WO2025058485A1 - Method for determining risk of developing normal tension glaucoma specific to koreans by using apolipoprotein e gene polymorphism analysis - Google Patents
Method for determining risk of developing normal tension glaucoma specific to koreans by using apolipoprotein e gene polymorphism analysis Download PDFInfo
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- the present invention relates to a method for determining the risk of developing normal tension glaucoma specific to Koreans by analyzing apolipoprotein E gene polymorphism.
- Glaucoma is a degenerative and progressive optic neuropathy characterized by glaucomatous optic nerve damage with visual field defects. Glaucoma is one of the leading causes of visual field loss and blindness worldwide. Recent studies have shown that open-angle glaucoma (OAG) is phenotypically and genetically heterogeneous and is polygenic in nature.
- OAG open-angle glaucoma
- NTG Normal tension glaucoma
- IOP intraocular pressure
- SNPs single nucleotide polymorphisms
- APOE apolipoprotein E
- the inventors of the present invention investigated the correlation between the incidence of normal tension glaucoma and APOE haplotype in a Korean cohort and confirmed a significant correlation, thereby completing the present invention.
- the purpose of the present invention is to provide a method for determining at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412 from a biological sample in order to provide information necessary for predicting the risk of developing normal tension glaucoma in Koreans.
- SNP single nucleotide polymorphism
- Another object of the present invention is to provide a biomarker composition for determining normal tension glaucoma in Koreans, comprising at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412.
- SNP single nucleotide polymorphism
- Another object of the present invention is to provide a composition for predicting the risk of developing normal tension glaucoma, comprising a preparation capable of detecting the biomarker composition.
- Another object of the present invention is to provide a kit for predicting the risk of developing normal tension glaucoma, comprising the composition.
- the present invention provides a method for determining at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412 from a biological sample, in order to provide information necessary for predicting the risk of developing normal tension glaucoma in Koreans.
- SNP single nucleotide polymorphism
- polymorphism refers to a case where two or more alleles exist at one locus, and among the polymorphic sites, a single nucleotide polymorphism (SNP) that differs only by a single base depending on the individual is called a single nucleotide polymorphism.
- SNP single nucleotide polymorphism
- a preferable polymorphic marker has two or more alleles that exhibit an occurrence frequency of 1% or more, more preferably 5% or 10% or more in a selected population. Therefore, genetic association for a polymorphic marker means that there is an association for one or more specific alleles of a specific polymorphic marker.
- a marker may include any variant form of an allele found in a genome, including a single nucleotide polymorphism (SNP), a microsatellite, an insertion, a deletion, a duplication, and a translocation.
- an allele or biallelic trait refers to multiple types of a gene existing at the same locus of a homologous chromosome.
- An allele is also used to indicate polymorphism, for example, a SNP has two types of alleles.
- rs_id means rs-ID, an independent marker assigned to all initially registered SNPs by NCBI, which began accumulating SNP information in 1998. In the present invention, it is described in the form of rs2946370.
- the rs_id described in such a table means a SNP marker, which is a polymorphic marker of the present invention. Those skilled in the art will be able to easily confirm the location and sequence of the SNP using the rs_id.
- rs449647, rs769446, rs405509, rs429358, and rs7412 used to predict the risk of developing normal tension glaucoma in Koreans are each registered in the Single Nucleotide Polymorphism Database of the National Center for Biotechnology Information (NCBI dbSNP, http:/http:/www.ncbi.nlm.nih.gov/snp/) of the United States.
- rs769446C>T located on chromosome 19 of apolipoprotein E (APO E) it can be determined that the risk of normal tension glaucoma (NTG) is increased.
- the single nucleotide polymorphism may be located on chromosome 19 of the apolipoprotein E (APO E) gene.
- the biological sample may be blood, tissue, cell, serum, plasma, saliva, urine, etc., but is not limited thereto.
- the subject of the biological sample may be a Korean.
- the single nucleotide polymorphism may be determined using a haplotype.
- the present invention provides a biomarker composition for determining normal tension glaucoma in Koreans, comprising at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412.
- SNP single nucleotide polymorphism
- the present invention provides a composition for predicting the risk of developing normal tension glaucoma, comprising a preparation capable of detecting the biomarker composition.
