WO2018212371A1 - Polymorphisme mononucléotidique de promoteur d'apoe associé à un risque de maladie d'alzheimer et son utilisation - Google Patents

Polymorphisme mononucléotidique de promoteur d'apoe associé à un risque de maladie d'alzheimer et son utilisation Download PDF

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WO2018212371A1
WO2018212371A1 PCT/KR2017/005137 KR2017005137W WO2018212371A1 WO 2018212371 A1 WO2018212371 A1 WO 2018212371A1 KR 2017005137 W KR2017005137 W KR 2017005137W WO 2018212371 A1 WO2018212371 A1 WO 2018212371A1
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alzheimer
disease
apoe
cognitive impairment
mild cognitive
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PCT/KR2017/005137
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English (en)
Korean (ko)
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이건호
최규영
이장재
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조선대학교산학협력단
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Priority to PCT/KR2017/005137 priority Critical patent/WO2018212371A1/fr
Priority to JP2019536313A priority patent/JP7399465B2/ja
Priority to EP18801295.9A priority patent/EP3626830A4/fr
Priority to PCT/KR2018/000649 priority patent/WO2018212427A1/fr
Priority to US15/932,345 priority patent/US20200370101A1/en
Priority to CN201880009624.6A priority patent/CN110249061A/zh
Publication of WO2018212371A1 publication Critical patent/WO2018212371A1/fr
Priority to JP2021178702A priority patent/JP2022033735A/ja

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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

