WO2020204313A1 - Gba 유전자의 단일염기다형성을 포함하는 뇌동맥류 진단용 snp 마커 - Google Patents

Gba 유전자의 단일염기다형성을 포함하는 뇌동맥류 진단용 snp 마커 Download PDF

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WO2020204313A1
WO2020204313A1 PCT/KR2019/018408 KR2019018408W WO2020204313A1 WO 2020204313 A1 WO2020204313 A1 WO 2020204313A1 KR 2019018408 W KR2019018408 W KR 2019018408W WO 2020204313 A1 WO2020204313 A1 WO 2020204313A1
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snp
gene
allele
cerebral aneurysm
diagnosing
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PCT/KR2019/018408
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English (en)
French (fr)
Korean (ko)
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전진평
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한림대학교 산학협력단
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Priority to CN201980005528.9A priority Critical patent/CN113166810A/zh
Publication of WO2020204313A1 publication Critical patent/WO2020204313A1/ko

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention comprises a SNP of the GBA gene, a SNP marker composition for diagnosing a cerebral aneurysm, a composition for diagnosing a cerebral aneurysm comprising an agent capable of detecting or amplifying the SNP marker, a kit for diagnosing a cerebral aneurysm comprising the composition, and the composition And a method of providing information for diagnosing a cerebral aneurysm using a kit.
  • Polymorphism refers to a nucleotide sequence variation that appears with a frequency of more than 1%, of which 90% is single nucleotide polymorphism (SNP).
  • SNP single nucleotide polymorphism
  • the human genetic sequence is 99.9% identical, and SNPs appear every about 250 to 1000 bp. In the case of the human genome, there are about 2 million SNPs and about 21,000 of these genes are present.
  • mutations of other single bases that appear with a frequency of 1% or less are commonly referred to as mutations.
  • the nucleotide sequence mutation analysis or SNP plays an important role as a marker capable of not only analyzing DNA sequencing, but also discovering genes that cause diseases such as cancer, asthma, and diabetes, or determining association with specific diseases. Therefore, by analyzing single nucleotide polymorphism, it can be helpful in preventing congenital diseases caused by differences in base sequence or treatment of onset diseases by grasping an individual's susceptibility to specific diseases in humans.
  • Cerebral aneurysms specifically intracranial aneurysms, account for about 85% of all subarachnoid hemorrhages (subarachnoid hemorrhage), which has a high mortality rate of up to 50%. Cerebral aneurysms are generally caused by subarachnoid hemorrhage, which can be first confirmed by cerebral CT scan. If subarachnoid hemorrhage is suspected but not visible on CT, it can also be diagnosed by checking the blood-infused cerebrospinal fluid through a lumbar puncture.
  • the ruptured area In addition, in order to establish a treatment plan for an actually ruptured cerebral aneurysm, the ruptured area must be identified and the location, size, shape, and number of the ruptured cerebral aneurysms must be accurately identified. These include CT angiography and MRI angiography.
  • CT angiography CT angiography
  • MRI angiography MRI angiography
  • the present inventors have endeavored to develop a method for efficiently and easily diagnosing the onset of cerebral aneurysms, predicting the risk of onset, and predicting the prognosis.
  • the invention was completed.
  • the first aspect of the present application is to provide a SNP marker composition for diagnosing a cerebral aneurysm, including rs75822236, which is a single nucleotide polymorphism (SNP) of the GBA (Glucocerebrosidase) gene.
  • SNP single nucleotide polymorphism
  • a second aspect of the present application is to provide a composition for diagnosing a cerebral aneurysm, including an agent capable of detecting or amplifying rs75822236, which is the SNP of the GBA gene.
  • a third aspect of the present application is to provide a kit for diagnosing a cerebral aneurysm, including a composition for diagnosing a cerebral aneurysm.
  • a fourth aspect of the present application is to provide a method of providing information for diagnosing a cerebral aneurysm, comprising determining an allele of rs75822236, which is a SNP of the GBA gene, from a biological sample isolated from an individual.
  • single nucleotide polymorphism (SNP) on the GBA gene is used for the onset of cerebral aneurysms in Koreans or Asians. It can be used as a marker for risk prediction or diagnosis.
  • 1 is a diagram showing a procedure for diagnosing a cerebral aneurysm using SNP of the GBA gene.
  • FIG. 2 is a diagram showing the GWAS results in a Manhattan flute.
  • FIG. 3 is a diagram showing a regional plot for the position ⁇ 500 kb of the rs371331393 variant, which is a SNP of the ARHGAP32 gene, in which 250 patients with cerebral aneurysms and 294 controls (age, sex, hypertension, diabetes, hyperlipidemia, Smoking and coordinating four major factors) and rs371331393 in association with cerebral aneurysms.
  • the X-axis represents the chromosomal location (Mb), and the Y-axis represents the value obtained by converting the P-value to -log 10 .