- the agent capable of detecting the biomarker composition may be, but is not limited to, a primer or probe that specifically binds to a polynucleotide comprising a SNP marker or a complementary polynucleotide thereof.
- the primer or probe that specifically binds to the polynucleotide or its complementary polynucleotide is allele-specific.
- a primer refers to a short nucleic acid sequence having a short free hydroxyl group, which can form base pairs with a complementary template and serves as a starting point for copying the template strand.
- the primer of the present invention can be chemically synthesized using a method known in the art, such as, for example, a phosphoramidite solid support method.
- the probe refers to a nucleic acid fragment such as RNA or DNA consisting of several to several hundred bases that can specifically bind to mRNA and is labeled so that the presence or absence of a specific mRNA can be confirmed.
- the probe can be produced in the form of an oligonucleotide probe, a single-stranded DNA probe, a double-stranded DNA probe, an RNA probe, etc., and can be labeled with biotin, FITC, rhodamine, DIG, etc., or labeled with a radioisotope, etc.
- the probe may be labeled with a detectable substance, for example, a radioactive label that provides a suitable signal and has a sufficient half-life.
- a detectable substance for example, a radioactive label that provides a suitable signal and has a sufficient half-life.
- the labeled probe may be hybridized to a nucleic acid on a solid support as described in the literature (Sambook et al., Molecular Cloning, A Laboratory Manual, 1989).
- the probe is an allele-specific probe, and since there is a polymorphic site in the nucleic acid fragment, it may hybridize to a nucleic acid fragment including one allele but not to a nucleic acid fragment including the other allele.
- the hybridization conditions must be sufficiently stringent so that there is a significant difference in hybridization intensity between the alleles and hybridize to only one of the alleles.
- the probe may be single-stranded for maximum efficiency in hybridization, but is not limited thereto.
- detection of a specific nucleic acid using the primer can be performed by amplifying the sequence of a target gene using an amplification method such as PCR and then confirming whether the gene is amplified using a method known in the art.
- detection of a specific nucleic acid using a probe can be performed by contacting a sample nucleic acid with a probe under suitable conditions and then confirming the presence of a hybridized nucleic acid.
- methods for detecting a specific nucleic acid using the probe or primer include, but are not limited to, polymerase chain reaction (PCR), DNA sequencing, RT-PCR, primer extension (Nikiforeov et al., Nucl Acids Res 22, 4167-4175, 1994), oligonucleotide extension analysis (Nickerson et al., Pro Nat Acad Sci USA, 87, 8923-8927, 1990), allele-specific PCR (Rust et al., Nucl Acids Res, 6, 3623-3629, 1993), RNase mismatch cleavage (Myers et al., Science, 230, 1242-1246, 1985), single strand conformation lymorphism (Ori- ta et al., Pro Nat Acad Sci USA, 87, 8923-8927, 1990).
- PCR polymerase chain reaction
- DNA sequencing DNA sequencing
- RT-PCR primer extension
- primer extension Niikiforeov et al., Nu
- the present invention provides a kit for predicting the risk of developing normal tension glaucoma, comprising the composition.
- the kit may include a polynucleotide, primer or probe for identifying one or more markers among polymorphic markers, as well as one or more other component compositions, solutions or devices suitable for the analysis method.
- the kit may be a kit including essential elements necessary for performing PCR.
- the PCR kit may include a test tube or other appropriate container, a reaction buffer (with various pH and magnesium concentrations), deoxynucleotides (dNTPs), enzymes such as Taq polymerase and reverse transcriptase, DNase, RNAse inhibitor, DEPC water, and sterile water.
- dNTPs deoxynucleotides
- enzymes such as Taq polymerase and reverse transcriptase, DNase, RNAse inhibitor, DEPC water, and sterile water.
- Figure 1 shows five SNPs displayed in the UCSC genome browser.
- Glaucomatous visual field defect was defined as a cluster of three or more points with a probability ⁇ 5% or a probability ⁇ 5% on the pattern deviation map in at least one hemifield with at least one point with a probability ⁇ 1%, and a field outcome of “normal limits on the external glaucoma hemifield test” or a pattern standard deviation with a probability ⁇ 5%.
