CN114438193A - Gene marker for detecting Alzheimer disease, detection method and application - Google Patents
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Abstract
The invention discloses a gene marker for detecting Alzheimer disease, a detection method and application, and belongs to the technical field of high-throughput sequencing. The detection method comprises the following steps: extracting the genome DNA of a detection object, and sequentially carrying out fragmentation, purification and Pre-PCR amplification reaction on the genome DNA to obtain a target region DNA library; capturing and enriching a target gene coding region of a target region DNA library and DNA adjacent to a shearing region through a chip to obtain a target region library; and (3) carrying out gene detection on the target region library by using a high-throughput sequencing platform, comparing the obtained sequencing data with a reference sequence of the genome DNA, finding out existing gene mutation, carrying out data analysis, and obtaining gene mutation information related to Alzheimer disease pathogenesis. The invention has the advantages of high sensitivity, strong pertinence, comprehensive coverage, large flux, high accuracy and the like, and has huge application space in the aspects of clinical diagnosis and drug development.
Description
Technical Field
The invention belongs to the technical field of high-throughput sequencing, and particularly relates to a gene marker for detecting Alzheimer disease, a detection method and application.
Background
Alzheimer's Disease (AD), also known as senile dementia, is a neurodegenerative disease that seriously affects human health, and is clinically characterized by progressive memory impairment, cognitive dysfunction and behavioral abnormalities, and pathologically characterized by brain atrophy, senile plaques and neurofibrillary tangles in the brain, and neuronal loss. Because the etiology and pathogenesis of AD are not clear, an effective radical treatment means is lacked in the current clinical treatment, a special method/medicine is not available for reversing and stopping the progress of the disease, symptomatic treatment is mainly carried out in an early stage, AD patients diagnosed in the clinic are basically in a middle and late stage, and the existing treatment can only improve symptoms and cannot organize or reverse the progress of the disease. Therefore, the search for the gene markers related to the Alzheimer disease, especially the early warning monitoring and early diagnosis markers, can improve the diagnosis rate of the early Alzheimer disease, realize early diagnosis and intervention, can obviously reduce the harm of AD, and further relieve the burden of society and families.
Disclosure of Invention
Aiming at the problems in the detection and diagnosis of the Alzheimer disease in the prior art, the invention provides a gene marker, a detection method and application for detecting the Alzheimer disease, which are used for simultaneously mutating a plurality of Alzheimer disease pathogenic genes of one sample through high-throughput sequencing detection and have the advantages of high sensitivity, strong pertinence, comprehensive coverage, large flux, high accuracy and the like.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides a gene marker for detecting Alzheimer's disease, which comprises one or more than two of the following genes: APOE, PSEN, MAPT, A2, ABCA, ACE, ADAM, APBB, APP, ATP13A, ATXN, BIN, BLMH, C9ORF, CD2, CD, CHCHCHD, CHMP2, CLU, COL25A, CR, CTSC, DNMT, DNM1, DOCK, EPHA, FBX, FERMT, FUS, GBA, GIGYF, GRN, HFE, HLA-, HNRNPA2B, HS1BP, HTRA, INPP5, LRRK, MEOX, MPO, MS4A4, MS4A6, MSR, NOS, NPC, OLR, OPTN, PRKN, PAXIP, ALPICM, PINK, PLA2G, PLAU, PLD, PTK2, PRAN, RIN, RCS 27, GMMA, SLCP, SLC, STBR, SLCP, SQ, STBR, TRWB, TMBTRB, TPRB, TMBTRB, TPRB, TMBTR, TPRB, TMBTRB, TPRB, TPS.
Preferably, the gene markers include MEOX2 and MPO.
Preferably, the genetic markers include APBB2, PRNP and SORL 1.
The invention also provides application of the gene marker for detecting the Alzheimer disease in preparation of a medicine or a detection reagent for diagnosing the Alzheimer disease.
Preferably, the detection reagent is in the form of a kit.