  • 4A is a diagram showing a regional plot for the location ( ⁇ 500kb) of the rs6741819 variant, which is the SNP of the RNF144A gene, in which 250 patients with cerebral aneurysms and 294 controls (age, sex, hypertension, Rs6741819 in diabetes, hyperlipidemia, smoking, and coordinating four major factors) and cerebral aneurysms.
  • the X-axis represents the chromosomal location (Mb), and the Y-axis represents the value obtained by converting the P-value to -log 10 .
  • the X axis represents the genotype and the Y axis represents the rank-normalized gene expression level.
  • the reference type (Ref)/allele (Alt) allele of the variant genotype is the same as the major/minor allele.
  • 4C is a diagram showing a regional plot for the location ( ⁇ 500kb) of the rs1052270 variant, the SNP of the TMOD1 gene, in which 250 patients with cerebral aneurysms and 294 controls (age, sex, hypertension, Diabetes mellitus, hyperlipidemia, smoking, and coordinating the four major factors).
  • the X-axis represents the chromosomal location (Mb), and the Y-axis represents the value obtained by converting the P-value to -log 10 .
  • the X axis represents the genotype and the Y axis represents the rank-normalized gene expression level.
  • the reference type (Ref)/allele (Alt) allele of the variant genotype is the same as the major/minor allele.
  • 5A is a diagram showing a regional plot for the location ( ⁇ 500kb) of the rs6841581 variant, which is the SNP of the EDNRA gene, in which 250 patients with cerebral aneurysms and 294 controls (age, sex, hypertension, Rs6741819 in diabetes, hyperlipidemia, smoking, and coordinating four major factors) and cerebral aneurysms.
  • the X-axis represents the chromosomal location (Mb), and the Y-axis represents the value obtained by converting the P-value to -log 10 .
  • the X axis represents the genotype and the Y axis represents the rank-normalized gene expression level.
  • the reference type (Ref)/allele (Alt) allele of the variant genotype is the same as the major/minor allele.
  • Example 6 shows the results of analysis of the association between cerebral aneurysms and 10 SNPs in Example 4.
  • Example 7 shows the results of analysis of the haplotype association between cerebral aneurysms and 10 SNPs in Example 4.
  • Example 8 shows the results of analysis of the association between a cerebral aneurysm and four SNPs in Example 4.
  • the first aspect of the present application provides a SNP marker composition for diagnosing a cerebral aneurysm, including rs75822236, which is a single nucleotide polymorphism (SNP) of the GBA (Glucocerebrosidase) gene.
  • SNP single nucleotide polymorphism
  • SNP single nucleotide polymorphism
  • the term "marker” used throughout the specification of the present application means a biomarker and can detect changes in a living organism, thereby objectively measuring the normal or pathological state of the living organism, and the degree of reaction to a drug.
  • Cerebral aneurysm or brain aneurysm as used throughout the present specification is also referred to as intracranial aneurysm.
  • IA intracranial aneurysm
  • a common location for a cerebral aneurysm is an artery at the base of the brain, known as the Circle of Willis.
  • About 85% of cerebral aneurysms occur in the anterior part of the Willis ring and include the internal carotid arteries and their major branches that supply blood to the anterior and middle parts of the brain. Cerebral aneurysms are classified by size and shape.
  • Small aneurysm has a diameter of less than 15 mm. Larger aneurysms include aneurysms classified as large (15-25 mm), giant (25-50 mm), and super giant (> 50 mm).
  • a saccular aneurysm is an aneurysm with saccular outpouching and is the most common form of cerebral aneurysm.
  • Strawberry-like aneurysms are cystic aneurysms with a strawberry-like neck or stem. Fusiform aneurysm (fusiform aneurysm) is a stemless aneurysm.
  • the SNP marker composition for diagnosing a cerebral aneurysm of the present application may diagnose the onset of a cerebral aneurysm, predict the risk of developing a cerebral aneurysm, or predict the prognosis of a cerebral aneurysm, but is not limited thereto.
  • diagnosis means determining whether a cerebral aneurysm has already occurred in a specific individual.
  • prediction is to determine whether there is a possibility of developing a cerebral aneurysm in a specific individual, or whether the likelihood of developing a cerebral aneurysm is relatively high compared to a large number of unspecified individuals. it means.
  • rs75822236 which is the SNP of the GBA gene, may include the 26th nucleotide of SEQ ID NO: 1, and the allele of the base of rs75822236 may be C or T.
  • the allele of the base of rs75822236 is C or the allele of its complementary base is G, it is possible to diagnose the occurrence of a cerebral aneurysm or to predict the risk of the onset at a high level.
  • rs75822236 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance of 1.00) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • allele or “allele” as used throughout this specification refers to multiple types of a gene present at the same locus of a homologous chromosome. Alleles are sometimes used to represent polymorphism, for example SNP has two or more types, for example, two types of alleles.