- a total of 210 NTG patients (80 males and 130 females) with a mean age of 67.15 ⁇ 12.8 years met the inclusion criteria.
- Control subjects (117 patients, 46 males and 71 females, mean age 70.3 ⁇ 10.9 years) met the following criteria at recruitment: normal optic nerve head; normal IOP ( ⁇ 21 mmHg); no history of elevated IOP; and no family history of glaucoma.
- Genomic DNA was isolated from blood using the MG Blood Genomic DNA Extraction SV kit (MGmed, Seoul, Korea). Five SNPs (four including rs449647, see Table 1) of each gene locus for APOE were analyzed in the present invention.
- Genotyping for 19 polymorphisms including rs2946370 was performed with the QuantStudio real-time polymerase chain reaction system (Applied Biosystems) using TaqMan SNP Genotyping Assay IDs C____2485201_10, C__11916555_30, C__15840320_10, and C___2485225_20 (Applied Biosystems, Foster City, CA), respectively.
- the five APOE SNP information was extracted from all control groups using the Axiom Biobank Array version 1.1 (Korean-chip Microarray sequencing) method and the genotypes that had completed NARD2 imputation were utilized for haplotype analysis.
- GWAS genome-wide association study
- Haplotype analysis was performed using SHE-sis web-based software (Analysis tool for random samples, by YongYong Shi. (bio-x.cn)) for five SNPs (three promoter SNPs rs449647, rs769446, rs405509 and two exonic SNPs (rs429358, rs7412) located on chromosome 19 of apolipoprotein E (APO E) (Fig. 1).
- the mean age was 53.8 ⁇ 8.0 years, and the male-to-female ratio was 66% female, which was confirmed in the KoGES database.
- the number of alleles, allele frequencies, and genotype frequencies of the five SNPs together with the p-values showed that the rs769446 genotypes were significantly different between the cases and the controls.
- the second promoter SNP rs769446 minor allele C was a protective allele for normal tension glaucoma (Fig. 2).
- the allele and genotype frequencies of the five APOE SNPs in the cases and controls are shown in Table 2.
- haplotype analysis confirmed that haplotypes A-C-G-T-T (protective) and A-T-G-T-T (risk) had statistically significant p-values (Fig. 3).
- the five haplotypes are in the order mentioned above.
- the results of haplotype analysis using SHE-sis software are shown in Table 3.
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Abstract
Description
본 발명은 아포지질단백질 E 유전자 다형성 분석에 의한 한국인 특이적 정상안압 녹내장 발병 위험도 판별방법에 관한 것이다.The present invention relates to a method for determining the risk of developing normal tension glaucoma specific to Koreans by analyzing apolipoprotein E gene polymorphism.
녹내장은 시야 결손을 동반한 녹내장성 시신경 손상을 특징으로 하는 퇴행성 및 진행성 시신경병증이다. 전 세계적으로 녹내장은 시야 손실과 실명의 주요 원인 중 하나이다. 최근 연구에 따르면 개방각 녹내장(OAG)은 표현형 및 유전적으로 이질적이며 사실상 다유전자성이라는 것이 밝혀진 바 있다.Glaucoma is a degenerative and progressive optic neuropathy characterized by glaucomatous optic nerve damage with visual field defects. Glaucoma is one of the leading causes of visual field loss and blindness worldwide. Recent studies have shown that open-angle glaucoma (OAG) is phenotypically and genetically heterogeneous and is polygenic in nature.
증가된 안압(increased intraocular pressure, IOP)은 녹내장 진단에 필수적인 요소는 아니다. 한국인에게 정상안압 녹내장(normal tension glaucoma, NTG)은 녹내장의 가장 흔한 아형이다. 다양한 인종 집단에 대한 연구 결과에 따르면 정상안압 녹내장과 고안압 녹내장은 일부 유전적 위험 요소를 공유하지만 유전적 변이에 따라 녹내장과의 연관성이 다를 수 있다.Increased intraocular pressure (IOP) is not an essential factor in the diagnosis of glaucoma. Normal tension glaucoma (NTG) is the most common subtype of glaucoma in Koreans. Studies of various ethnic groups have shown that NTG and NTG share some genetic risk factors, but the association with glaucoma may differ depending on genetic variation.