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  • the present invention relates to a single base mutation for early diagnosis of Alzheimer's disease and prediction of Alzheimer's disease risk.
  • the present invention also relates to a method for early diagnosis of Alzheimer's disease and prediction of Alzheimer's disease risk using a single base mutation.
  • the present invention is a research project of "Identification of MRI-based Alzheimer's Dementia-specific Brain Injury and Brain Mapping" among the brain science and technology development projects of the Ministry of Science, ICT and Future Planning (Korea Research Foundation). Completed with the support of
  • Alzheimer's dementia Currently, many pharmaceutical companies are developing treatment for Alzheimer's dementia, but there is no clear treatment, and thus, there is a high need for early diagnosis and early prediction. Diagnostic techniques for Alzheimer's dementia include neuropsychological testing, MRI brain imaging, clinical findings by specialists, and pathological examination through amyloid-PET based on cerebrospinal fluid and florbetaben. In the case of clinical diagnosis, dementia or mild cognitive impairment can be diagnosed, but it is difficult to distinguish from other brain diseases, and it is not suitable for the purpose of early diagnosis because the diagnosis can be made only after the onset of symptoms.
  • cerebrospinal fluid test In the case of cerebrospinal fluid test, it is performed through quantitative analysis such as beta amyloid protein and tau protein analysis, and the subject's rejection is very high due to reliable diagnosis of dementia or invasive cerebrospinal fluid collection.
  • Pathological examination with amyloid-PET is reliable but expensive.
  • brain damage associated with dementia such as cerebral cortex atrophy and hippocampal atrophy, is being developed and the technique for early diagnosis is being developed.
  • diagnosis technology for dementia through blood is actively progressed, but there is a limitation in the scale and accuracy of the test subject population, so reliability verification is required for clinical application.
  • Alzheimer's dementia is a highly hereditary disease with a genetic impact of more than 70%.
  • APOE is encoded by three homologous variants on chromosome 19 q13.2, and proteins by polymorphism of this gene form three major variants (APOE E2, E3, E4) by analysis of amino acid sequences.
  • the E4 allele is known as a risk factor for Alzheimer's disease. People with the APOE E4 allele have a high incidence of early family or sporadic Alzheimer's disease and a high risk of atherosclerotic heart disease. But.
  • the present inventors studied not only APOE E4 genetic mutations, but also genetic variations that may affect the dementia risk of APOE E4 around the APOE gene.
  • APOE E4 homozygotes homozygote
  • the ethnic differences in the risk of dementia was identified, and this was analyzed to analyze the cause.
  • the gene single base mutation located in the APOE promoter not only explains the differences in racial risks of APOE E4 homozygotes, but also shows the difference in cerebral cortical thickness according to the allele, thus completing the present invention. It was.
  • the present invention provides a single nucleotide polymorphism (SNP) genetic variation for predicting dementia risk due to Alzheimer's disease and / or Alzheimer's disease.
  • SNP single nucleotide polymorphism
  • Another object of the present invention is to detect a single base polymorphism (SNP) genetic variation and to predict the risk of dementia caused by Alzheimer's disease and / or Alzheimer's disease.
  • SNP single base polymorphism
  • the present invention provides a method for providing information on predicting Alzheimer's dementia using the APOE epsilon genetic mutations (rs429358 and rs7412) and rs405509 genetic mutations.
  • the present invention provides for the isolation and purification of genomic DNA from samples isolated from a subject, for example, cells, tissues, blood, or body fluids, and (a) genes encoding APOE E4 alleles or Contacting the sample with a reagent capable of detecting the presence or absence of the genetic variation in a gene selected from a gene product of; And (b) contacting the sample with a reagent capable of detecting the presence or absence of the genetic variation selected from the gene encoding rs405509 T allele of the APOE promoter or a gene product thereof. And / or diagnose Alzheimer's dementia.
  • the present invention may further comprise obtaining an image of the subject's cerebral cortical thickness in performing the diagnosis, if the cerebral cortical thickness is confirmed to be atrophic, the subject is mild cognitive impairment or Alzheimer's disease Patients are considered to have a high risk for mild to severe disorders or Alzheimer's disease.
  • the risk of Alzheimer's dementia can be diagnosed more accurately by examining the genetic variation of rs405509.
  • the table in FIG. 1 shows the odds ratios of APOE E4 / E4 to APOE E3 / E3 by race.
  • Figure 2 graphically shows the odds ratios of APOE E4 / E4 by race.
  • Figure 3 shows the difference in the degree of atrophy of APOE E4 / E4 based on APOE E3 / E3 for all races in the cerebral cortex difference analysis between Asians and Caucasians. The difference between E4 and E3 / E3 is large.
  • Figure 5 shows the APOE gene structure, the APOE gene is located on human chromosome 19, rs405509 SNP is located in the APOE promoter portion.
  • Figure 6 shows the ethnic differences of the rs405509 SNP, showing the ratio of the three genotypes TT, TG and GG to the T and G allele.
  • FIG. 7 shows the difference in cerebral cortex thickness for each genotype TT, TG, and GG in the population with APOE E4 / E4 of the Caucasus, compared to APOE E3 / E3.
  • FIG. 8 shows an Alzheimer's dementia association analysis of each genotype TT, TG, and GG of rs405509 in a population with APOE E4 / E4 from the Caucasus. Based on TT, the risks of GG or GG and GT genotypes are shown.
  • the onset provides single nucleotide polymorphism (SNP) that can be used to predict the risk of dementia due to Alzheimer's disease and / or Alzheimer's disease. More specifically, the SNP is rs405509, which is located on chromosome 19 44905579 based on the human gene map GRCh38.p7 version, and its alleles are T and G. There was a difference in minor allele frequency (MAF) between races,
  • the invention provides for the isolation and purification of genomic DNA from samples isolated from a subject, for example, cells, tissues, blood, or body fluids, analysis of the rs405509 monobasic polymorphisms and APOE genotypes of the APOE promoter. Check and predict the risk of dementia.
  • APOE epsilon genetic mutation rs429358 and rs7412
  • rs405509 genetic mutation there is provided a method for providing information for predicting Alzheimer's dementia.
