside Triphosphate Diphosphohydrolase 6, Gene ID: 955), EFCC1 (EF-Hand And Coiled-Coil Domain Containing 1, Gene ID: 79825),HNRNPUL2-BSCL2 (HNRNPUL2-BSCL2 Readthrough, Gene ID: 100534595), DLEU1 (Deleted In Lymphocytic Leukemia 1, Gene ID: 10301), CCNJ (Cyclin J, Gene ID: 54619), TAF12 (TATA-Box Binding Protein Associated Factor 12, Gene ID: 6883), CLCN5 (Chloride Voltage-Gated Channel 5, Gene ID: 1184), PLEKHG2 (Pleckstrin Homology And RhoGEF Domain Containing G2, Gene ID: 64857), ZNF542P (Zinc Finger Protein 542, Pseudogene Gene ID: 147947), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), CBWD3 (Zn regulated GTPase metalloprotein activator 1C, Gene ID: 445571), ASXL1 (ASXL Transcriptional Regulator 1, Gene ID: 171023), FAM214A (Family With Sequence Similarity 214 Member A, Gene ID: 56204), MIR6894 (MicroRNA 6894, Gene ID: 102466759), TRAM1 (Translocation Associated Membrane Protein 1, Gene ID: 23471), GABBR1 (Gamma-Aminobutyric Acid Type B Receptor Subunit 1, Gene ID: 2550),STT3A (STT3 Oligosaccharyltransferase Complex Catalytic Subunit A, Gene ID: 3703), PRIM2 (DNA Primase Subunit 2, Gene ID: 5558), COPG2 (Coatomer Protein Complex Subunit Gamma 2, Gene ID: 26958), MTCH2 (Mitochondrial Carrier 2, Gene ID: 23788), HSF5 (Heat Shock Transcription Factor Family Member 5, Gene ID: 124535), RABGAP1L (RAB GTPase Activating Protein 1 Like, Gene ID: 9910), SEC13 (SEC13 Homolog, Nuclear Pore And COPII Coat Complex Component, Gene ID: 6396), TMEM209 (Transmembrane Protein 209, Gene ID: 84928), IL32 (Interleukin 32, Gene ID: 84928), MBNL1 (Muscleblind Like Splicing Regulator 1, Gene ID: 4154), CD38 (CD38 Molecule, Gene ID: 952), UBE2G1 (Ubiquitin Conjugating Enzyme E2 G1, Gene ID: 7326), KCNIP2 (Kv Channel Interacting Protein 2, Gene ID: 30819), TRIM68 (Tripartite Motif Containing 68, Gene ID: 55128), TTC41P (Tetratricopeptide Repeat Domain 41, Pseudogene, Gene ID: 253724), MIR5692C2 (MicroRNA 5692c-2, Gene ID: 100847017), CD9 (CD9 Molecule, Gene ID: 928),WDFY4 (WD Repeat And FYVE Domain Containing 4, Gene ID: 57705), LOC283710 (Uncharacterized LOC283710 Gene ID: 283710), ESS2 (ESS2 Splicing Factor Homolog, Gene ID: 8220), TSPAN14 (Tetraspanin 14, Gene ID: 81619), LOC107986704 (Uncharacterized LOC107986704, Gene ID: 107986704), RPS12P14 (Ribosomal Protein S12 Pseudogene 14, Gene ID: 100271058), IGHV3-43 (Immunoglobulin Heavy Variable 3-43, Gene ID: 28426), IGHV7-4-1 (Immunoglobulin Heavy Variable 7-4-1, Gene ID: 57289), MIR21 (MicroRNA 21, Gene ID: 406991), ZNF606 (Zinc Finger Protein 606, Gene ID: 80095), FAM30A (Family With Sequence Similarity 30 Member A, Gene ID: 9834), SNHG12 (Small Nucleolar RNA Host Gene 12, Gene ID: 85028), TXNDC11 (Thioredoxin Domain Containing 11, Gene ID: 51061), TMEM154 (Transmembrane Protein 154, Gene ID: 201799), CCDC18 (Coiled-Coil Domain Containing 18, Gene ID: 343099), LOC107984281 (Uncharacterized LOC107984281, Gene ID: 107984281), IGHJ6 (Immunoglobulin Heavy Joining 6, Gene ID: 28475),IGHV3-64 (Immunoglobulin Heavy Variable 3-64, Gene ID: 28414), IGHV3-73 (Immunoglobulin Heavy Variable 3-73, Gene ID: 28409), IGHV4-59 (Immunoglobulin Heavy Variable 4-59, Gene ID: 28392), TAOK3 (Thousand And One Kinase 3, Gene ID: 51347), TRAK1 (Trafficking Kinesin-Binding Protein 1, Gene ID: 22906), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), CCNJ (Cyclin J, Gene ID: 54619), CHSY1 (Chondroitin Sulfate Synthase 1, Gene ID: 22856), ZHX3 (Zinc Fingers And Homeoboxes 3, Gene ID: 23051), WASHC1 (WASH Complex Subunit 1, Gene ID: 100287171), FANK1 (Fibronectin Type III And Ankyrin Repeat Domains 1, Gene ID: 92565), PTCRA (Pre T-Cell Antigen Receptor Alpha, Gene ID: 171558), CLCN5 (Chloride Voltage-Gated Channel 5, Gene ID: 1184), PLEKHG2 (Pleckstrin Homology And RhoGEF Domain Containing G2, Gene ID: 64857), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504),EFCAB12 (EF-Hand Calcium Binding Domain 12, Gene ID: 90288), DOT1L (DOT1 Like Histone Lysine Methyltransferase, Gene ID: 84444), KIAA0319L (KIAA0319 Like, Gene ID: 79932), ASXL1 (ASXL Transcriptional Regulator 1, Gene ID: 171023), MIR6894 (MicroRNA 6894, Gene ID: 102466759), P2RY8 (Purinergic Receptor P2Y8, Gene ID: 286530), PRIM2 (DNA Primase Subunit 2, Gene ID: 5558), TMEM116 (Transmembrane Protein 116, Gene ID: 89894), SEC13 (SEC13 Homolog, Nuclear Pore And COPII Coat Complex Component, Gene ID: 6396), PCBD1 (Pterin-4 Alpha-Carbinolamine Dehydratase / Dimerization Cofactor Of Hepatocyte Nuclear Factor 1 Alpha, Gene ID: 5092), TMEM209 (Transmembrane Protein 209, Gene ID: 84928), IL32 (Interleukin 32, Gene ID: 9235), UBE2G1 (Ubiquitin Conjugating Enzyme E2 G1, Gene ID: 7326), MIR4435-2HG (MIR4435-2 Host Gene, Gene ID: 541471), KIAA2026 (KIAA2026, Gene ID: 158358), PPIP5K1 (Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Beta, Gene ID: 9677), ESS2 (ESS2 Splicing Factor Homolog,Gene ID: 8220), FAM172A (Family With Sequence Similarity 172 Member A, Gene ID: 83989), LOC105369194 (Uncharacterized LOC105369194, Gene ID: 105369194), LOC107986704 (Uncharacterized LOC107986704, Gene ID: 107986704), MIR21 (MicroRNA 21, Gene ID: 406991), SH2B2 (SH2B Adaptor Protein 2, Gene ID: 10603), WDR7 (WD Repeat Domain 7, Gene ID: 23335), MARCHF1 (Membrane Associated Ring-CH-Type Finger 1, Gene ID: 55016), ABLIM3 (Actin Binding LIM Protein Family Member 3, Gene ID: 22885), ZGRF1 (Zinc Finger GRF-Type Containing 1, Gene ID: 55345), DBF4B (DBF4 Zinc Finger B, Gene ID: 80174), WDSUB1 (WD Repeat And Sterile Alpha Motif Domain Containing 1, Gene ID: 151525), MIR8061 (MicroRNA 8061, Gene ID: 102466251), TRUB2 (TruB Pseudouridine (Psi) Synthase Family Member 2, Gene ID: 26995), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), ANKS1A (Ankyrin Repeat And Sterile Alpha Motif Domain Containing 1A, Gene ID: 23294), EIF3B (Eukaryotic Translation Initiation Factor 3 Subunit B,Gene ID: 8662), PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma, Gene ID: 5294), INTS14 (Integrator Complex Subunit 14, Gene ID: 81556), LOC105376253 (Uncharacterized LOC105376253, Gene ID: 105376253), FBXW5 (F-Box And WD Repeat Domain Containing 5, Gene ID: 54461), NAB1 (NGFI-A Binding Protein 1, Gene ID: 4664), DENND3 (DENN Domain Containing 3, Gene ID: 22898), LRRC27 (Leucine Rich Repeat Containing 27, Gene ID: 80313), GPS2P2 (G Protein Pathway Suppressor 2 Pseudogene 2, Gene ID: 100132058), PSMD14P1 (Proteasome 26S Subunit, Non-ATPase 14 Pseudogene 1, Gene ID: 100131284), SLC4A8 (Solute Carrier Family 4 Member 8, Gene ID: 9498) and SDCBPP3 (Syndecan Binding Protein Like 3, Gene ID: 100131656).,

[0012] According to one side, the allergic disease may be at least one selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis, urticaria, drug allergy, anaphylaxis, and allergic conjunctivitis.