  • the SNP marker composition for diagnosing a cerebral aneurysm is 1) rs112859779, which is the SNP of the TCF24 (transcription factor 24) gene, 2) rs79134766, which is the SNP of the OLFML2A (Olfactomedin Like 2A) gene, 3) ARHGAP32 (Rho GTPase Activating Protein 32) SNP of gene rs371331393, 4) CD163L1 (CD163 Molecule Like 1) gene SNP rs138525217, 5) CUL4A (cullin 4A) gene SNP rs74115822, 6) LOC102724084 SNP of gene rs75861150, 7) LRRC3 (Leucine rich repeat containing 3) gene SNP rs116969723, 8) RNF144A (Ring Finger Protein 144A) gene SNP rs6741819, 9) FLJ45964 gene SNP rs
  • rs112859779 which is the SNP of the TCF24 gene, may include the 26th nucleotide of SEQ ID NO: 2, and the allele of the base of rs112859779 may be C or T.
  • the allele of the base of rs112859779 is T or the allele of its complementary base is A, it may be diagnosed as not developing a cerebral aneurysm or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs112859779 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 0.94) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs79134766 which is the SNP of the OLFML2A gene, may include the 26th nucleotide of SEQ ID NO: 3, and the allele of the base of rs79134766 may be G or A.
  • the allele of the base of rs79134766 is A or the allele of its complementary base is T, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs79134766 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 0.96) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs371331393 which is the SNP of the ARHGAP32 gene, may include the 26th nucleotide of SEQ ID NO: 4, and the allele of the base of rs371331393 may be G or A.
  • the allele of the base of rs371331393 is G or the allele of its complementary base is C, the occurrence of a cerebral aneurysm can be diagnosed or the risk of developing a cerebral aneurysm can be predicted at a high level.
  • rs371331393 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 1.00) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs138525217 which is the SNP of the CD163L1 gene, may include the 26th nucleotide of SEQ ID NO: 5, and the allele of the base of rs138525217 may be C or T.
  • the allele of the base of rs138525217 is C or the allele of its complementary base is G, the occurrence of a cerebral aneurysm can be diagnosed or the risk of developing a cerebral aneurysm can be predicted at a high level.
  • rs138525217 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 1.00) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs74115822 which is the SNP of the CUL4A gene, may include the 26th nucleotide of SEQ ID NO: 6, and the allele of the base of rs74115822 may be G or A.
  • the allele of the base of rs74115822 is G or the allele of its complementary base is C, the occurrence of a cerebral aneurysm can be diagnosed or the risk of developing a cerebral aneurysm can be predicted at a high level.
  • rs74115822 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance of 0.80) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs75861150 which is the SNP of the LOC102724084 gene, may include the 26th nucleotide of SEQ ID NO: 7, and the allele of the base of rs75861150 may be T or C.
  • the allele of the base of rs75861150 when the allele of the base of rs75861150 is C or the allele of its complementary base is G, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs75861150 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 1.00) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs116969723 which is the SNP of the LRRC3 gene, may include the 26th nucleotide of SEQ ID NO: 8, and the allele of the base of rs116969723 may be G or A.
  • the allele of the base of rs116969723 is A or the allele of its complementary base is T, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing it may be predicted at a low level.
  • rs116969723 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance of 0.81) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm can do.
  • rs6741819 which is the SNP of the RNF144A gene, may include the 26th nucleotide of SEQ ID NO: 9, and the allele of the base of rs6741819 may be C or T.
  • the allele of the base of rs6741819 when the allele of the base of rs6741819 is T or the allele of its complementary base is A, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs6741819 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 0.72) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm can do.
  • rs59626274 which is the SNP of the FLJ45964 gene, may include the 26th nucleotide of SEQ ID NO: 10, and the allele of the base of rs59626274 may be C or T.
  • the allele of the base of rs59626274 when the allele of the base of rs59626274 is T or the allele of its complementary base is A, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs59626274 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance of 0.71) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs17688188 which is the SNP of the SPCS3 gene, may include the 26th nucleotide of SEQ ID NO: 11, and the allele of the base of rs17688188 may be G or A.
  • the allele of the base of rs17688188 when the allele of the base of rs17688188 is A or the allele of its complementary base is T, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs17688188 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance of 0.73) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm can do.
  • rs56942085 which is the SNP of the LINGO2 gene, may include the 26th nucleotide of SEQ ID NO: 12, and the allele of the base of rs56942085 may be G or A.
  • the allele of the base of rs56942085 is G or the allele of its complementary base is C, the occurrence of a cerebral aneurysm can be diagnosed or the risk of developing a cerebral aneurysm can be predicted at a high level.
  • rs56942085 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance 0.78) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • rs72835045 which is the SNP of the MINK1 gene, may include the 26th nucleotide of SEQ ID NO: 13, and the allele of the base of rs72835045 may be G or A.
  • the allele of the base of rs72835045 when the allele of the base of rs72835045 is A or the allele of its complementary base is T, it may be diagnosed as not developing a cerebral aneurysm, or the risk of developing a cerebral aneurysm may be predicted at a low level.