The invention also provides a method for detecting the gene mutation related to the pathogenesis of the Alzheimer disease, which comprises the following steps:
s1, extracting the genome DNA of the detection object;
s2, sequentially fragmenting, purifying and performing Pre-PCR amplification reaction on the genome DNA to obtain a target region DNA library;
s3, capturing and enriching the target gene coding region of the target region DNA library and the DNA adjacent to the shearing region through the chip to obtain a target region library;
s4, carrying out gene detection on the target region library by using a high-throughput sequencing platform to obtain sequencing data;
s5, comparing the obtained sequencing data with the reference sequence of the genome DNA, finding out existing gene mutation, and carrying out data analysis to obtain gene mutation information related to Alzheimer disease pathogenesis;
the genomic DNA is selected from the group consisting of: APOE, PSEN, MAPT, A2, ABCA, ACE, ADAM, APBB, APP, ATP13A, ATXN, BIN, BLMH, C9ORF, CD2, CD, CHCHCHD, CHMP2, CLU, COL25A, CR, CTSC, DNMT, DNM1, DOCK, EPHA, FBX, FERMT, FUS, GBA, GIGYF, GRN, HFE, HLA-, HNRNPA2B, HS1BP, HTRA, INPP5, LRRK, MEOX, MPO, MS4A4, MS4A6, MSR, NOS, NPC, OLR, OPTN, PRKN, PAXIP, ALPICM, PINK, PLA2G, PLAU, PLD, PTK2, PRAN, RIN, RCS 27, GMMA, SLCP, SLC, STBR, SLCP, SQ, STBR, TRWB, TMBTRB, TPRB, TMBTRB, TPRB, TMBTR, TPRB, TMBTRB, TPRB, TPS.
Preferably, the genomic DNA is derived from human blood, saliva or isolated tissue.
Preferably, the gene mutation is a point mutation or a deletion insertion mutation within 20 bp.
Preferably, the gene mutations are located at MEOX2 and MPO.
Preferably, the genetic mutations are located in APBB2, PRNP and SORL 1.
Preferably, the gene mutation detection related to Alzheimer disease pathogenesis is carried out in the form of a kit.
Compared with the prior art, the invention has the following beneficial effects:
the invention takes the genome DNA of blood, saliva or other isolated tissue sources of a detected person as a detection material, firstly breaks the genome DNA and prepares a library, then captures and enriches the DNA of a target gene coding region and a near shearing region through a chip, carries out the sequencing of a gene exon coding region by using a high-throughput sequencing platform, and finally compares the sequencing with a reference sequence to discover the possible gene mutation.
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FIG. 1 is a comparison of the reference sequence (A) and the sequencing result (B) of the MEOX2 gene in example 1.
FIG. 2 is a comparison of the reference sequence (A) and the sequencing result (B) of the MPO gene in example 1.
Detailed Description
The technical scheme of the present invention will be further described by the following specific examples. It should be understood that the following specific examples are illustrative only and are not limiting upon the present invention. The described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and all other embodiments obtained without any inventive work by those skilled in the art are within the scope of the present invention.
The following examples are examples of genetic markers for detecting alzheimer's disease comprising a combination of one or more of the following genes: APOE, PSEN, MAPT, A2, ABCA, ACE, ADAM, APBB, APP, ATP13A, ATXN, BIN, BLMH, C9ORF, CD2, CD, CHCHCHD, CHMP2, CLU, COL25A, CR, CTSC, DNMT, DNM1, DOCK, EPHA, FBX, FERMT, FUS, GBA, GIGYF, GRN, HFE, HLA-, HNRNPA2B, HS1BP, HTRA, INPP5, LRRK, MEOX, MPO, MS4A4, MS4A6, MSR, NOS, NPC, OLR, OPTN, PRKN, PAXIP, ALPICM, PINK, PLA2G, PLAU, PLD, PTK2, PRAN, RIN, RCS 27, GMMA, SLCP, SLC, STBR, SLCP, SQ, STBR, TRWB, TMBTRB, TPRB, TMBTRB, TPRB, TMBTR, TPRB, TMBTRB, TPRB, TPS.