[0013] According to one side, the heavy metal may be at least one selected from the group consisting of cadmium (Cd), lead (Pb), zinc (Zn), and vanadium (V).

[0014] According to another embodiment of the present invention, S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1, MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061,A composition for determining exposure to heavy metals in the air in a patient with an allergic disease is provided, comprising an agent capable of measuring the expression level of any one or more genes selected from the group consisting of TRUB2, ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3 or a protein which is an expression product thereof.

[0015] According to one aspect, the agent capable of measuring the expression level of the protein may be an antibody or an antigen-binding fragment thereof that specifically binds to the protein; or an aptamer that specifically binds to the protein.

[0016] According to one aspect, the agent capable of measuring the expression level of the gene may be a primer or probe that specifically binds to a nucleic acid molecule of the gene.

[0017] According to another embodiment of the present invention, there is provided a method for providing information necessary to determine whether an individual suffering from an allergic disease is exposed to heavy metals in the air:

[0018] a) A step of collecting a biological sample from an individual with an allergic disease;

[0019] <h2 style=";text-align:left;direction:ltr">b) 상기 생물학적 시료로부터 S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1, MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2,A step of measuring the expression level of any one or more genes selected from the group consisting of ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3; and,

[0020] c) a step of comparing the gene expression level with the gene expression level of an allergic disease patient who has not been exposed to heavy metals;

[0021] A method of providing information, including:

[0022] According to one aspect, the biological sample may be any one selected from the group consisting of tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid, urine, and nasopharyngeal swab.

[0023] According to one side, the allergic disease may be at least one selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis, urticaria, drug allergy, anaphylaxis, and allergic conjunctivitis.

[0024] According to one side, the heavy metal may be at least one selected from the group consisting of cadmium (Cd), lead (Pb), zinc (Zn), and vanadium (V).

[0025] According to another embodiment of the present invention, a diagnostic kit for exposure to heavy metals in the air in a patient with allergic disease is provided, comprising a specific agent for one or more genes or their expression products selected from the group consisting of: S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1,MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2, ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3.,

[0026] The genetic biomarker provided in the present invention has been confirmed to have a significant causal relationship between exposure to heavy metals in the air in patients with allergic diseases and an increase in expression levels, and by measuring the expression level thereof, exposure to heavy metals in the air in patients with allergic diseases can be confirmed, and can be usefully used in the diagnosis, treatment, treatment progress, and prediction of prognosis of allergic diseases.

[0027] The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the detailed description of the present invention or the composition of the invention described in the claims.

[0028] Figure 1 shows the time-based regression model for PM2.5.

[0029] Figure 2a shows the CR value (correlation coefficient) of each biomarker with respect to the overall average of the indoor and outdoor sum of Pb.

[0030] Figure 2b shows the CR value of each biomarker for the daily cumulative average of the indoor and outdoor total of Pb.

[0031] Figure 2c shows the CR value of each biomarker relative to the overall indoor average of Pb.

[0032] Figure 2d shows the CR value of each biomarker for the indoor daily cumulative average of Pb.

[0033] Figure 2e shows the CR value of each biomarker relative to the outdoor overall average of Pb.

[0034] Figure 2f shows the CR value of each biomarker for the outdoor daily cumulative average of Pb.

[0035] Figure 3a shows the CR value of each biomarker relative to the overall average of the indoor and outdoor sum of Cd.

[0036] Figure 3b shows the CR value of each biomarker for the daily cumulative average of the indoor and outdoor sum of Cd.

[0037] Figure 3c shows the CR value of each biomarker relative to the overall indoor average of Cd.

[0038] Figure 3d shows the CR value of each biomarker for the indoor daily cumulative average of Cd.

[0039] Figure 3e shows the CR value of each biomarker relative to the outdoor overall average of Cd.

[0040] Figure 3f shows the CR value of each biomarker for the outdoor daily cumulative average of Cd.

[0041] Figure 4a shows the CR value of each biomarker relative to the overall average of the indoor and outdoor sum of Zn.

[0042] Figure 4b shows the CR value of each biomarker for the daily cumulative average of the indoor and outdoor sum of Zn.

[0043] Figure 4c shows the CR value of each biomarker relative to the overall indoor average of Zn.

[0044] Figure 4d shows the CR value of each biomarker for the indoor daily cumulative average of Zn.

[0045] Figure 4e shows the CR value of each biomarker relative to the outdoor overall average of Zn.

[0046] Figure 4f shows the CR value of each biomarker for the outdoor daily cumulative average of Zn.

[0047] Figure 5a shows the CR value of each biomarker relative to the overall average of the indoor and outdoor sum of V.

[0048] Figure 5b shows the CR value of each biomarker for the daily cumulative average of the indoor and outdoor sum of V.

[0049] Figure 5c shows the CR value of each biomarker relative to the overall average of the room of V.

[0050] Figure 5d shows the CR value of each biomarker for the daily cumulative average in V.

[0051] Figure 5e shows the CR value of each biomarker relative to the overall outdoor average of V.

[0052] Figure 5f shows the CR value of each biomarker for the daily cumulative average outdoors of V.

[0053] The present inventors have identified genes whose expression level increases when exposed to heavy metals in the air in a group with allergic diseases, and have completed the invention of a biomarker for confirming exposure to heavy metals in the air and provide it.

[0054] According to one embodiment of the present invention, a biomarker composition for confirming or diagnosing exposure to heavy metals in the air in an allergic disease patient is provided, comprising at least one gene selected from the group consisting of the following, or an expression product of the corresponding gene: S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1,MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2, ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3.,

[0055] In one specific embodiment of the present invention, "diagnosis" means confirming the presence or characteristics of a pathological condition or determining whether a person has been exposed to a specific substance in the past that affects the gene expression level of the current individual. For the purpose of the present invention, diagnosis is to determine whether a patient with an allergic disease has been exposed to heavy metals in the air. In the present invention, the diagnosis of an allergic disease can be made by confirming the expression level of the biomarker contained in a blood sample collected from the subject of the test.

[0056] The expression product of the above gene preferably refers to a protein which is a transcription product of the gene.

[0057] According to one side, the allergic disease may be at least one selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis, urticaria, drug allergy, anaphylaxis, and allergic conjunctivitis, but is not limited thereto.

[0058] According to one side, the heavy metal may be at least one selected from the group consisting of cadmium (Cd), lead (Pb), zinc (Zn), and vanadium (V).

[0059] In particular, among the genetic biomarkers listed above, S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, and SDCBPP3 may be biomarkers of cadmium exposure.

[0060] Among the genetic biomarkers listed above, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, ZNF542P, VSTM1, CNNM4, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, MTCH2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, WDFY4, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, ZNF606, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, LOC107984281, IGHJ6, IGHV3-64, IGHV3-73, and IGHV4-59 may be biomarkers of lead exposure.