  • rs72835045 has a high statistical significance in diagnosing a cerebral aneurysm as a result of an overall genetic association analysis (statistical significance of 0.79) (Table 2), and the use of the SNP effectively diagnoses a cerebral aneurysm. can do.
  • the SNP marker composition for diagnosing a cerebral aneurysm is a polynucleotide consisting of 10 or more consecutive bases including the 205th base (rs2303656) of the sequence of SEQ ID NO: 14 in the LOX (lysyl oxidase) gene, or A complementary polynucleotide, a polynucleotide consisting of 10 or more consecutive bases including the 488th base (rs3900446) of the sequence of SEQ ID NO: 15, or a complementary polynucleotide thereof, the 678th base (rs763497) of the sequence of SEQ ID NO: 15
  • a polynucleotide composed of 10 or more consecutive bases, or a complementary polynucleotide thereof, and a combination thereof may be additionally included, but are not limited thereto.
  • the allele of the 205th base of SEQ ID NO: 14 when the allele of the 205th base of SEQ ID NO: 14 is T or the allele of its complementary base is A, the allele of the 205th base of SEQ ID NO: 14 is G or its It can be predicted that the risk of developing a cerebral aneurysm is lower than when the allele of the complementary base is C.
  • the allele of the 488th base of SEQ ID NO: 15 when the allele of the 488th base of SEQ ID NO: 15 is G or the allele of its complementary base is C, the allele of the 488th base of SEQ ID NO: 15 is A or its It can be predicted that the risk of developing a cerebral aneurysm is higher than that of the case where the allele of the complementary base is T, or it can be diagnosed.
  • the allele of the 678th base of SEQ ID NO: 15 when the allele of the 678th base of SEQ ID NO: 15 is G or the allele of its complementary base is C, the allele of the 678th base of SEQ ID NO: 15 is A or its It can be predicted that the risk of developing a cerebral aneurysm is higher than that of the case where the allele of the complementary base is T, or it can be diagnosed.
  • the allele of the 488th base of SEQ ID NO: 15 is G or the allele of its complementary base is C, and the allele of the 678th base of SEQ ID NO: 15 is G or its complementary
  • the allele of the base base is C
  • the allele of the 488th base of SEQ ID NO: 15 is A or the allele of the complementary base is T
  • the allele of the 678th base of SEQ ID NO: 15 is A or its It can be predicted that the risk of developing a cerebral aneurysm is higher than that of the case where the allele of the complementary base is T, or it can be diagnosed.
  • the SNP marker composition for diagnosing a cerebral aneurysm is a polynucleotide consisting of 10 or more consecutive bases including the 326th base (rs1072737) of the sequence of SEQ ID NO: 38 in the SOX17 (SRY-box 17) gene. Or it may be to further include a complementary polynucleotide thereof, but is not limited thereto.
  • the allele of the 326th base of SEQ ID NO: 38 when the allele of the 326th base of SEQ ID NO: 38 is C or the allele of its complementary base is G, the allele of the 326th base of SEQ ID NO: 38 is A or its It can be predicted that the risk of developing a cerebral aneurysm is higher than when the allele of the complementary base is T.
  • Genetic information of the SNP contained in the SNP marker composition for diagnosing a cerebral aneurysm according to an embodiment of the present application can be obtained from a known database, for example, GenBank of the National Center for Biotechnology Information (NCBI). Etc., but is not limited thereto.
  • the SNP marker composition for diagnosing a cerebral aneurysm may be used to diagnose a cerebral aneurysm in Koreans and Asians, but is not limited thereto.
  • the SNP contained in the SNP marker composition for diagnosing a cerebral aneurysm was developed through a full-length genome-related analysis, and by confirming the allele of the SNP, it is possible to diagnose a cerebral aneurysm simply and efficiently. .
  • GWAS gene-wide association study
  • a second aspect of the present application provides a composition for diagnosing a cerebral aneurysm, including an agent capable of detecting or amplifying rs75822236, which is a SNP of the GBA gene.
  • the content overlapping with the first aspect also applies to the composition for diagnosing a cerebral aneurysm of the second aspect.
  • the composition for diagnosing a cerebral aneurysm comprises 1) rs112859779, which is the SNP of the TCF24 gene, 2) rs79134766, which is the SNP of the OLFML2A gene, 3) rs371331393, which is the SNP of the ARHGAP32 gene, 4) rs138525217, which is the SNP of the CD163L1 gene, 5) CUL4A gene SNP rs74115822, 6) LOC102724084 gene SNP rs75861150, 7) LRRC3 gene SNP rs116969723, 8) RNF144A gene SNP rs6741819, 9) FLJ45964 gene SNP rs59626274, 10) SPCS3 gene It may further include an agent capable of detecting or amplifying one or more SNPs selected from the group consisting of SNPs rs17688188, 11) LINGO2 SNPs rs
  • agent capable of detecting SNP refers to an agent capable of specifically binding and recognizing the SNP marker or SNP contained in the SNP marker composition, or detecting and amplifying the SNP.