  • a sample isolated from a subject comprising genomic DNA in a sample isolated from a subject comprising genomic DNA, (a) detecting the presence or absence of said genetic variation in a gene encoding an APOE E4 allele or a gene selected from a gene product thereof. Contacting the sample with a reagent that may be present; And (b) contacting said sample with a reagent capable of detecting the presence or absence of said genetic variation selected from a gene encoding rs405509 T allele of an APOE promoter or a gene product thereof, wherein said APOE E4 / E4 and rs405509 T / T genetic variation is a diagnosis of mild cognitive impairment or Alzheimer's disease, which indicates that the subject is a patient with mild cognitive impairment or Alzheimer's disease, or that the subject has a high risk for mild impairment or Alzheimer's disease Or predicting the risk for these diseases is provided.
  • the method may further include obtaining an image of a subject's cerebral cortex thickness, and if the cerebral cortex thickness is confirmed to be atrophy, the subject is a patient with mild cognitive impairment or Alzheimer's disease, or a mild impairment or Alzheimer's disease. Indicates a high risk for the disease.
  • the image of the cerebral cortex thickness may be MR brain imaging, the method of diagnosing the mild cognitive impairment or Alzheimer's disease or predict the risk for these diseases, neuropsychological test, cerebrospinal fluid ( And additionally performing one or more of the examinations consisting of a CSF) test and an amyloid-PET test.
  • the diagnosis or prediction of mild cognitive impairment or Alzheimer's disease in Asians comprising primer sets complementary to APOE monobasic polymorphism APOE E4 and APOE promoter monobasic polymorphism rs405509 T / T. Kits are provided.
  • the diagnosis or prediction may be targeted to Koreans.
  • the present invention provides for the presence of said genetic variation in a gene selected from a gene encoding APOE E4 allele or a gene product thereof in a sample isolated from a subject comprising genomic DNA or Contacting the sample with a reagent capable of detecting absence; And (b) contacting said sample with a reagent capable of detecting the presence or absence of said genetic variation selected from a gene encoding rs405509 T allele of an APOE promoter or a gene product thereof, wherein said APOE E4 / E4 and rs405509 T / T genetic variation is a diagnosis of mild cognitive impairment or Alzheimer's disease, which indicates that the subject is a patient with mild cognitive impairment or Alzheimer's disease, or that the subject has a high risk for mild impairment or Alzheimer's disease Or provide information about predicting the risk for these diseases.
  • the full-length genetic information was utilized.
  • a study on 2075 subjects of the dementia cohort (centered on Chosun University Hospital and other cooperative hospitals, average age of normal people 73.45 ⁇ 5.30 (mean ⁇ SD), average age of patients with Alzheimer's disease 71.65 ⁇ 5.65 (mean ⁇ SD), Full-length genome information was obtained using blood of 62.4% of women and 61.5% of patients with Alzheimer's disease, and brain imaging information was obtained through MRI scans (3T MRI, Skyra, Siemems) of each subject.
  • Neuropsychological tests for diagnosis of dementia were performed on each subject, and as a result, the diagnosis of normal, mild cognitive impairment, or dementia by a dementia clinician was confirmed. As a result of diagnosis, 1145 patients were normal and 930 patients were dementia.
  • the genomes of the Caucasus are available from the public databases 1000 Genomes ( https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/ ) and ADNI (Alzheimers Disease Neuroimaging Initiative; http: //adni.loni.usc. edu /) database and Caucasus brain images were also obtained from ADNI database.
  • ADNI dataset Caucasus brain imaging data
  • NRCD dataset Asian brain imaging data
  • 1569 samples were used in combination with E3 / E3 and E4 / E4 (see FIG. 3).
  • Cortical thickness analysis of TT, TG, and GG genotypes of rs405509 in APOE E4 / E4 background is based on E3 / E3: 1) E4 / E4-TT vs E3 / E3, 2) E4 / E4 vs E3 / E3 -GT, 3) 1) 757 samples, 2) 740 samples, 3) 715 samples were used in each case of E4 / E4-GG versus E3 / E3 (see FIG. 7).
  • the Caucasus genome used for the odds ratio of rs405509 uses the National Institute on Aging-late onset Alzheimer's disease (NIA-LOAD), the National Cell Repository for Alzheimer's Disease (NCRAD), and the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. It was. Two datasets or three datasets were combined and analyzed. APOE promoter monobases of individuals with E4 / E4 genotype were used. When NIA-LOAD, NCRAD, and ADNI were combined and analyzed, a total of 395 individuals with E4 / E4 genotype were identified, including 330 Alzheimer's patients with Alzheimer's disease. 65 persons were used.
  • Total genome information was quantified after extracting gDNA using buffy coats isolated from blood of subjects diagnosed as normal, Alzheimer's mild cognitive impairment patients and Alzheimer's dementia patients, using a QIAGEN DNA mini kit. Quantification was performed using an ND-1000 spectrophotometer and Quant-iT PicoGreen dsDNA Reagent and Kits. Next, the DNA quality was confirmed by electrophoresis on agarose 1.0% TBE (Tris-borate-EDTA, Invitrogen) gel, and then microarray-based genotyping was performed on the sample that passed DNA quality control. Axiom Korean chips from Affymetrix were used according to the manufacturer's instructions to obtain information on each genotype. SNPs that were not microarrayed were genotyped by imputation.
  • FIG. 1 graphically shows the odds ratios of APOE E4 / E4 by race. 1 and 2 in the name of the National Research Center for Dementia, NRCD refers to Korean samples recruited from Chosun University Dementia Research Center. As seen in FIGS. 1 and 2, the risk of APOE E4 / E4 was highest in Asians.
  • Figure 3 is an analysis of the cerebral cortex difference between Asians and Caucasians, showing the degree of atrophy of APOE E4 / E4 on the basis of APOE E3 / E3 for each race for every point of the cerebral cortex. The darker the red, the larger the difference between E4 / E4 and E3 / E3.
  • rs405509 is located in the promoter region of the APOE gene on chromosome 19 (FIG. 5). 6 shows genotype frequencies of ras405509 by race. For East Asian, Caucasian, and African, the ratios under APOE E4 / E4, along with the overall ratios, are shown.
  • the ratio of the T allele was Asian> Caucasian> African in interracial proportions, and specifically, the odds ratio (OR) of APOE E4 / E4 to Asians was> Caucasus> African. This suggests that the T allele of rs405509 increases the risk of dementia in APOE E4 / E4.
  • each genotype TT, TG, and GG of rs405509 was analyzed using the cortical data of the Caucasian race.
  • genotypes of rs405509 were classified as TT, TG and GG, and the cortical thickness was compared with the sample with genotype of APOE E3 / E3.
  • the present invention provides a more accurate method for predicting dementia risk by analyzing the genetic variation of rs405509 in the APOE promoter as well as the APOE genotype in genomic DNA taken from blood or biological samples.
  • the present invention can contribute to the future diagnosis technology based on dementia big data along with complex clinical and pathological information such as MRI brain imaging, neuropsychological examination, cerebrospinal fluid (CSF) test, amyloid-PET test.
  • CSF cerebrospinal fluid