[0061] Among the genetic biomarkers listed above, TAOK3, TRAK1, ZNF542P, CCNJ, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, CLCN5, PLEKHG2, VSTM1, CNNM4, EFCAB12, DOT1L, KIAA0319L, ASXL1, MIR6894, P2RY8, PRIM2, TMEM116, SEC13, PCBD1, TMEM209, IL32, UBE2G1, MIR4435-2HG, KIAA2026, PPIP5K1, ESS2, FAM172A, LOC105369194, LOC107986704, MIR21, SH2B2, WDR7, and MARCHF1 may be biomarkers of zinc exposure.

[0062] Among the genetic biomarkers listed above, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2, ZNF542P, ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8, and SDCBPP3 may be biomarkers of vanadium exposure.

[0063] According to another embodiment of the present invention, S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1, MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061,A composition for determining exposure to heavy metals in the air in a patient with an allergic disease is provided, comprising an agent capable of measuring the expression level of any one or more genes selected from the group consisting of TRUB2, ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3 or a protein which is an expression product thereof.

[0064] According to one aspect, the agent capable of measuring the expression level of the protein may be an antibody or an antigen-binding fragment thereof that specifically binds to the protein; or an aptamer that specifically binds to the protein.

[0065] The term “antibody” in this specification is a term known in the art and refers to a specific immunoglobulin directed against an antigenic site. For example, the antibody can specifically bind to one or more proteins or fragments thereof selected from the group consisting of CLC, TNFAIP8, EVI5L, ISG15, PIGS, SLC4A1, MYH1, CLTA, CCAR2, GRK6, ATP5F1D, ASRGL1, BST1, CYBA, ASAP1, MAP2K4, RNASE2, NIPSNAP2, MMP1, EWSR1, CCL28, LEG1, ACBP, APOM, TFF3, FOLR1, WFDC2, SERPINA1, SLURP1, DEFB4A, SLPI, IGFBP7, IGLV1-51, SERPINI1, IGLV3-9, SERPINA3, SPATS2L, APOC1, IGKV2-29, and KALRN. The above fragment refers to a protein fragment having one or more epitopes that can be recognized by an antibody against the protein, and may be, for example, an immunogenic fragment. The form of the antibody includes a polyclonal antibody, a monoclonal antibody, or a recombinant antibody, and includes all immunoglobulin antibodies. In addition, the antibody also includes specialized antibodies such as humanized antibodies.

[0066] Using these antibodies, it is possible to determine whether the protein is expressed in a biological sample by methods known in the art, such as enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), sandwich assay, Western blotting on polyacrylic gel, or immunoblotting.

[0067] The term "antibody fragment" as used herein refers to a polypeptide that does not have the structure of an intact antibody, peptide, or protein, but has a specific antigen-binding site or binding domain directed against an antigenic site. The fragment includes a functional fragment of an antibody molecule other than a complete antibody having two light chains and two heavy chains. A functional fragment of an antibody molecule means a fragment that retains at least an antigen-binding function, and may be Fab, F(ab'), F(ab')2, or Fv. The binding fragment may comprise at least 7 amino acids, for example, 9 amino acids, or 12 amino acids.

[0068] Analysis methods for detecting the above protein include, but are not limited to, Western blot, enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioimmunodiffusion, Ouchterlony immunodiffusion, rocket immunoelectrophoresis, tissue immunostaining, immunoassay, immunohistochemistry assay, immunoprecipitation assay, complement fixation assay, flow cytometry (Fluorescence Activated Cell Sorter, FACS), protein chip, etc.

[0069] According to one aspect, the agent capable of measuring the expression level of the gene may be a primer or probe that specifically binds to the nucleic acid molecule of the gene. As an analysis method, for example, one or more methods selected from the group consisting of reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), real-time reverse transcription polymerase reaction (Realtime RT-PCR), RNase protection assay (RPA), Northern blotting, and DNA chips may be used.

[0070] The term "primer" as used herein refers to a nucleic acid sequence having a free 3' hydroxyl group, which can form base pairs with a template complementary to a specific base sequence and serves as a starting point for copying the template strand. The primer can initiate DNA synthesis in the presence of a reagent for polymerization (i.e., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates in an appropriate buffer and temperature. For example, PCR amplification using sense and antisense primers having a sequence of 7 to 50 nucleotides as specific primers for a gene or mRNA encoding one or more proteins selected from the group consisting of CLC, TNFAIP8, EVI5L, ISG15, PIGS, SLC4A1, MYH1, CLTA, CCAR2, GRK6, ATP5F1D, ASRGL1, BST1, CYBA, ASAP1, MAP2K4, RNASE2, NIPSNAP2, MMP1, EWSR1, CCL28, LEG1, ACBP, APOM, TFF3, FOLR1, WFDC2, SERPINA1, SLURP1, DEFB4A, SLPI, IGFBP7, IGLV1-51, SERPINI1, IGLV3-9, SERPINA3, SPATS2L, APOC1, IGKV2-29 and KALRN By measuring the amount of the desired product produced, the exposure of the subject to heavy metals can be confirmed. PCR conditions and the length of the sense and antisense primers can be appropriately selected according to techniques known in the art. The primers may have 10 to 100, 15 to 100, 10 to 80, 10 to 50, 10 to 30, 10 to 20, 15 to 80, 15 to 50, 15 to 30, 15 to 20, 20 to 100, 20 to 80, 20 to 50, or 20 to 30 nt.

[0071] The term "probe" in this specification refers to a nucleic acid fragment such as RNA or DNA that can specifically bind to a target nucleic acid, for example, mRNA, and may be labeled so as to enable detection of the presence, content, and expression level of a specific mRNA. The probe may be produced in the form of an oligonucleotide probe, a single-stranded DNA probe, a double-stranded DNA probe, an RNA probe, etc. For example, by performing hybridization using a probe having a nucleic acid sequence complementary to a gene or mRNA encoding one or more proteins selected from the group consisting of CLC, TNFAIP8, EVI5L, ISG15, PIGS, SLC4A1, MYH1, CLTA, CCAR2, GRK6, ATP5F1D, ASRGL1, BST1, CYBA, ASAP1, MAP2K4, RNASE2, NIPSNAP2, MMP1, EWSR1, CCL28, LEG1, ACBP, APOM, TFF3, FOLR1, WFDC2, SERPINA1, SLURP1, DEFB4A, SLPI, IGFBP7, IGLV1-51, SERPINI1, IGLV3-9, SERPINA3, SPATS2L, APOC1, IGKV2-29 and KALRN, the expression level of mRNA is measured through the degree of hybridization, thereby identifying the individual. Heavy metal exposure can be diagnosed. Selection of an appropriate probe and hybridization conditions can be appropriately selected according to techniques known in the art. The probe may have 10 to 100, 15 to 100, 10 to 80, 10 to 50, 10 to 30, 10 to 20, 15 to 80, 15 to 50, 15 to 30, 15 to 20, 20 to 100, 20 to 80, 20 to 50, or 20 to 30 nt.

[0072] The primer or probe can be chemically synthesized using phosphoramidite solid support synthesis or other well-known methods. In addition, such nucleic acid sequences can be modified using various methods known in the art. Examples of such modifications can include methylation, capping, substitution with one or more homologs of a natural nucleotide, or modification between nucleotides, such as modification with an uncharged linker (e.g., methyl phosphonate, phosphotriester, phosphoramidate, carbamate, etc.) or a charged linker (e.g., phosphorothioate, phosphorodithioate, etc.). In addition, the primer or probe can be modified using a label that can directly or indirectly provide a detectable signal. Examples of such labels can include radioisotopes, fluorescent molecules, or biotin.

[0073] According to another embodiment of the present invention, there is provided a method for providing information necessary to determine whether an individual suffering from an allergic disease is exposed to heavy metals in the air:

[0074] a) A step of collecting a biological sample from an individual with an allergic disease;

[0075] <h2 style=";text-align:left;direction:ltr">b) 상기 생물학적 시료로부터 S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1, MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2,A step of measuring the expression level of any one or more genes selected from the group consisting of ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3; and,

[0076] c) a step of comparing the gene expression level with the gene expression level of an allergic disease patient who has not been exposed to heavy metals;

[0077] A method of providing information, including:

[0078] In the present invention, the term "subject" is not limited to a mammal such as a livestock or a human that requires prevention, treatment, and / or diagnosis of the allergic disease, but may preferably be a human.