한편, 아포지질단백질 E(APO E)의 단일염기다형성(SNP)이 개방각 녹내장과 정상안압 녹내장에 미치는 영향은 아직까지 논란이 되고 있으며, 기존 보고에 따르면 APOE e3/e4 대립유전자는 이미 알츠하이머병에 중요한 영향을 미치는 것으로 알려져 있다.Meanwhile, the influence of single nucleotide polymorphisms (SNPs) of apolipoprotein E (APOE) on open-angle glaucoma and normal-tension glaucoma is still controversial, and according to previous reports, the APOE e3/e4 allele is already known to have a significant effect on Alzheimer's disease.
이에 본 발명자들은 한국인 코호트에서 정상안압 녹내장의 발병률과 APOE 일배체형(haplotype)과의 연관성을 조사하였으며 이들의 유의적인 연관성이 있는 것을 확인하여 본 발명을 완성하게 되었다.Accordingly, the inventors of the present invention investigated the correlation between the incidence of normal tension glaucoma and APOE haplotype in a Korean cohort and confirmed a significant correlation, thereby completing the present invention.
본 발명의 목적은 한국인의 정상안압 녹내장(normal tension glaucoma) 발생 위험 예측에 필요한 정보를 제공하기 위하여, 생물학적 시료로부터 rs449647, rs769446, rs405509, rs429358 및 rs7412으로 이루어진 군으로부터 선택된 어느 하나 이상의 단일염기다형성(SNP)을 판별하는 방법을 제공하는 것이다.The purpose of the present invention is to provide a method for determining at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412 from a biological sample in order to provide information necessary for predicting the risk of developing normal tension glaucoma in Koreans.
본 발명의 다른 목적은 rs449647, rs769446, rs405509, rs429358 및 rs7412으로 이루어진 군으로부터 선택된 어느 하나 이상의 단일염기다형성(SNP)을 포함하는 한국인의 정상안압 녹내장(normal tension glaucoma) 판별용 바이오마커 조성물을 제공하는 것이다.Another object of the present invention is to provide a biomarker composition for determining normal tension glaucoma in Koreans, comprising at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412.
본 발명의 또 다른 목적은 상기 바이오마커 조성물을 검출할 수 있는 제제를 포함하는, 정상안압 녹내장(normal tension glaucoma) 발생 위험 예측용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for predicting the risk of developing normal tension glaucoma, comprising a preparation capable of detecting the biomarker composition.
본 발명의 또 다른 목적은 상기 조성물을 포함하는, 정상안압 녹내장(normal tension glaucoma) 발생 위험 예측용 키트를 제공하는 것이다.Another object of the present invention is to provide a kit for predicting the risk of developing normal tension glaucoma, comprising the composition.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the detailed description of the invention, the claims and the drawings which follow.
본 발명은 한국인의 정상안압 녹내장(normal tension glaucoma) 발생 위험 예측에 필요한 정보를 제공하기 위하여, 생물학적 시료로부터 rs449647, rs769446, rs405509, rs429358 및 rs7412으로 이루어진 군으로부터 선택된 어느 하나 이상의 단일염기다형성(SNP)을 판별하는 방법을 제공한다.The present invention provides a method for determining at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412 from a biological sample, in order to provide information necessary for predicting the risk of developing normal tension glaucoma in Koreans.
본 발명에서 다형성(polymorphism)은 하나의 유전자좌(locus)에 두 가지 이상의 대립 유전자 (allele)가 존재하는 경우를 말하며 다형성 부위 중에서, 사람에 따라 단일염기만이 다른 것을 단일염기다형성(single nucleotide polymorphism, SNP)이라 한다. 바람직한 다형성 마커는 선택된 집단에서 1% 이상, 더욱 바람직하게는 5% 또는 10% 이상의 발생 빈도를 나타내는 두 가지 이상의 대립 유전자를 가진다. 따라서, 다형성 마커에 대한 유전적 연관 (genetic association)은 특정한 다형성 마커의 하나 이상의 특정한 대립형질에 대해 연관이 있다는 것을 의미한다. 마커는 단일염기다형성(SNP), 마이크로새틀라이트 (microsatellite), 삽입, 결실, 중복 및 전위 (translocation)를 포함한, 게놈에서 발견되는 임의의 변이 형태의 대립형질을 포함할 수 있다.In the present invention, polymorphism refers to a case where two or more alleles exist at one locus, and among the polymorphic sites, a single nucleotide polymorphism (SNP) that differs only by a single base depending on the individual is called a single nucleotide polymorphism. A preferable polymorphic marker has two or more alleles that exhibit an occurrence frequency of 1% or more, more preferably 5% or 10% or more in a selected population. Therefore, genetic association for a polymorphic marker means that there is an association for one or more specific alleles of a specific polymorphic marker. A marker may include any variant form of an allele found in a genome, including a single nucleotide polymorphism (SNP), a microsatellite, an insertion, a deletion, a duplication, and a translocation.