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Abstract

La présente invention concerne un polymorphisme mononucléotidique (SNP) qui peut être utilisé pour prédire un risque de maladie d'Alzheimer. Le SNP est le rs405509 et est situé sur le chromosome 19, 44905579 sur la base de la carte du génome humain GRCh38.p7. La présente invention suggère que l'allèle T de rs405509 a pour rôle d'augmenter de manière accrue le risque de démence de l'APOE E4/E4. Le résultat de la comparaison de l'épaisseur corticale cérébrale et du volume hippocampique entre les génotypes d'APOE suggère que la contraction en E4/E4 est supérieure à celle en E3/E3 dans les populations de type asiatique. Le cortex cérébral de personnes possédant un génotype T/T rs405509, parmi les populations de type caucasien possédant un génotype E4/E4, est bien davantage atrophié. Par conséquent, la présente invention permet de confirmer le polymorphisme T/T rs405509 conjointement avec l'APOE E4/E4 et peut donc être utilisée pour diagnostiquer ou prédire un risque de maladie d'Alzheimer et/ou de démence due à la maladie d'Alzheimer.
PCT/KR2017/005137 2017-05-15 2017-05-17 Polymorphisme mononucléotidique de promoteur d'apoe associé à un risque de maladie d'alzheimer et son utilisation WO2018212371A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/KR2017/005137 WO2018212371A1 (fr) 2017-05-17 2017-05-17 Polymorphisme mononucléotidique de promoteur d'apoe associé à un risque de maladie d'alzheimer et son utilisation
JP2019536313A JP7399465B2 (ja) 2017-05-15 2018-01-15 アルツハイマー病の危険性と関連するａｐｏｅプロモーターの一塩基多型およびその使用
EP18801295.9A EP3626830A4 (fr) 2017-05-15 2018-01-15 Polymorphisme mononucléotidique de promoteur d'apoe associé à un risque de maladie d'alzheimer et son utilisation
PCT/KR2018/000649 WO2018212427A1 (fr) 2017-05-15 2018-01-15 Polymorphisme mononucléotidique de promoteur d'apoe associé à un risque de maladie d'alzheimer et son utilisation
US15/932,345 US20200370101A1 (en) 2017-05-15 2018-01-15 Apoe promotor snp associated with risk of alzheimer's disease and the use thereof
CN201880009624.6A CN110249061A (zh) 2017-05-15 2018-01-15 与阿尔茨海默病风险相关的apoe启动子单核苷酸多态性及其用途
JP2021178702A JP2022033735A (ja) 2017-05-15 2021-11-01 アルツハイマー病の危険性と関連するａｐｏｅプロモーターの一塩基多型およびその使用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112151113A (zh) * 2020-09-27 2020-12-29 类承斌 一种迟发性阿尔茨海默症关联基因变异的早期筛查方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150119264A1 (en) * 2009-07-03 2015-04-30 University College Cardiff Consultants Limited Diagnosis and treatment of alzheimer's disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150119264A1 (en) * 2009-07-03 2015-04-30 University College Cardiff Consultants Limited Diagnosis and treatment of alzheimer's disease

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEN, Y ET AL.: "The Effects of an APOE Promoter Polymorphism on Human Cortical Morphology during Nondemented Aging", JOURNAL OF NEUROSCIENCE, vol. 35, no. 4, 28 January 2015 (2015-01-28), pages 1423 - 1431, XP055559882 *
CHOI, K. Y. ET AL.: "Effects of APOE Gene Polymorphisms on Late Onset Alzheimer's Disease in a Korean Population", ALZHEIMER'S & DEMENTIA, vol. 12, no. 7, 26 July 2016 (2016-07-26), pages P850, XP029770331 *
LIMON-SZTENCEL, A. ET AL.: "The Algorithm for Alzheimer Risk Assessment Based on APOE Promoter Polymorphisms", ALZHEIMER'S RESEARCH & THERAPY, vol. 8, no. 19, 19 May 2016 (2016-05-19), pages 1 - 7, XP055559876 *
MA, C ET AL.: "The TT Allele of R s405509 Synergizes with APOE epsilon4 in the Impairment of Cognition and Its Underlying Default Mode Network in Non-demented Elderly", CURRENT ALZHEIMER RESEARCH, vol. 13, no. 6, 2016, pages 708 - 717, XP055559886 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112151113A (zh) * 2020-09-27 2020-12-29 类承斌 一种迟发性阿尔茨海默症关联基因变异的早期筛查方法

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