[0079] Methods for measuring the expression level include, but are not limited to, Western blot, protein chip, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, immunoprecipitation, immunodiffusion, immunoelectrophoresis, tissue immunostaining, complement fixation assay, flow cytometry (FACS), mass spectrometry, or tissue microarray at the protein level. Methods for measuring the expression level include, but are not limited to, polymerase chain reaction (PCR), reverse transcription polymerase chain reaction, competitive polymerase chain reaction, real-time polymerase chain reaction, nuclease protection assay, nucleic acid microarray, or Northern blot at the nucleic acid level.

[0080] According to one aspect, the biological sample may be any one selected from the group consisting of tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid, urine, and nasopharyngeal swab.

[0081] According to one side, the allergic disease may be at least one selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis, urticaria, drug allergy, anaphylaxis, and allergic conjunctivitis.

[0082] According to one side, the heavy metal may be at least one selected from the group consisting of cadmium (Cd), lead (Pb), zinc (Zn), and vanadium (V).

[0083] According to another embodiment of the present invention, a diagnostic kit for exposure to heavy metals in the air in a patient with allergic disease is provided, comprising a specific agent for one or more genes or their expression products selected from the group consisting of: S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1,MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2, ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3.,

[0084] In the present invention, the "agent specific for a gene or its expression product" refers to a molecule that can be used to detect a biomarker of the present invention by confirming the expression level of a protein or gene, and specific examples are as described above.

[0085] The kit may be, for example, a kit for peptidizing the protein. Peptidization is not limited to a known method for mass spectrometry pretreatment of proteins. The kit may further include a known substance required for peptidization of the protein. For example, the kit may further include dithiothreitol (DTT), iodoacetamide (IAA), tris(2-chloroethyl) phosphate (TCEP), methyl methanethiosulfonate (MMTS), a protease, a buffer, cofactor, and / or a substrate required for its activity. The protease may be trypsin, endoproteinase Lys-C, endoproteinase Glu-C, or a combination thereof.

[0086] In addition, the kit may be a kit for amplifying the gene. The amplification method is not limited to a known method for nucleic acid amplification, and may require terminal cycling or be performed isothermally. The amplification method may include polymerase chain reaction (PCR), nucleic acid sequence-based amplification (NASBA), ligase chain reaction (LCR), strand displacement amplification (SDA), rolling circle amplification (RCA), etc. The amplification method may also include reverse transcription (RT) or reverse transcription-PCR. In addition, the kit may further include a known substance required for amplification of the target nucleic acid. For example, the kit may further include a nucleic acid polymerase, a buffer necessary for its activity, a cofactor, and / or a substrate. The nucleic acid polymerase may be a DNA polymerase, an RNA polymerase, a reverse transcriptase, or a combination thereof.

[0087]

[0088] Hereinafter, embodiments are described in detail with reference to the attached drawings. However, the embodiments may be modified in various ways, and the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, or alternatives to the embodiments are included within the scope of the patent application.

[0089] In addition, when describing with reference to the attached drawings, identical components will be assigned the same reference numerals regardless of the drawing numbers, and redundant descriptions thereof will be omitted. When describing embodiments, if a detailed description of a related known technology is judged to unnecessarily obscure the gist of the embodiment, the detailed description will be omitted.

[0090]

[0091] The present invention is susceptible to various modifications and embodiments. Specific embodiments are illustrated in the drawings and described in detail in the following detailed description. However, this is not intended to limit the present invention to specific embodiments, but rather to encompass all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention. In describing the present invention, detailed descriptions of related known technologies will be omitted if they are deemed to obscure the gist of the present invention.

[0092] Example 1: Marker derivation

[0093] We selected a patient group with at least one of four allergic diseases (asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis). Blood samples were collected from the patients and bulk RNA sequencing was performed. Heavy metals, including Pb, Zn, Cd, and V, which are predicted to be highly associated with allergic diseases based on the literature, were targeted. Heavy metal exposure was estimated using fixed measurement network data, which was verified through personal portable fine dust meter measurements, and modeled predictions based on personal location information.

[0094] The heavy metal exposure amount used in the present invention is an estimated value by applying PM2.5 values ​​and temperature, humidity, and wind speed information collected from a fixed measurement network corresponding to an individual's location to a previously developed statistical model. The heavy metal exposure estimation model was developed as a regression equation with outdoor PM2.5 measurements, indoor PM2.5 estimates, temperature, humidity, and wind speed as independent variables. Here, the 'indoor PM2.5 estimate' was derived as a prediction model developed as a regression equation using outdoor PM2.5 concentration, outdoor PM10 concentration, temperature, and relative humidity as independent variables. The indoor PM2.5 prediction model was developed by dividing it into 11 types of indoor spaces (houses, apartments, daycare centers, subway stations, etc.) by time zone. This is as shown in Figure 1.

[0095] The correlation between gene expression levels identified by bulk RNA sequencing and heavy metal exposure levels was presented. The analysis was performed using the cor.test function in the R library, an interpreted programming language. Spearman parameters were used, and genes with |CR| > 0.60 and p-value < 0.001 were identified. These markers were derived by calculating the average and cumulative variables for indoor / outdoor / total, respectively, and are presented in Tables 1 to 6 below. More specifically, Table 1 shows the indoor / outdoor total average, Table 2 shows the daily cumulative average of indoor and outdoor totals, Table 3 shows the indoor average, Table 4 shows the indoor daily cumulative average, Table 5 shows the outdoor average, and Table 6 shows the outdoor daily cumulative average. The indoor / outdoor distinction was based on the 30-minute time activity diary records of the subjects. The time activity diary recorded the measurement location as one of 'outdoor, residential indoor, office, school or academy, transportation, or other indoor.' Heavy metal exposure was estimated and recorded 288 times per day in 5-minute intervals. The total mean is the average of the estimated values ​​across the entire study period. The total cumulative is the average of the exposure values ​​calculated by summing them by measurement date.

[0096] Heavy metalsCdPbZnVTotal meanBiomarkerS100A13AURKAIP1TAOK3ABLIM3USP9XZCCHC17TRAK1ZGRF1SNORD33ENTPD6ZNF542PDBF4BPDHBEFCC1CCNJWDSUB1USP9XHNRNPUL2-BSCL2CHSY1MIR8061EIF4E3DLEU1ZHX3EBF1CCNJWASHC1TAF12FANK1PTCRA

[0097] Heavy MetalCdPbZnVTotal cumulative biomarkerPOLR2J3CLCN5CLCN5TRUB2CPNE5PLEKHG2PLEKHG2ZNF542PADD1ZNF542PZNF542PANKS1APOLR2J2VSTM1VSTM1EIF3BZNF542PCNNM4CNNM4PIK3C GCAPN10-DTCBWD3EFCAB12INTS14VSTM1ASXL1DOT1LRASA4DPFAM214AKIAA0319LCCDC138MIR6894ASXL1CNNM4MIR6894DLG1LOC105374942LOC105371573RPS2P40

[0098] Heavy metalsCdPbZnVIndoor meanBiomarkersUSP9XAURKAIP1TAOK3ABLIM3SNORD33ZCCHC17TRAK1DBF4BUSP9XTRAM1ZNF542PEIF4E3ENTPD6P2RY8EBF1EFCC1CHSY1GABBR1ZHX3STT3AWASHC1HNRNPUL2-BSCL2FANK1DLEU1PTCRACCNJTAF12

[0099] 중금속CdPbZnVIndoor cumulative 바이오마커POLR2J3CLCN5CLCN5TRUB2CLASP2PRIM2PRIM2ZNF542PSPTAN1COPG2PLEKHG2ANKS1APOLR2J2PLEKHG2ZNF542PEIF3BZNF542PZNF542PVSTM1PIK3CGVSTM1VSTM1CNNM4INTS14RASA4DPCNNM4DOT1LLOC105376253CNNM4MTCH2TMEM116TNS3HSF5MTCH2FAM214ADOT1LMIR6894DNM3DLG1TMEM116LOC105374942LOC105371573MAN2A2THUMPD3P1