본 발명에서 대립 유전자(allele) 또는 대립 형질은 상동 염색체의 동일한 유전자좌에 존재하는 한 유전자의 여러 타입을 말한다. 대립 유전자는 다형성을 나타내는데 사용되기도 하며, 예컨대, SNP는 두 종류의 대립 인자 (biallele)를 갖는다.In the present invention, an allele or biallelic trait refers to multiple types of a gene existing at the same locus of a homologous chromosome. An allele is also used to indicate polymorphism, for example, a SNP has two types of alleles.
본 발명에서 rs_id는 1998년부터 SNP 정보를 축적하기 시작한 NCBI가 초기에 등록되는 모든 SNP에 대하여 부여한 독립된 표지자인 rs-ID를 의미한다. 본 발명에서는 rs2946370과 같은 형태로 기재하였다. 이와 같은 표에 기재된 rs_id는 본 발명의 다형성 마커인 SNP 마커를 의미한다. 당업자라면 상기 rs_id를 이용하여 SNP의 위치 및 서열을 용이하게 확인할 수 있을 것이다. In the present invention, rs_id means rs-ID, an independent marker assigned to all initially registered SNPs by NCBI, which began accumulating SNP information in 1998. In the present invention, it is described in the form of rs2946370. The rs_id described in such a table means a SNP marker, which is a polymorphic marker of the present invention. Those skilled in the art will be able to easily confirm the location and sequence of the SNP using the rs_id.
본 발명에서 한국인의 정상안압 녹내장 발생 위험 예측에 이용하는 rs449647, rs769446, rs405509, rs429358 및 rs7412는 미국 국립생물정보센터의 단일염기다형성 데이터베이스(NCBI dbSNP, http:/http:/www.ncbi.nlm.nih.gov/snp/)에 각각 등록되어 있다.In the present invention, rs449647, rs769446, rs405509, rs429358, and rs7412 used to predict the risk of developing normal tension glaucoma in Koreans are each registered in the Single Nucleotide Polymorphism Database of the National Center for Biotechnology Information (NCBI dbSNP, http:/http:/www.ncbi.nlm.nih.gov/snp/) of the United States.
본 발명의 일실시예에 따라, 아포지질단백질 E(APO E)의 19번 염색체에 위치한 rs769446C>T인 경우, 정상안압 녹내장(normal tension glaucoma, NTG)에 대한 위험이 증가된 것으로 판별할 수 있다. According to one embodiment of the present invention, when rs769446C>T located on chromosome 19 of apolipoprotein E (APO E) is present, it can be determined that the risk of normal tension glaucoma (NTG) is increased.
본 발명에서 상기 단일염기다형성(SNP)은 아포지질단백질 E(APO E) 유전자의 19번 염색체에 위치하는 것일 수 있다.In the present invention, the single nucleotide polymorphism (SNP) may be located on chromosome 19 of the apolipoprotein E (APO E) gene.
본 발명에서 상기 생물학적 시료는 혈액, 조직, 세포, 혈청, 혈장, 타액, 소변 등을 사용할 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the biological sample may be blood, tissue, cell, serum, plasma, saliva, urine, etc., but is not limited thereto.
본 발명에서 상기 생물학적 시료의 대상은 한국인인 것일 수 있다.In the present invention, the subject of the biological sample may be a Korean.