The above genes are exemplified as follows:
MEOX 2: the gene encodes a member of a non-clustered, forked, homeobox gene subfamily similar to the homeobox, the encoded protein may play a regulatory role in vertebrate limb myogenesis, and MEOX 2-associated diseases including alzheimer's disease, female stress urinary incontinence and cleft palate (X-linkage).
MPO: myeloperoxidase (MPO) is a heme protein synthesized during the differentiation of the medullary system, is the main component of neutrophil azurophil granules, and MPO-associated diseases include myeloperoxidase deficiency and Alzheimer's disease.
APBB 2: the gene encodes a protein that interacts with amyloid beta protein (a4) precursor protein and amyloid-2-like cytoplasmic domains, which contains two phosphotyrosine binding (PTB) domains, thought to play a role in signal transduction, and diseases associated with APBB2 include alzheimer's disease and giant axonal neuropathy.
PRNP: the protein encoded by the gene is a membrane glycosyl phosphatidyl inositol anchored glycoprotein, which tends to aggregate into rod-like structures, and PRNP-related diseases including creutzfeldt-jakob disease and fatal familial insomnia.
SOLL 1: the encoded protein also contains fibronectin type III repeats and epidermal growth factor repeats, and the encoded preproprotein is proteolytically processed to generate mature receptors that may play a role in endocytosis and sorting, diseases associated with SORL1 including alzheimer's disease.
In some embodiments, the gene markers include MEOX2 and MPO.
In some embodiments, the gene markers include APBB2, PRNP, and SORL 1.
The gene markers for detecting Alzheimer's disease in the following examples are used for preparing a drug for diagnosing Alzheimer's disease or a detection reagent, and for example, the detection reagent may be in the form of a kit.
In the following embodiments, a method (e.g., in the form of a kit) for detecting a gene mutation associated with alzheimer disease pathogenesis is adopted, and the main technical processes include genomic DNA extraction, library preparation, library quality inspection and quantification, on-machine sequencing, and data comparative analysis, and include the following steps:
s1, extracting the genome DNA of the detection object, wherein the genome DNA comprises the following genes: APOE, PSEN, MAPT, A2, ABCA, ACE, ADAM, APBB, APP, ATP13A, ATXN, BIN, BLMH, C9ORF, CD2, CD, CHCHCHD, CHMP2, CLU, COL25A, CR, CTSC, DNMT, DNM1, DOCK, EPHA, FBX, FERMT, FUS, GBA, GIGYF, GRN, HFE, HLA-, HNRNPA2B, HS1BP, HTRA, INPP5, LRRK, MEOX, MPO, MS4A4, MS4A6, MSR, NOS, NPC, OLR, OPTN, PRKN, PAXIP, ALPICM, PINK, PLA2G, PLAU, PLD, PTK2, PRAN, RIN, RCS 27, GMMA, SLRB 3, SLC, STRB, STBC, SQ, STBR, TRWB, TMZCP, TRYP, TRPB, TRYP, TRCP 4A, TRYP, TRPB, TRYP, TRPB, TRPC, TRYP, TROB, TRPC, TRYP, TRPC, TRPB, TRYP, TROB, TRPC, TRYP, TRPC, TROCB, TRPC, TRYP, TRPC, TRYP, TRYPB, TRPC, TRYPB, TRPC;
s2, sequentially fragmenting, purifying and performing Pre-PCR amplification reaction on the genome DNA to obtain a target region DNA library;
s3, capturing and enriching the target gene coding region of the target region DNA library and the DNA adjacent to the shearing region through the chip to obtain a target region library;
s4, carrying out gene detection on the target region library by using a high-throughput sequencing platform to obtain sequencing data;
s5, comparing the obtained sequencing data with the reference sequence of the genome DNA, finding the existing gene mutation, and carrying out data analysis to obtain the gene mutation information related to the Alzheimer disease pathogenesis.
In some embodiments, the genomic DNA may be derived from human blood, saliva, or ex vivo tissue.
In some embodiments, the gene mutation is a point mutation or a deletion insertion mutation within 20 bp.