[0100] 중금속CdPbZnVOutdoor mean 바이오마커CPNE5RABGAP1LSEC13FBXW5ZNF606SEC13PCBD1NAB1CD79ATMEM209TMEM209DENND3POC1BIL32IL32LRRC27LOC101927365MBNL1UBE2G1GPS2P2WDFY4CD38MIR4435-2HGPSMD14P1FAM135AUBE2G1KIAA2026LMO7KCNIP2PPIP5K1CBWD5TRIM68ESS2LOC107984281TTC41PFAM172ALOC105376624MIR5692C2LOC105369194NAGPACD9LOC107986704GYG1P3WDFY4MIR21IGLV4-60LOC283710ESS2TSPAN14LOC107986704RPS12P14IGHV3-43IGHV7-4-1MIR21

[0101] 중금속CdPbZnVOutdoor cumulative바이오마커SH2B2ZNF606SH2B2SLC4A8WDR7PLEKHG2WDR7SDCBPP3SDCBPP3FAM30AMARCHF1SNHG12TXNDC11TMEM154CCDC18LOC107984281IGHJ6IGHV3-43IGHV3-64IGHV3-73IGHV4-59

[0102] The markers with a high correlation between exposure to heavy metals in the air and increased gene expression in patients with allergic diseases were as follows:

[0103] Cd마커: S100A13 (S100 calcium-binding protein A13, Gene ID: 6283), USP9X (Ubiquitin Specific Peptidase 9, X-Linked, Gene ID: 8239), SNORD33 (Small Nucleolar RNA, C / D Box 33, Gene ID: 26818), PDHB (Pyruvate Dehydrogenase E1 Beta Subunit, Gene ID: 5162), EIF4E3 (Eukaryotic Translation Initiation Factor 4E Family Member 3, Gene ID: 317649), EBF1 (Early B Cell Factor 1, Gene ID: 1879), POLR2J3 (RNA Polymerase II Subunit J3, Gene ID: 548644), CPNE5 (Copine 5, Gene ID: 57699), ADD1 (Adducin 1, Gene ID: 118), POLR2J2 (RNA Polymerase II Subunit J2, Gene ID: 246721), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), CAPN10-DT (CAPN10 Divergent Transcript, Gene ID: 101752400), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), RASA4DP (RAS P21 Protein Activator 4, Divergent Pseudogene, Gene ID: 100133005), CCDC138 (Coiled-Coil Domain Containing 138, Gene ID: 165055), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504),DLG1 (Discs Large MAGUK Scaffold Protein 1, Gene ID: 1739), LOC105374942 (Gene ID: 105374942), LOC105371573 (Gene ID: 105371573), RPS2P40 (Ribosomal Protein S2 Pseudogene 40, Gene ID: 91561), CLASP2 (CLIP-Associating Protein 2, Gene ID: 23122), SPTAN1 (Spectrin Alpha, Non-Erythrocytic 1, Gene ID: 6709), TNS3 (Tensin 3, Gene ID: 64759), MTCH2 (Mitochondrial Carrier 2, Gene ID: 23788), DOT1L (DOT1 Like Histone Lysine Methyltransferase, Gene ID: 84444), DNM3 (Dynamin 3, Gene ID: 26052), TMEM116 (Transmembrane Protein 116, Gene ID: 89894), MAN2A2 (Mannosidase Alpha Class 2A Member 2, Gene ID: 4126), THUMPD3P1 (THUMP Domain Containing 3 Pseudogene 1, Gene ID: 100419989), ZNF606 (Zinc Finger Protein 606, Gene ID: 80095), CD79A (CD79a Molecule, Immunoglobulin-Associated Alpha, Gene ID: 973), POC1B (POC1 Centriolar Protein B, Gene ID: 282809), LOC101927365 (Gene ID: 101927365), WDFY4 (WD Repeat And FYVE Domain Containing 4, Gene ID: 57705),FAM135A (Family With Sequence Similarity 135 Member A, Gene ID: 57579), LMO7 (LIM Domain 7, Gene ID: 4008), CBWD5 (COBW Domain Containing 5, Gene ID: 220869), LOC107984281 (Gene ID: 107984281), LOC105376624 (Gene ID: 105376624), NAGPA (N-Acetylglucosamine-1-Phosphodiester Alpha-N-Acetylglucosaminidase, Gene ID: 51172), GYG1P3 (Glycogenin 1 Pseudogene 3, Gene ID: 645506), IGLV4-60 (Immunoglobulin Lambda Variable 4-60, Gene ID: 28785), SH2B2 (SH2B Adaptor Protein 2, Gene ID: 10603), WDR7 (WD Repeat Domain 7, Gene ID: 23335) 및 SDCBPP3 (Syndecan Binding Protein Like 3, Gene ID: 100131656),

[0104] Pb마커: AURKAIP1 (Aurora Kinase A Inhibitory Protein 1, Gene ID: 54998), ZCCHC17 (Zinc Finger CCHC-Type Containing 17, Gene ID: 51538), ENTPD6 (Ectonucleoside Triphosphate Diphosphohydrolase 6, Gene ID: 955), EFCC1 (EF-Hand And Coiled-Coil Domain Containing 1, Gene ID: 79825), HNRNPUL2-BSCL2 (HNRNPUL2-BSCL2 Readthrough, Gene ID: 100534595), DLEU1 (Deleted In Lymphocytic Leukemia 1, Gene ID: 10301), CCNJ (Cyclin J, Gene ID: 54619), TAF12 (TATA-Box Binding Protein Associated Factor 12, Gene ID: 6883), CLCN5 (Chloride Voltage-Gated Channel 5, Gene ID: 1184), PLEKHG2 (Pleckstrin Homology And RhoGEF Domain Containing G2, Gene ID: 64857), ZNF542P (Zinc Finger Protein 542, Pseudogene Gene ID: 147947), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), CBWD3 (Zn regulated GTPase metalloprotein activator 1C, Gene ID: 445571), ASXL1 (ASXL Transcriptional Regulator 1, Gene ID: 171023),FAM214A (Family With Sequence Similarity 214 Member A, Gene ID: 56204), MIR6894 (MicroRNA 6894, Gene ID: 102466759), TRAM1 (Translocation Associated Membrane Protein 1, Gene ID: 23471), GABBR1 (Gamma-Aminobutyric Acid Type B Receptor Subunit 1, Gene ID: 2550), STT3A (STT3 Oligosaccharyltransferase Complex Catalytic Subunit A, Gene ID: 3703), PRIM2 (DNA Primase Subunit 2, Gene ID: 5558), COPG2 (Coatomer Protein Complex Subunit Gamma 2, Gene ID: 26958), MTCH2 (Mitochondrial Carrier 2, Gene ID: 23788), HSF5 (Heat Shock Transcription Factor Family Member 5, Gene ID: 124535), RABGAP1L (RAB GTPase Activating Protein 1 Like, Gene ID: 9910), SEC13 (SEC13 Homolog, Nuclear Pore And COPII Coat Complex Component, Gene ID: 6396), TMEM209 (Transmembrane Protein 209, Gene ID: 84928), IL32 (Interleukin 32, Gene ID: 84928), MBNL1 (Muscleblind Like Splicing Regulator 1, Gene ID: 4154), CD38 (CD38 Molecule, Gene ID: 952), UBE2G1 (Ubiquitin Conjugating Enzyme E2 G1, Gene ID: 7326),KCNIP2 (Kv Channel Interacting Protein 2, Gene ID: 30819), TRIM68 (Tripartite Motif Containing 68, Gene ID: 55128), TTC41P (Tetratricopeptide Repeat Domain 41, Pseudogene, Gene ID: 253724), MIR5692C2 (MicroRNA 5692c-2, Gene ID: 100847017), CD9 (CD9 Molecule, Gene ID: 928), WDFY4 (WD Repeat And FYVE Domain Containing 4, Gene ID: 57705), LOC283710 (Uncharacterized LOC283710 Gene ID: 283710), ESS2 (ESS2 Splicing Factor Homolog, Gene ID: 8220), TSPAN14 (Tetraspanin 14, Gene ID: 81619), LOC107986704 (Uncharacterized LOC107986704, Gene ID: 107986704), RPS12P14 (Ribosomal Protein S12 Pseudogene 14, Gene ID: 100271058), IGHV3-43 (Immunoglobulin Heavy Variable 3-43, Gene ID: 28426), IGHV7-4-1 (Immunoglobulin Heavy Variable 7-4-1, Gene ID: 57289), MIR21 (MicroRNA 21, Gene ID: 406991), ZNF606 (Zinc Finger Protein 606, Gene ID: 80095), FAM30A (Family With Sequence Similarity 30 Member A, Gene ID: 9834), SNHG12 (Small Nucleolar RNA Host Gene 12, Gene ID: 85028),TXNDC11 (Thioredoxin Domain Containing 11, Gene ID: 51061), TMEM154 (Transmembrane Protein 154, Gene ID: 201799), CCDC18 (Coiled-Coil Domain Containing 18, Gene ID: 343099), LOC107984281 (Uncharacterized LOC107984281, Gene ID: 107984281), IGHJ6 (Immunoglobulin Heavy Joining 6, Gene ID: 28475), IGHV3-64 (Immunoglobulin Heavy Variable 3-64, Gene ID: 28414), IGHV3-73 (Immunoglobulin Heavy Variable 3-73, Gene ID: 28409) 및 IGHV4-59 (Immunoglobulin Heavy Variable 4-59, Gene ID: 28392).,