본 발명에서 상기 단일염기다형성(SNP)은 일배체형을 이용하여 판별되는 것일 수 있다.In the present invention, the single nucleotide polymorphism (SNP) may be determined using a haplotype.
또한, 본 발명은 rs449647, rs769446, rs405509, rs429358 및 rs7412으로 이루어진 군으로부터 선택된 어느 하나 이상의 단일염기다형성(SNP)을 포함하는 한국인의 정상안압 녹내장(normal tension glaucoma) 판별용 바이오마커 조성물을 제공한다.In addition, the present invention provides a biomarker composition for determining normal tension glaucoma in Koreans, comprising at least one single nucleotide polymorphism (SNP) selected from the group consisting of rs449647, rs769446, rs405509, rs429358, and rs7412.
또한, 본 발명은 상기 바이오마커 조성물을 검출할 수 있는 제제를 포함하는, 정상안압 녹내장(normal tension glaucoma) 발생 위험 예측용 조성물을 제공한다.In addition, the present invention provides a composition for predicting the risk of developing normal tension glaucoma, comprising a preparation capable of detecting the biomarker composition.
본 발명에서 상기 바이오마커 조성물을 검출할 수 있는 제제는 SNP 마커를 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드에 특이적으로 결합하는 프라이머 또는 프로브일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the agent capable of detecting the biomarker composition may be, but is not limited to, a primer or probe that specifically binds to a polynucleotide comprising a SNP marker or a complementary polynucleotide thereof.
본 발명에서 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드와 특이적으로 결합하는 프라이머 또는 프로브는 대립형질 특이적 (allele-specific)이다.In the present invention, the primer or probe that specifically binds to the polynucleotide or its complementary polynucleotide is allele-specific.
본 발명에서 프라이머는 짧은 자유 수산화기를 가지는 핵산서열로서 상보적인 템플리트와 염기쌍을 형성할 수 있고 템플리트 가닥 복사를 위한 시작 지점으로 기능하는 짧은 핵산서열을 말한다. 본 발명의 프라이머는 예를 들면, 포스포르아미다이트 고체 지지체 방법과 같은 당 분야에 공지된 방법을 이용하여 화학적으로 합성할 수 있다.In the present invention, a primer refers to a short nucleic acid sequence having a short free hydroxyl group, which can form base pairs with a complementary template and serves as a starting point for copying the template strand. The primer of the present invention can be chemically synthesized using a method known in the art, such as, for example, a phosphoramidite solid support method.
본 발명에서 상기 프로브는 mRNA와 특이적으로 결합할 수 있는 수개 내지 수백 개의 염기로 이루어진 RNA 또는 DNA 등의 핵산 단편을 의미하며 라벨링되어 있어 특정 mRNA의 존재유무를 확인할 수 있다. 프로브는 올리고뉴클레오타이드 프로브, 단쇄 DNA 프로브, 이중쇄 DNA 프로브, RNA 프로브 등의 형태로 제작될 수 있고 비오틴, FITC, 로다민, DIG 등으로 표지되거나 방사선 동위 원소 등으로 표지될 수 있다.In the present invention, the probe refers to a nucleic acid fragment such as RNA or DNA consisting of several to several hundred bases that can specifically bind to mRNA and is labeled so that the presence or absence of a specific mRNA can be confirmed. The probe can be produced in the form of an oligonucleotide probe, a single-stranded DNA probe, a double-stranded DNA probe, an RNA probe, etc., and can be labeled with biotin, FITC, rhodamine, DIG, etc., or labeled with a radioisotope, etc.
본 발명에서 상기 프로브는 검출 가능한 물질 예를 들면, 적합한 신호를 제공하고 충분한 반감기를 갖는 방사성 표지로 표지할 수 있다. 표지된 프로브는 문헌 (Sambook et al., Molecular Cloning, A LaboratoryMannual, 1989)에 공지된 바와 같은 고체 지지체 상의 핵산에 혼성화시킬 수 있다.In the present invention, the probe may be labeled with a detectable substance, for example, a radioactive label that provides a suitable signal and has a sufficient half-life. The labeled probe may be hybridized to a nucleic acid on a solid support as described in the literature (Sambook et al., Molecular Cloning, A Laboratory Manual, 1989).