  • an agent capable of amplifying a SNP marker refers to an agent capable of increasing the number of SNP markers or SNPs contained in the SNP marker composition by repeating replication, for example, including the SNP It may refer to a primer capable of specifically amplifying the polynucleotide or a probe capable of specifically binding, but is not limited thereto.
  • the primers used for the SNP amplification are under appropriate conditions (e.g., 4 different nucleoside triphosphates and a polymerizing agent such as DNA, RNA polymerase or reverse transcriptase) and a template-directed DNA synthesis under an appropriate temperature. It may be a single-stranded oligonucleotide that can serve as a starting point of, and the appropriate length of the primer may vary depending on the purpose of use, but is usually 15 to 30 nucleotides. Short primer molecules generally require a lower temperature to form a stable hybrid with the template.
  • the primer sequence need not be completely complementary to the polynucleotide containing the SNP, but must be sufficiently complementary to hybridize with the polynucleotide containing the SNP.
  • primer is a base sequence having a short free 3'hydroxyl group, which can form a base pair with a complementary template, and the template strand copy Refers to a short sequence that functions as a starting point for Primers can initiate DNA synthesis in the presence of a reagent for polymerization (ie, DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates at an appropriate buffer and temperature. At this time, PCR conditions, the length of the sense and antisense primers can be modified based on those known in the art.
  • a reagent for polymerization ie, DNA polymerase or reverse transcriptase
  • the probe used for SNP detection may refer to a hybridization probe, and refers to an oligonucleotide capable of sequence-specific binding to a complementary strand of a nucleic acid.
  • Hybridization conditions should be sufficiently stringent so that only one of the alleles hybridizes to show a significant difference in hybridization strength between alleles. It is preferable that the central region of the probe of the present invention is aligned with the polymorphic region of the polymorphic sequence. Accordingly, a good hybridization difference between different allelic forms can be induced.
  • the probe may be used in a kit such as a microarray or a prediction method for diagnosing cerebral aneurysms by detecting alleles.
  • the probes of interest can be labeled to detect, for example, radioisotopes, fluorescent compounds, bioluminescent compounds, chemiluminescent compounds, metal chelates or enzymes. Appropriately labeling such a probe is a technique well known in the art, and can be performed through a conventional method.
  • the primer or probe may be chemically synthesized using a phosphoramidite solid support method, or other well-known method.
  • Such nucleic acid sequences can also be modified using a number of means known in the art. Non-limiting examples of such modifications include methylation, encapsulation, substitution of one or more homologs of natural nucleotides, and modifications between nucleotides, e.g., uncharged linkers (e.g. methyl phosphonate, phosphotriester, phosphoro Amidates, carbamates, etc.) or to charged linkers (eg phosphorothioate, phosphorodithioate, etc.).
  • uncharged linkers e.g. methyl phosphonate, phosphotriester, phosphoro Amidates, carbamates, etc.
  • charged linkers eg phosphorothioate, phosphorodithioate, etc.
  • rs75822236 which is the SNP of the GBA gene, may include the 26th nucleotide of SEQ ID NO: 1, and the allele of the base of rs75822236 may be C or T.
  • the composition for diagnosing a cerebral aneurysm is a polynucleotide consisting of 10 or more consecutive bases including the 205th base (rs2303656) of the sequence of SEQ ID NO: 14 in the LOX (lysyl oxidase) gene or a complementary thereof.
  • Polynucleotide a polynucleotide consisting of 10 or more consecutive bases including the 488th base (rs3900446) of the sequence of SEQ ID NO: 15, or a complementary polynucleotide thereof, comprising the 678th base of the sequence of SEQ ID NO: 15 (rs763497)
  • a polynucleotide composed of 10 or more consecutive bases or a complementary polynucleotide thereof, and an agent capable of detecting or amplifying a combination thereof may be additionally included, but is not limited thereto.
  • the composition for diagnosing a cerebral aneurysm is a polynucleotide consisting of 10 or more consecutive bases including the 326th base (rs1072737) of the sequence of SEQ ID NO: 38 in the SOX17 (SRY-box 17) gene, or It may further include an agent capable of detecting or amplifying the complementary polynucleotide, but is not limited thereto.
  • a third aspect of the present application provides a kit for diagnosing a cerebral aneurysm, including the composition for diagnosing a cerebral aneurysm.
  • the content overlapping with the first side and the second side also applies to the second side of the cerebral aneurysm diagnosis kit.
  • the kit may be a PCR kit, an RT-PCR kit, or a DNA chip kit, but is not limited thereto.
  • the kit may include SNP, polynucleotide, cDNA, etc. of the present application, as well as other constituent compositions, solutions, or devices suitable for analysis methods.
  • the PCT kit for diagnosing a cerebral aneurysm may be a kit including essential elements necessary to perform PCR.
  • PCR kits in addition to the polynucleotides, primers or probes specific for the SNP, test tubes or other suitable containers, reaction buffers (varies in pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and reverse transcriptase.