[0105] Zn 마커: TAOK3 (Thousand And One Kinase 3, Gene ID: 51347), TRAK1 (Trafficking Kinesin-Binding Protein 1, Gene ID: 22906), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), CCNJ (Cyclin J, Gene ID: 54619), CHSY1 (Chondroitin Sulfate Synthase 1, Gene ID: 22856), ZHX3 (Zinc Fingers And Homeoboxes 3, Gene ID: 23051), WASHC1 (WASH Complex Subunit 1, Gene ID: 100287171), FANK1 (Fibronectin Type III And Ankyrin Repeat Domains 1, Gene ID: 92565), PTCRA (Pre T-Cell Antigen Receptor Alpha, Gene ID: 171558), CLCN5 (Chloride Voltage-Gated Channel 5, Gene ID: 1184), PLEKHG2 (Pleckstrin Homology And RhoGEF Domain Containing G2, Gene ID: 64857), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), EFCAB12 (EF-Hand Calcium Binding Domain 12, Gene ID: 90288), DOT1L (DOT1 Like Histone Lysine Methyltransferase, Gene ID: 84444), KIAA0319L (KIAA0319 Like, Gene ID: 79932),ASXL1 (ASXL Transcriptional Regulator 1, Gene ID: 171023), MIR6894 (MicroRNA 6894, Gene ID: 102466759), P2RY8 (Purinergic Receptor P2Y8, Gene ID: 286530), PRIM2 (DNA Primase Subunit 2, Gene ID: 5558), TMEM116 (Transmembrane Protein 116, Gene ID: 89894), SEC13 (SEC13 Homolog, Nuclear Pore And COPII Coat Complex Component, Gene ID: 6396), PCBD1 (Pterin-4 Alpha-Carbinolamine Dehydratase / Dimerization Cofactor Of Hepatocyte Nuclear Factor 1 Alpha, Gene ID: 5092), TMEM209 (Transmembrane Protein 209, Gene ID: 84928), IL32 (Interleukin 32, Gene ID: 9235), UBE2G1 (Ubiquitin Conjugating Enzyme E2 G1, Gene ID: 7326), MIR4435-2HG (MIR4435-2 Host Gene, Gene ID: 541471), KIAA2026 (KIAA2026, Gene ID: 158358), PPIP5K1 (Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Beta, Gene ID: 9677), ESS2 (ESS2 Splicing Factor Homolog, Gene ID: 8220), FAM172A (Family With Sequence Similarity 172 Member A, Gene ID: 83989), LOC105369194 (Uncharacterized LOC105369194, Gene ID: 105369194),LOC107986704 (Uncharacterized LOC107986704, Gene ID: 107986704), MIR21 (MicroRNA 21, Gene ID: 406991), SH2B2 (SH2B Adaptor Protein 2, Gene ID: 10603), WDR7 (WD Repeat Domain 7, Gene ID: 23335) 및 MARCHF1 (Membrane Associated Ring-CH-Type Finger 1, Gene ID: 55016).,

[0106] V 마커: ABLIM3 (Actin Binding LIM Protein Family Member 3, Gene ID: 22885), ZGRF1 (Zinc Finger GRF-Type Containing 1, Gene ID: 55345), DBF4B (DBF4 Zinc Finger B, Gene ID: 80174), WDSUB1 (WD Repeat And Sterile Alpha Motif Domain Containing 1, Gene ID: 151525), MIR8061 (MicroRNA 8061, Gene ID: 102466251), TRUB2 (TruB Pseudouridine (Psi) Synthase Family Member 2, Gene ID: 26995), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), ANKS1A (Ankyrin Repeat And Sterile Alpha Motif Domain Containing 1A, Gene ID: 23294), EIF3B (Eukaryotic Translation Initiation Factor 3 Subunit B, Gene ID: 8662), PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma, Gene ID: 5294), INTS14 (Integrator Complex Subunit 14, Gene ID: 81556), LOC105376253 (Uncharacterized LOC105376253, Gene ID: 105376253), FBXW5 (F-Box And WD Repeat Domain Containing 5, Gene ID: 54461), NAB1 (NGFI-A Binding Protein 1, Gene ID: 4664), DENND3 (DENN Domain Containing 3, Gene ID: 22898),LRRC27 (Leucine Rich Repeat Containing 27, Gene ID: 80313), GPS2P2 (G Protein Pathway Suppressor 2 Pseudogene 2, Gene ID: 100132058), PSMD14P1 (Proteasome 26S Subunit, Non-ATPase 14 Pseudogene 1, Gene ID: 100131284), SLC4A8 (Solute Carrier Family 4 Member 8, Gene ID: 9498) and SDCBPP3 (Syndecan Binding Protein Like 3, Gene ID: 100131656).,

[0107] The CR value graphs of each marker for Cd, Pb, Zn, and V are shown in Figures 2 to 5, respectively.

[0108] Although the embodiments described above have been described with limited drawings, those skilled in the art will appreciate that various technical modifications and variations can be applied based on the above. For example, appropriate results can still be achieved even if the described techniques are performed in a different order than described, and / or components of the described systems, structures, devices, circuits, etc. are combined or combined in a different manner than described, or are replaced or substituted with other components or equivalents.

[0109] Therefore, other implementations, other embodiments, and equivalents to the claims also fall within the scope of the claims described below.