본 발명에서 상기 프로브는 대립유전자 특이적 프로브로서, 핵산 단편 중에 다형성 부위가 존재하여, 하나의 대립유전자를 포함한 핵산 단편에는 혼성화하지만, 다른 대립유전자를 포함한 핵산 단편에는 혼성화하지 않을 수 있다. 이 경우 혼성화 조건은 대립형질 간의 혼성화 강도에 있어서 유의한 차이를 보여 대립형질 중 하나에만 혼성화되도록 충분히 엄격해야 한다. 바람직하게는 프로브는 혼성화에서의 최대 효율을 위하여 단일 가닥일 수 있으나, 이에 제한되지 않는다.In the present invention, the probe is an allele-specific probe, and since there is a polymorphic site in the nucleic acid fragment, it may hybridize to a nucleic acid fragment including one allele but not to a nucleic acid fragment including the other allele. In this case, the hybridization conditions must be sufficiently stringent so that there is a significant difference in hybridization intensity between the alleles and hybridize to only one of the alleles. Preferably, the probe may be single-stranded for maximum efficiency in hybridization, but is not limited thereto.
본 발명에서 상기 프라이머를 이용한 특정 핵산의 검출은 PCR과 같은 증폭 방법을 사용하여 목적 유전자의 서열을 증폭한 다음 당 분야에 공지된 방법으로 유전자의 증폭여부를 확인함으로써 수행될 수 있다. 또한, 프로브를 이용한 특정 핵산의 검출은 적합한 조건하에서 시료 핵산을 프로브와 접촉시킨 후 혼성화되는 핵산의 존재여부를 확인함으로써 수행될 수 있다.In the present invention, detection of a specific nucleic acid using the primer can be performed by amplifying the sequence of a target gene using an amplification method such as PCR and then confirming whether the gene is amplified using a method known in the art. In addition, detection of a specific nucleic acid using a probe can be performed by contacting a sample nucleic acid with a probe under suitable conditions and then confirming the presence of a hybridized nucleic acid.
본 발명에서 상기 프로브나 프라이머를 이용하여 특정 핵산을 검출할 수 있는 방법으로는 예를 들면, 이에 한정되지는 않으나 중합효소 연쇄반응 (PCR), DNA 시퀀싱, RT-PCR, 프라이머 연장법 (Nikiforeov et al., Nucl Acids Res 22, 4167-4175, 1994), 올리고뉴클레오타이드 연장 분석 (Nickerson et al., Pro Nat Acad Sci USA, 87, 8923-8927, 1990), 대립형질 특이적 PCR법 (Rust et al., Nucl Acids Res, 6, 3623-3629, 1993), RNase 불일치절단 (RNase mismatch cleavage, Myers et al., Science, 230, 1242-1246, 1985), 단일가닥 입체 다형화 (single strand conformation lymorphism, Orita et al., Pro Nat Acad Sci USA, 86, 2766-2770, 1989), SSCP 및 헤테로두플렉스 동시 분석법 (Lee et al., Mol Cells, 5:668-672, 1995), 변성 구배 젤 전기영동 (DGGE, Cariello et al., Am J Hum Genet, 42, 726-734, 1988), 변성 고압 액체 크로마토그래피 (Underhill et al., Genome Res, 7, 996-1005, 1997), 혼성화 반응, DNA 칩 등이 있다. 상기 혼성화 반응의 예로는 노던 하이브리다이제이션 (Maniatis T. et al., Molecular Cloning, Cold Spring Habor Laboratory, NY, 1982), 인시츄 하이브리다이제이션 (Jacquemier et al., Bull Cancer, 90:31-8, 2003) 및 마이크로어레이 (Macgregor, Expert, Rev Mol Diagn 3:185-200, 2003) 방법 등이 있다.In the present invention, methods for detecting a specific nucleic acid using the probe or primer include, but are not limited to, polymerase chain reaction (PCR), DNA sequencing, RT-PCR, primer extension (Nikiforeov et al., Nucl Acids Res 22, 4167-4175, 1994), oligonucleotide extension analysis (Nickerson et al., Pro Nat Acad Sci USA, 87, 8923-8927, 1990), allele-specific PCR (Rust et al., Nucl Acids Res, 6, 3623-3629, 1993), RNase mismatch cleavage (Myers et al., Science, 230, 1242-1246, 1985), single strand conformation lymorphism (Ori- ta et al., Pro Nat Acad Sci USA, 87, 8923-8927, 1990). Sci USA, 86, 2766-2770, 1989), simultaneous SSCP and heteroduplex analysis (Lee et al., Mol Cells, 5:668-672, 1995), denaturing gradient gel electrophoresis (DGGE, Cariello et al., Am J Hum Genet, 42, 726-734, 1988), denaturing high pressure liquid chromatography (Underhill et al., Genome Res, 7, 996-1005, 1997), hybridization reactions, DNA chips, etc. Examples of such hybridization reactions include Northern hybridization (Maniatis T. et al., Molecular Cloning, Cold Spring Harbor Laboratory, NY, 1982), in situ hybridization (Jacquemier et al., Bull Cancer, 90:31-8, 2003), and microarray (Macgregor, Expert, Rev Mol Diagn 3:185-200, 2003) methods.