  • Enzymes such as, DNase, RNAse inhibitor, DEPC-water and sterile water may be included.
  • the DNA chip kit for diagnosing a cerebral aneurysm may be a kit including essential elements necessary to perform a DNA chip, and the DNA chip kit includes a specific polynucleotide, primer, or probe for the SNP. It includes a substrate to which it is attached, and the substrate may include a nucleic acid corresponding to a quantitative control gene or a fragment thereof.
  • the RT-PCR kit for diagnosing a cerebral aneurysm may be a kit including essential elements necessary to perform RT-PCR, and the RT-PCR kit is each primer specific for the SNP.
  • reaction buffers varies in pH and magnesium concentration
  • deoxynucleotides dNTPs
  • didioxynucleotides ddNTPs
  • enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterilized water, and the like may be included.
  • a fourth aspect of the present application provides a method of providing information for diagnosing a cerebral aneurysm, comprising determining an allele of rs75822236, a SNP of the GBA gene, from a biological sample isolated from an individual.
  • the content overlapping with the first to third aspects also applies to the method of providing information for diagnosing a cerebral aneurysm of the fourth aspect.
  • the diagnosis of a cerebral aneurysm of the present application may be diagnosing the onset of a cerebral aneurysm, predicting the risk of developing a cerebral aneurysm, or diagnosing the prognosis of a cerebral aneurysm, but is not limited thereto.
  • the term "individual” refers to any organism that has or is likely to develop a cerebral aneurysm, and specific examples include mammals including mice, monkeys, cows, pigs, mini pigs, livestock, humans, etc. It may include animals, farmed fish, etc., but is not limited thereto.
  • sample refers to a substance derived from an individual who develops or is likely to develop a cerebral aneurysm, and specifically, tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid, urine It may include, but is not limited thereto.
  • a gene sample may be obtained from these samples, and the gene sample may include a nucleic acid, for example, DNA, mRNA, or cDNA synthesized from mRNA, and as long as the base information of the SNP can be confirmed therefrom, The kind is not limited thereto.
  • the individual may be a human, and specifically, may be a Korean or Asian, but is not limited thereto.
  • non-genetic information in order to perform risk prediction or diagnosis of the individual, further comprising the step of analyzing non-genetic information, wherein the non-genetic information is sex, age, hypertension, diabetes, It may be one or more selected from the group consisting of hyperlipidemia, smoking, family history of aneurysms, biochemical scales, and clinical scales.
  • determining the base of the SNP in the information providing method may mean a step of confirming the genotype of the SNP.
  • the step of confirming the genotype of SNP includes sequencing analysis, e.g., sequencing analysis using an automatic sequencing analyzer, pyrosequencing, hybridization by microarray, PCR-RELP (restriction fragment length polymorphism) method, PCR -SSCP (single strand conformation polymorphism) method, PCR-SSO (specific sequence oligonucleotide) method, ASO (allele specific oligonucleotide) hybridization method combining PCR-SSO method and dot hybridization method, TaqMan-PCR method, MALDI-TOF/MS method , Rolling circle amplification (RCA) method, high resolution melting (HRM) method, primer extension method, Southern blot hybridization method, dot hybridization method, and the like.
  • sequencing analysis e.g., sequencing analysis using an automatic sequencing analyzer, pyrosequencing, hybrid
  • the step of determining the base of the SNP in the method for providing information of the present application includes, for example, sequencing a nucleotide sequence containing the SNP site from a nucleic acid isolated from a sample obtained from a subject, and determining the SNP allele. It can be done by checking directly. Sequencing of the nucleotide sequence may be performed through a method known in the art. For example, sequencing of the base sequence is performed using a nucleic acid isolated from a sample obtained from an individual as a template, and performing PCR using a primer capable of amplifying a gene site including each SNP site, and the PCR reaction product It can be accomplished by sequentially performing the step of confirming the sequence by the restriction enzyme cleavage method.
  • rs75822236 which is the SNP of the GBA gene, may include the 26th nucleotide of SEQ ID NO: 1, and when the allele of rs75822236 is C, it is diagnosed as developing a cerebral aneurysm or risk of developing it. It may be to further include the step of predicting to a high level.
  • the method for providing information for diagnosing a cerebral aneurysm is from a biological sample isolated from an individual, 1) rs112859779, which is the SNP of the TCF24 gene, 2) rs79134766, which is the SNP of the OLFML2A gene, 3) SNP of the ARHGAP32 gene.
  • the method of providing information for diagnosing a cerebral aneurysm includes 1) when the allele of rs371331393, which is the SNP of the ARHGAP32 gene, is G, 2) when the allele of rs138525217, which is the SNP of the CD163L1 gene, is C, 3) If the allele of rs74115822, the SNP of the CUL4A gene is G, 4) If the allele of rs56942085, the SNP of the LINGO2 gene, is G, or a combination of two or more of them, it is diagnosed as developing or onset of a cerebral aneurysm It may be to further include a step of predicting the risk at a high level.