Claims

1. A biomarker composition for determining whether a patient with an allergic disease is exposed to heavy metals in the air, comprising at least one gene selected from the group consisting of the following, or an expression product of the gene: S100A13 (S100 calcium-binding protein A13, Gene ID: 6283), USP9X (Ubiquitin Specific Peptidase 9, X-Linked, Gene ID: 8239), SNORD33 (Small Nucleolar RNA, C / D Box 33, Gene ID: 26818), PDHB (Pyruvate Dehydrogenase E1 Beta Subunit, Gene ID: 5162), EIF4E3 (Eukaryotic Translation Initiation Factor 4E Family Member 3, Gene ID: 317649), EBF1 (Early B Cell Factor 1, Gene ID: 1879), POLR2J3 (RNA Polymerase II Subunit J3, Gene ID: 548644), CPNE5 (Copine 5, Gene ID: 57699), ADD1 (Adducin 1, Gene ID: 118), POLR2J2 (RNA Polymerase II Subunit J2, Gene ID: 246721), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), CAPN10-DT (CAPN10 Divergent Transcript, Gene ID: 101752400), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), RASA4DP (RAS P21 Protein Activator 4, Divergent Pseudogene, Gene ID: 100133005), CCDC138 (Coiled-Coil Domain Containing) 138, Gene ID: 165055),CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), DLG1 (Discs Large MAGUK Scaffold Protein 1, Gene ID: 1739), LOC105374942 (Gene ID: 105374942), LOC105371573 (Gene ID: 105371573), RPS2P40 (Ribosomal Protein S2 Pseudogene 40, Gene ID: 91561), CLASP2 (CLIP-Associating Protein 2, Gene ID: 23122), SPTAN1 (Spectrin Alpha, Non-Erythrocytic 1, Gene ID: 6709), TNS3 (Tensin 3, Gene ID: 64759), MTCH2 (Mitochondrial Carrier 2, Gene ID: 23788), DOT1L (DOT1 Like Histone Lysine Methyltransferase, Gene ID: 84444), DNM3 (Dynamin 3, Gene ID: 26052), TMEM116 (Transmembrane Protein 116, Gene ID: 89894), MAN2A2 (Mannosidase Alpha Class 2A Member 2, Gene ID: 4126), THUMPD3P1 (THUMP Domain Containing 3 Pseudogene 1, Gene ID: 100419989), ZNF606 (Zinc Finger Protein 606, Gene ID: 80095), CD79A (CD79a Molecule, Immunoglobulin-Associated Alpha, Gene ID: 973), POC1B (POC1 Centriolar Protein B, Gene ID: 282809), LOC101927365 (Gene ID: 101927365),WDFY4 (WD Repeat And FYVE Domain Containing 4, Gene ID: 57705), FAM135A (Family With Sequence Similarity 135 Member A, Gene ID: 57579), LMO7 (LIM Domain 7, Gene ID: 4008), CBWD5 (COBW Domain Containing 5, Gene ID: 220869), LOC107984281 (Gene ID: 107984281), LOC105376624 (Gene ID: 105376624), NAGPA (N-Acetylglucosamine-1-Phosphodiester Alpha-N-Acetylglucosaminidase, Gene ID: 51172), GYG1P3 (Glycogenin 1 Pseudogene 3, Gene ID: 645506), IGLV4-60 (Immunoglobulin Lambda Variable 4-60, Gene ID: 28785), SH2B2 (SH2B Adaptor Protein 2, Gene ID: 10603), WDR7 (WD Repeat Domain 7, Gene ID: 23335), SDCBPP3 (Syndecan Binding Protein Like 3, Gene ID: 100131656), AURKAIP1 (Aurora Kinase A Inhibitory Protein 1, Gene ID: 54998), ZCCHC17 (Zinc Finger CCHC-Type Containing 17, Gene ID: 51538), ENTPD6 (Ectonucleoside Triphosphate Diphosphohydrolase 6, Gene ID: 955), EFCC1 (EF-Hand And Coiled-Coil Domain Containing 1, Gene ID: 79825), HNRNPUL2-BSCL2 (HNRNPUL2-BSCL2 Readthrough, Gene ID: 100534595),DLEU1 (Deleted In Lymphocytic Leukemia 1, Gene ID: 10301), CCNJ (Cyclin J, Gene ID: 54619), TAF12 (TATA-Box Binding Protein Associated Factor 12, Gene ID: 6883), CLCN5 (Chloride Voltage-Gated Channel 5, Gene ID: 1184), PLEKHG2 (Pleckstrin Homology And RhoGEF Domain Containing G2, Gene ID: 64857), ZNF542P (Zinc Finger Protein 542, Pseudogene Gene ID: 147947), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), CBWD3 (Zn regulated GTPase metalloprotein activator 1C, Gene ID: 445571), ASXL1 (ASXL Transcriptional Regulator 1, Gene ID: 171023), FAM214A (Family With Sequence Similarity 214 Member A, Gene ID: 56204), MIR6894 (MicroRNA 6894, Gene ID: 102466759), TRAM1 (Translocation Associated Membrane Protein 1, Gene ID: 23471), GABBR1 (Gamma-Aminobutyric Acid Type B Receptor Subunit 1, Gene ID: 2550), STT3A (STT3 Oligosaccharyltransferase Complex Catalytic Subunit A, Gene ID: 3703),PRIM2 (DNA Primase Subunit 2, Gene ID: 5558), COPG2 (Coatomer Protein Complex Subunit Gamma 2, Gene ID: 26958), MTCH2 (Mitochondrial Carrier 2, Gene ID: 23788), HSF5 (Heat Shock Transcription Factor Family Member 5, Gene ID: 124535), RABGAP1L (RAB GTPase Activating Protein 1 Like, Gene ID: 9910), SEC13 (SEC13 Homolog, Nuclear Pore And COPII Coat Complex Component, Gene ID: 6396), TMEM209 (Transmembrane Protein 209, Gene ID: 84928), IL32 (Interleukin 32, Gene ID: 84928), MBNL1 (Muscleblind Like Splicing Regulator 1, Gene ID: 4154), CD38 (CD38 Molecule, Gene ID: 952), UBE2G1 (Ubiquitin Conjugating Enzyme E2 G1, Gene ID: 7326), KCNIP2 (Kv Channel Interacting Protein 2, Gene ID: 30819), TRIM68 (Tripartite Motif Containing 68, Gene ID: 55128), TTC41P (Tetratricopeptide Repeat Domain 41, Pseudogene, Gene ID: 253724), MIR5692C2 (MicroRNA 5692c-2, Gene ID: 100847017), CD9 (CD9 Molecule, Gene ID: 928), WDFY4 (WD Repeat And FYVE Domain Containing 4, Gene ID: 57705),LOC283710 (Uncharacterized LOC283710 Gene ID: 283710), ESS2 (ESS2 Splicing Factor Homolog, Gene ID: 8220), TSPAN14 (Tetraspanin 14, Gene ID: 81619), LOC107986704 (Uncharacterized LOC107986704, Gene ID: 107986704), RPS12P14 (Ribosomal Protein S12 Pseudogene 14, Gene ID: 100271058), IGHV3-43 (Immunoglobulin Heavy Variable 3-43, Gene ID: 28426), IGHV7-4-1 (Immunoglobulin Heavy Variable 7-4-1, Gene ID: 57289), MIR21 (MicroRNA 21, Gene ID: 406991), ZNF606 (Zinc Finger Protein 606, Gene ID: 80095), FAM30A (Family With Sequence Similarity 30 Member A, Gene ID: 9834), SNHG12 (Small Nucleolar RNA Host Gene 12, Gene ID: 85028), TXNDC11 (Thioredoxin Domain Containing 11, Gene ID: 51061), TMEM154 (Transmembrane Protein 154, Gene ID: 201799), CCDC18 (Coiled-Coil Domain Containing 18, Gene ID: 343099), LOC107984281 (Uncharacterized LOC107984281, Gene ID: 107984281), IGHJ6 (Immunoglobulin Heavy Joining 6, Gene ID: 28475), IGHV3-64 (Immunoglobulin Heavy Variable 3-64, Gene ID: 28414),IGHV3-73 (Immunoglobulin Heavy Variable 3-73, Gene ID: 28409), IGHV4-59 (Immunoglobulin Heavy Variable 4-59, Gene ID: 28392), TAOK3 (Thousand And One Kinase 3, Gene ID: 51347), TRAK1 (Trafficking Kinesin-Binding Protein 1, Gene ID: 22906), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), CCNJ (Cyclin J, Gene ID: 54619), CHSY1 (Chondroitin Sulfate Synthase 1, Gene ID: 22856), ZHX3 (Zinc Fingers And Homeoboxes 3, Gene ID: 23051), WASHC1 (WASH Complex Subunit 1, Gene ID: 100287171), FANK1 (Fibronectin Type III And Ankyrin Repeat Domains 1, Gene ID: 92565), PTCRA (Pre T-Cell Antigen Receptor Alpha, Gene ID: 171558), CLCN5 (Chloride Voltage-Gated Channel 5, Gene ID: 1184), PLEKHG2 (Pleckstrin Homology And RhoGEF Domain Containing G2, Gene ID: 64857), VSTM1 (V-Set And Transmembrane Domain Containing 1, Gene ID: 284415), CNNM4 (Cyclin And CBS Domain Divalent Metal Cation Transport Mediator 4, Gene ID: 26504), EFCAB12 (EF-Hand Calcium Binding Domain 12, Gene ID: 90288),DOT1L (DOT1 Like Histone Lysine Methyltransferase, Gene ID: 84444), KIAA0319L (KIAA0319 Like, Gene ID: 79932), ASXL1 (ASXL Transcriptional Regulator 1, Gene ID: 171023), MIR6894 (MicroRNA 6894, Gene ID: 102466759), P2RY8 (Purinergic Receptor P2Y8, Gene ID: 286530), PRIM2 (DNA Primase Subunit 2, Gene ID: 5558), TMEM116 (Transmembrane Protein 116, Gene ID: 89894), SEC13 (SEC13 Homolog, Nuclear Pore And COPII Coat Complex Component, Gene ID: 6396), PCBD1 (Pterin-4 Alpha-Carbinolamine Dehydratase / Dimerization Cofactor Of Hepatocyte Nuclear Factor 1 Alpha, Gene ID: 5092), TMEM209 (Transmembrane Protein 209, Gene ID: 84928), IL32 (Interleukin 32, Gene ID: 9235), UBE2G1 (Ubiquitin Conjugating Enzyme E2 G1, Gene ID: 7326), MIR4435-2HG (MIR4435-2 Host Gene, Gene ID: 541471), KIAA2026 (KIAA2026, Gene ID: 158358), PPIP5K1 (Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Beta, Gene ID: 9677), ESS2 (ESS2 Splicing Factor Homolog, Gene ID: 8220),FAM172A (Family With Sequence Similarity 172 Member A, Gene ID: 83989), LOC105369194 (Uncharacterized LOC105369194, Gene ID: 105369194), LOC107986704 (Uncharacterized LOC107986704, Gene ID: 107986704), MIR21 (MicroRNA 21, Gene ID: 406991), SH2B2 (SH2B Adaptor Protein 2, Gene ID: 10603), WDR7 (WD Repeat Domain 7, Gene ID: 23335), MARCHF1 (Membrane Associated Ring-CH-Type Finger 1, Gene ID: 55016), ABLIM3 (Actin Binding LIM Protein Family Member 3, Gene ID: 22885), ZGRF1 (Zinc Finger GRF-Type Containing 1, Gene ID: 55345), DBF4B (DBF4 Zinc Finger B, Gene ID: 80174), WDSUB1 (WD Repeat And Sterile Alpha Motif Domain Containing 1, Gene ID: 151525), MIR8061 (MicroRNA 8061, Gene ID: 102466251), TRUB2 (TruB Pseudouridine (Psi) Synthase Family Member 2, Gene ID: 26995), ZNF542P (Zinc Finger Protein 542, Pseudogene, Gene ID: 147947), ANKS1A (Ankyrin Repeat And Sterile Alpha Motif Domain Containing 1A, Gene ID: 23294), EIF3B (Eukaryotic Translation Initiation Factor 3 Subunit B, Gene ID: 8662),PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma, Gene ID: 5294), INTS14 (Integrator Complex Subunit 14, Gene ID: 81556), LOC105376253 (Uncharacterized LOC105376253, Gene ID: 105376253), FBXW5 (F-Box And WD Repeat Domain Containing 5, Gene ID: 54461), NAB1 (NGFI-A Binding Protein 1, Gene ID: 4664), DENND3 (DENN Domain Containing 3, Gene ID: 22898), LRRC27 (Leucine Rich Repeat Containing 27, Gene ID: 80313), GPS2P2 (G Protein Pathway Suppressor 2 Pseudogene 2, Gene ID: 100132058), PSMD14P1 (Proteasome 26S Subunit, Non-ATPase 14 Pseudogene 1, Gene ID: 100131284), SLC4A8 (Solute Carrier Family 4 Member 8, Gene ID: 9498) 및 SDCBPP3 (Syndecan Binding Protein Like 3, Gene ID: 100131656)., 2. In paragraph 1, A biomarker composition, wherein the above allergic disease is at least one selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis, urticaria, drug allergy, anaphylaxis, and allergic conjunctivitis.