In some embodiments, the gene mutations are located at MEOX2 and MPO.
In some embodiments, the gene mutations are located in APBB2, PRNP, and SORL 1.
In some embodiments, the detection of the gene mutation associated with the pathogenesis of alzheimer's disease may be performed using a kit.
The technical solution of the present invention is explained below by specific examples.
Example 1
Proband, male, age 58, submitted to hospital: people hospitals in Sichuan province.
Sample type: whole blood.
The clinical manifestations are as follows: the memory declines.
Detecting items: alzheimer disease pathogenesis related gene mutation.
Detection numbering: AD-2021051201.
Detection area: exon regions of about 99 genes in human genomic DNA.
And (3) detection strategy: and analyzing the specific pathogenic relation genes recorded in the OMIM database.
The detection method comprises the following steps: NGS chips capture high throughput sequencing.
And (3) detection results: 2 single gene mutations or variations that were significantly associated with the clinical phenotype were detected in the probands described above, and as shown in table 1, fig. 1 and fig. 2, the homozygous mutation for MEOX2 was found to be highly associated with alzheimer's disease.
TABLE 1
FIG. 1 is a comparison of the reference sequence (FIG. 1A) and the sequencing results (FIG. 1B) of the MEOX2 gene in example 1. Neurovascular dysfunction is the major cause of alzheimer's disease, manifested by altered cerebral blood flow, abnormal angiogenesis and vascular remodeling, and insufficient β -amyloid clearance. Detection of human brain endothelial cells using cDNA microarray analysis found decreased expression of MEOX2 gene in cells from 16 alzheimer patients compared to age-matched controls; total capillary length of AD cortical brain tissue was reduced by about 60% compared to age-matched controls and was negatively correlated with dementia score. The human MEOX2 gene transfects AD cerebrovascular endothelial cells to improve the expression of Vascular Endothelial Growth Factor (VEGF); mediated capillary formation and increased low density lipoprotein receptor-related protein-1 (LRP1), the major β -amyloid clearing receptor of the blood brain barrier, combined with figure 1, MEOX2 is known to be associated with neurovascular dysfunction in AD.
FIG. 2 is a comparison of the reference sequence (FIG. 2A) and the sequencing result (FIG. 2B) of the MPO gene in example 1. Reynolds et al (2000) found that the MPO-463A allele bound to APOE4 significantly increased the risk of Alzheimer's disease in men, Zappia et al (2004) found that patients with the G/G genotype had a odds ratio of 1.65 in studies with 148 sporadic Alzheimer's disease patients in southern Italy, and when bound to the alpha-2-macroglobulin polymorphic genotype 1000val/val, the odds ratio increased to 23.19, and it was evident from FIG. 2 that MPO is associated with AD.
Furthermore, 3 single gene mutations or variations significantly associated with the clinical phenotype were detected in additional subjects, as shown in table 2.
TABLE 2
In summary, the invention uses genomic DNA from blood, saliva or other tissues of a subject as a detection material, firstly breaks the DNA and prepares a library, then captures and enriches the DNA of a target gene coding region and a near-cutting region through a chip, and finally performs mutation detection by using a high-throughput sequencing platform to find out possible gene mutation. The invention is suitable for point mutation and deletion insertion mutation (micro mutation) within 20bp, is not suitable for detecting special mutations such as heterozygosity gene large fragment copy number variation, dynamic mutation, complex recombination and the like, and is also not suitable for detecting genome structure variation (such as large fragment deletion, replication and inversion rearrangement), large fragment heterozygosity insertion mutation (such as Alu-mediated insertion) and mutation positioned in a gene regulation region and a deep intron region. In addition, due to the fact that part of genes have high-repetition low-complexity regions or pseudogenes, detection cannot completely cover all exon regions of the genes, but the total coverage can reach more than 95%, and the method has the advantages of high sensitivity, strong pertinence, comprehensive coverage, high flux, high accuracy and the like, is beneficial to finding and verifying target genes and key sites related to the Alzheimer's disease, is used for delaying or even preventing the symptomatic AD, and has a huge application space in the aspects of clinical diagnosis and drug development.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A gene marker for detecting alzheimer's disease, comprising a combination of one or more of the following genes: APOE, PSEN, MAPT, A2, ABCA, ACE, ADAM, APBB, APP, ATP13A, ATXN, BIN, BLMH, C9ORF, CD2, CD, CHCHCHD, CHMP2, CLU, COL25A, CR, CTSC, DNMT, DNM1, DOCK, EPHA, FBX, FERMT, FUS, GBA, GIGYF, GRN, HFE, HLA-, HNRNPA2B, HS1BP, HTRA, INPP5, LRRK, MEOX, MPO, MS4A4, MS4A6, MSR, NOS, NPC, OLR, OPTN, PRKN, PAXIP, ALPICM, PINK, PLA2G, PLAU, PLD, PTK2, PRAN, RIN, RCS 27, GMMA, SLCP, SLC, STBR, SLCP, SQ, STBR, TRWB, TMBTRB, TPRB, TMBTRB, TPRB, TMBTR, TPRB, TMBTRB, TPRB, TPS.