  • the method of providing information for diagnosing a cerebral aneurysm includes 1) when the allele of rs112859779, which is the SNP of the TCF24 gene, is T, 2) when the allele of rs79134766, which is the SNP of the OLFML2A gene, is A, 3) When the allele of rs75861150, the SNP of the LOC102724084 gene is C, 4) When the allele of rs116969723, the SNP of the LRRC3 gene, is A, 5) When the allele of rs6741819, the SNP of the RNF144A gene is T, 6) When the allele of rs59626274, the SNP of the FLJ45964 gene is T, 7) When the allele of rs17688188, the SNP of the SPCS3 gene, is A, 8) When the allele of rs72835045, the SNP of the MINK1 gene is
  • the method of providing information for diagnosing a cerebral aneurysm is from a biological sample isolated from an individual, the 205th base of the sequence of SEQ ID NO: 14 (rs2303656) in the LOX gene, the 488th of the sequence of SEQ ID NO: 15 The base (rs3900446), the 678th base (rs763497) of the sequence of SEQ ID NO: 15, and the allele of a combination thereof may be further included.
  • the method of providing information for diagnosing a cerebral aneurysm further includes the step of confirming the allele of the 326th base (rs1072737) of the sequence of SEQ ID NO: 38 in the SOX17 gene from a biological sample isolated from the individual. It may be included as.
  • the results of the SNP polymorphism may be statistically processed using a statistical analysis method commonly used in the art, for example, Student t -Student's t-test, Chi-square test, linear regression line analysis, multiple logistic regression analysis, meta-analysis, etc. It can be analyzed using variables such as continuous variables, categorical variables, odds ratio (OR), and 95% confidence interval (CI).
  • a statistical analysis method commonly used in the art, for example, Student t -Student's t-test, Chi-square test, linear regression line analysis, multiple logistic regression analysis, meta-analysis, etc. It can be analyzed using variables such as continuous variables, categorical variables, odds ratio (OR), and 95% confidence interval (CI).
  • the cohort for carrying out the present invention was derived from the Chuncheon Sacred Heart Hospital stroke database (2015-2018), and for database collection, patients showing clinical diagnosis and neuroimaging consistent with hemorrhagic or ischemic stroke were recruited.
  • patients over 18 years of age with saccular and sporadic cerebral aneurysms were analyzed.
  • non-cystic aneurysms such as vertebral, anatomical, traumatic, and infectious aneurysms, and familial aneurysms were excluded.
  • the control group satisfied the following criteria: 1) Patients who underwent computed tomography or magnetic resonance angiography for headache diagnosis or health examination, and 2) no neurological disorders such as cerebral arteriovenous malformation, intracranial hemorrhage, or infarction. , 3) no family history of cerebral aneurysm or subarachnoid hemorrhage in close relatives, 4) no Parkinson's or Alzheimer's disease, and 5) over 18 years of age.
  • the medical records were reviewed in consideration of various variables such as gender, age, clinical symptoms such as non-ruptured cerebral aneurysm or subarachnoid hemorrhage, high blood pressure, diabetes, hyperlipidemia, smoking, and family history of aneurysms, and the size and location of aneurysms (anterior circulation Or posterior circulation), and angiographic parameters for number (singular or plural) were reviewed.
  • This study was approved by the Clinical Trial Committee of Chuncheon Sacred Heart Hospital (No. 2016-3, 2017-9).
  • Genomic DNA was obtained from peripheral blood of the experimental group and the control group using the HiGene TM Genomic DNA Prep Kit (BIOFACT, Daejeon, Korea).
  • HiGene TM Genomic DNA Prep Kit BIOFACT, Daejeon, Korea.
  • PMRA Asia Precision Medicine Research Array
  • Kit Thermo Fisher Scientific, MA, USA
  • Descriptive analysis is expressed using the number of subjects (percentages) of individual and categorical variables, and the mean is expressed as standard error.
  • a multivariate symbol having 7 confounding factors (gender, age, hypertension, diabetes, hyperlipemia, smoking and 4 major factors) for 250 cerebral aneurysms and 294 controls.
  • a multivariate logistic analysis was performed, and the analysis was performed using STATA v11.2 (Stata Corp., TX, USA).
  • full-length genome-related analysis was performed to identify candidate genetic mutations for cerebral aneurysm susceptibility under an additional loci effect model after adjusting the seven confounding factors, and the PLINK 1.9 program ( https://www.cog-genomics). .org/plink/1.9/ ) was used.
  • Genotype-Tissue Expression (https://gtexportal.org/home/) was used to analyze a single tissue expression quantitative trait loci (eQTL).
  • the Manhattan plot and regional association plot are the " qqman " command ( https://cran.r-project.org/web/packages/qqman ) and LocusZoom v1 of the R package v3.4.0, respectively. 3 ( http://locuszoom.org/ ) was used.
  • the main elements are estimated by performing main element analysis with 4 clusters.