3. In paragraph 1, A biomarker composition wherein the heavy metal is at least one selected from the group consisting of cadmium (Cd), lead (Pb), zinc (Zn), and vanadium (V). 4.S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCA12. KIAA0319L, P2RY8, PCBD1, MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2, ANKS1A, EIF3B.A composition for determining whether a patient with an allergic disease is exposed to heavy metals in the air, comprising a preparation capable of measuring the expression level of any one or more genes selected from the group consisting of PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3 or a protein which is an expression product thereof.

5. A composition for determining exposure to heavy metals in the air in a patient with an allergic disease, wherein the agent capable of measuring the expression level of the protein in the fourth paragraph is an antibody or an antigen-binding fragment thereof that specifically binds to the protein; or an aptamer that specifically binds to the protein.

6. A composition for confirming exposure to heavy metals in the air in a patient with an allergic disease, wherein the agent capable of measuring the expression level of the gene in paragraph 4 is a primer or probe that specifically binds to a nucleic acid molecule of the gene.

7. A method for providing information necessary to determine whether an individual with an allergic disease is exposed to heavy metals in the air. a) A step of collecting a biological sample from an individual with an allergic disease; <h2 style=";text-align:left;direction:ltr">b) 상기 생물학적 시료로부터 S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40, CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA, GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43, IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1, MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2,A step of measuring the expression level of any one or more genes selected from the group consisting of ANKS1A, EIF3B, PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 and SDCBPP3; and, c) a step of comparing the gene expression level with the gene expression level of an allergic disease patient who has not been exposed to heavy metals; A method of providing information, including:

8. In paragraph 7, A method for providing information, wherein the biological sample is any one selected from the group consisting of tissue, cell, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid, urine, and nasopharyngeal swab.

9. In paragraph 7, A method for providing information, wherein the above allergic disease is at least one selected from the group consisting of asthma, allergic rhinitis, atopic dermatitis, urticaria, drug allergy, anaphylaxis, and allergic conjunctivitis.

10. In paragraph 7, A method for providing information, wherein the above heavy metal is at least one selected from the group consisting of cadmium (Cd), lead (Pb), zinc (Zn), and vanadium (V).

11. A diagnostic kit for exposure to heavy metals in the air in patients with allergic diseases, comprising a preparation specific to one or more genes or their expression products selected from the group consisting of: S100A13, USP9X, SNORD33, PDHB, EIF4E3, EBF1, POLR2J3, CPNE5, ADD1, POLR2J2, ZNF542P, CAPN10-DT, VSTM1, RASA4DP, CCDC138, CNNM4, DLG1, LOC105374942, LOC105371573, RPS2P40. CLASP2, SPTAN1, TNS3, MTCH2, DOT1L, DNM3, TMEM116, MAN2A2, THUMPD3P1, ZNF606, CD79A, POC1B, LOC101927365, WDFY4, FAM135A, LMO7, CBWD5, LOC107984281, LOC105376624, NAGPA. GYG1P3, IGLV4-60, SH2B2, WDR7, SDCBPP3, AURKAIP1, ZCCHC17, ENTPD6, EFCC1, HNRNPUL2-BSCL2, DLEU1, CCNJ, TAF12, CLCN5, PLEKHG2, CBWD3, ASXL1, FAM214A, MIR6894, TRAM1, GABBR1, STT3A, PRIM2, COPG2, HSF5, RABGAP1L, SEC13, TMEM209, IL32, MBNL1, CD38, UBE2G1, KCNIP2, TRIM68, TTC41P, MIR5692C2, CD9, LOC283710, ESS2, TSPAN14, LOC107986704, RPS12P14, IGHV3-43. IGHV7-4-1, MIR21, FAM30A, SNHG12, TXNDC11, TMEM154, CCDC18, IGHJ6, IGHV3-64, IGHV3-73, IGHV4-59, TAOK3, TRAK1, CHSY1, ZHX3, WASHC1, FANK1, PTCRA, EFCAB12, KIAA0319L, P2RY8, PCBD1. MIR4435-2HG, KIAA2026, PPIP5K1, FAM172A, LOC105369194, MARCHF1, ABLIM3, ZGRF1, DBF4B, WDSUB1, MIR8061, TRUB2, ANKS1A, EIF3B,PIK3CG, INTS14, LOC105376253, FBXW5, NAB1, DENND3, LRRC27, GPS2P2, PSMD14P1, SLC4A8 및 SDCBPP3.,

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