2. The genetic marker for detecting alzheimer's disease as claimed in claim 1, wherein said genetic marker comprises MEOX2 and MPO.
3. The genetic marker for detecting alzheimer's disease according to claim 1 wherein said genetic marker comprises APBB2, PRNP and SORL 1.
4. Use of the gene marker for detecting alzheimer's disease according to any of claims 1 to 3 for the preparation of a medicament or a detection reagent for the diagnosis of alzheimer's disease.
5. The use of claim 4, wherein the detection reagent is in the form of a kit.
6. A method for detecting a gene mutation associated with the pathogenesis of Alzheimer's disease, comprising the following steps:
s1, extracting the genome DNA of the detection object;
s2, sequentially fragmenting, purifying and performing Pre-PCR amplification reaction on the genome DNA to obtain a target region DNA library;
s3, capturing and enriching the target gene coding region of the target region DNA library and the DNA adjacent to the shearing region through the chip to obtain a target region library;
s4, carrying out gene detection on the target region library by using a high-throughput sequencing platform to obtain sequencing data;
s5, comparing the obtained sequencing data with the reference sequence of the genome DNA, finding out existing gene mutation, and carrying out data analysis to obtain gene mutation information related to Alzheimer disease pathogenesis;
the genomic DNA is selected from the group consisting of: APOE, PSEN, MAPT, A2, ABCA, ACE, ADAM, APBB, APP, ATP13A, ATXN, BIN, BLMH, C9ORF, CD2, CD, CHCHCHD, CHMP2, CLU, COL25A, CR, CTSC, DNMT, DNM1, DOCK, EPHA, FBX, FERMT, FUS, GBA, GIGYF, GRN, HFE, HLA-, HNRNPA2B, HS1BP, HTRA, INPP5, LRRK, MEOX, MPO, MS4A4, MS4A6, MSR, NOS, NPC, OLR, OPTN, PRKN, PAXIP, ALPICM, PINK, PLA2G, PLAU, PLD, PTK2, PRAN, RIN, RCS 27, GMMA, SLCP, SLC, STBR, SLCP, SQ, STBR, TRWB, TMBTRB, TPRB, TMBTRB, TPRB, TMBTR, TPRB, TMBTRB, TPRB, TPS.
7. The method for detecting the genetic mutation associated with the pathogenesis of Alzheimer's disease according to claim 6, wherein said genomic DNA is derived from human blood, saliva or isolated tissue.
8. The method of claim 6, wherein the genetic mutation is a point mutation or a deletion insertion mutation of 20bp or less.
9. The method for detecting the genetic mutation related to the pathogenesis of alzheimer's disease according to claim 8, wherein the genetic mutation is located between MEOX2 and MPO; and/or
The gene mutations were located in APBB2, PRNP and SORL 1.
10. The method for detecting the gene mutation related to the pathogenesis of Alzheimer's disease according to claim 6, wherein the gene mutation related to the pathogenesis of Alzheimer's disease is detected in a kit form.
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