  • SNPs with a pairwise linkage disequilibrium of less than 0.8 were removed, and a p-value of less than 5 x 10 -8 , a genome-wide significance threshold, was removed.
  • a total of 29 SNPs were selected. Details of the selected SNP are shown in Table 2 below.
  • SNPs located on the GBA , TCF24 , OLFML2A , ARHGAP32 , CD163L1 , CUL4A , LOC102724084 , and LRRC3 genes show statistical significance of 0.8 or more, and RNF144A , FLJ45964 SPCS3 , LINGO2 , and MINK1 genes
  • the located SNP has a statistical significance of 0.7 to 0.8, and the 13 SNPs can be used to predict the risk of developing a cerebral aneurysm or to diagnose the onset.
  • the control group consisted of matched patients who underwent computed tomography or magnetic resonance angiography for headache diagnosis or health examination, excluding other neurological disorders such as arteriovenous malformations, intracranial hemorrhage or infarction.
  • the medical records were reviewed in consideration of various variables such as sex, age, clinical symptoms such as non-ruptured cerebral aneurysm or subarachnoid hemorrhage, hypertension, diabetes, hyperlipidemia, smoking, and family history of aneurysms. Angiographic parameters for the size, location (anterior or posterior circulation), and number (singular or plural) of aneurysms were reviewed. This study was approved by the Clinical Trial Committee of Chuncheon Sacred Heart Hospital (No. 2016-31).
  • genomic DNA was extracted from peripheral blood of 160 subjects using a HiGene TM Genomic DNA preparation kit (BIOFACT, Daejeon, Korea).
  • Ten SNP primers were designed using the Primer-3 v.0.4.0 program (http://bioinfo.ut.ee/primer3-0.4.0/), and the designed primers are shown in Table 4 below.
  • PCR Polymerase chain reaction
  • the Kruskal-Wallis test was performed to evaluate the difference in non-genetic factors between 80 patients with cerebral aneurysms and 80 controls. Fisher's exact test was performed to estimate the antagonistic relationship between a cerebral aneurysm and 10 SNPs located near or on the LOX gene to estimate the odds ratio (OR).
  • rs2303656, rs3900446, and rs763497 showed a statistically significant association with cerebral aneurysms (p ⁇ 0.05) (Fig. 6).
  • Two SNPs (rs2303656 and rs3900446) reached Bonferroni-corrected levels of significance (p ⁇ 0.005).
  • 187 patients with a cerebral aneurysm confirmed to have a saccular shape radiologically and 372 controls matched with the age and sex of the patients in the patient group were recruited (the ratio of the patient group and the control group was 1:2).
  • the cerebral aneurysm fusiform or anatomical non-cystic aneurysm and traumatic or infectious aneurysm were excluded.
  • the control group consisted of matched patients who underwent computed tomography or magnetic resonance angiography for headache diagnosis or health examination, excluding other neurological disorders such as arteriovenous malformations, intracranial hemorrhage or infarction.
  • the medical records were reviewed in consideration of various variables such as sex, age, clinical symptoms such as non-ruptured cerebral aneurysm or subarachnoid hemorrhage, hypertension, diabetes, hyperlipidemia, smoking, and family history of aneurysms. Angiographic parameters for the size, location (anterior or posterior circulation), and number (singular or plural) of aneurysms were reviewed. This study was approved by the Clinical Trial Committee of Chuncheon Sacred Heart Hospital (No. 2017-9).
  • genomic DNA was extracted from peripheral blood of 559 subjects using a HiGene TM Genomic DNA preparation kit (BIOFACT, Daejeon, Korea).
  • Five SNP primers were designed using the Primer-3 v.0.4.0 program (http://bioinfo.ut.ee/primer3-0.4.0/), and the designed primers are shown in Table 6 below.
  • PCR Polymerase chain reaction
  • Univariate logistic regression analysis was performed to evaluate the difference between 187 patients with cerebral aneurysms and 372 controls for age, sex, hypertension, diabetes, hyperlipidemia, and smoking.
  • a generalized linear model was performed to evaluate the genetic association between cerebral aneurysms and SOX17 gene polymorphism under an additional effect inheritance model to estimate a 95% confidence interval (CI) and correspondence ratio (OR).
  • CI 95% confidence interval
  • OR correspondence ratio
  • Genotype and haplotype associations were analyzed using the PLINK program 1.07 (http://zzz.bwh.harvard.edu/plink/).
  • Example 2 After quality control assay, 4 out of the 5 SNPs selected in Example 2 had a complete genotype classification rate (GCR), a minor allele frequency (MAF) greater than 10%, and a Hardy-Weinberg equilibrium (HWE) P value of 0.05. The excess, pairwise linkage disequilibrium (LD) was greater than 0.8. Rs12541742, located in the intron region of the SOX17 gene, was excluded from this association test due to the Hardy-Weinberg equilibrium (HWE).
  • GCR genotype classification rate
  • MAF minor allele frequency
  • HWE Hardy-Weinberg equilibrium
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