또한, 본 발명은 상기 조성물을 포함하는, 정상안압 녹내장(normal tension glaucoma) 발생 위험 예측용 키트를 제공한다.In addition, the present invention provides a kit for predicting the risk of developing normal tension glaucoma, comprising the composition.
본 발명에서 상기 키트는 다형성 마커 중 1종 이상의 마커를 확인하기 위한 폴리뉴클레오티드, 프라이머 또는 프로브뿐만 아니라 분석 방법에 적합한 한 종류 또는 그 이상의 다른 구성 성분 조성물, 용액 또는 장치가 포함될 수 있다.In the present invention, the kit may include a polynucleotide, primer or probe for identifying one or more markers among polymorphic markers, as well as one or more other component compositions, solutions or devices suitable for the analysis method.
본 발명에서 상기 키트는 PCR을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있다. PCR 키트는, 상기 다형성 마커에 대한 특이적인 폴리뉴클레오티드, 프라이머 또는 프로브 외에도 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액 (pH 및 마그네슘 농도는 다양), 데옥시뉴클레오타이드 (dNTPs), Taq-폴리머라아제 및 역전사효소와 같은 효소, DNase, RNAse 억제제, DEPC-수 (DEPC-water) 및 멸균수 등을 포함할 수 있다.In the present invention, the kit may be a kit including essential elements necessary for performing PCR. In addition to a specific polynucleotide, primer or probe for the polymorphic marker, the PCR kit may include a test tube or other appropriate container, a reaction buffer (with various pH and magnesium concentrations), deoxynucleotides (dNTPs), enzymes such as Taq polymerase and reverse transcriptase, DNase, RNAse inhibitor, DEPC water, and sterile water.
본 발명에 따르면 단일염기다형성의 일배체형을 바탕으로 한국인의 정상안압 녹내장의 발생 위험을 예측하는데 유용하게 사용될 수 있는 이점이 있다.According to the present invention, there is an advantage in that it can be usefully used to predict the risk of developing normal tension glaucoma in Koreans based on the haplotype of single nucleotide polymorphism.
도 1은 UCSC 게놈 브라우저에 표시된 5개의 SNP를 나타낸 것이다.Figure 1 shows five SNPs displayed in the UCSC genome browser.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, in order to help understand the present invention, examples will be given and described in detail. However, the following examples are only intended to illustrate the content of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the art.
실시예 1. 실험 방법Example 1. Experimental method
1.1 연구 집단 선정1.1 Study group selection
관련 없는 NTG 환자와 건강한 대조군은 대한민국 의정부성모병원의 안과에서 모집되었다. 모든 피험자는 유전자 검사의 목적과 채혈 과정에 대한 설명을 들은 후 서면 동의서를 받았으며, 참여를 거부한 사람은 제외하였다. 대한민국 의정부성모병원 임상심사위원회의 승인을 받았으며(승인번호: UC16SISE0060), 헬싱키 선언의 원칙에 따라 수행되었다. 일배체형 분석에는 의정부성모병원에서 모집한 NTG 환자 178명과 KoGES 코호트 녹내장이 없는 대조군 32,858명이 활용되었다.Unrelated NTG patients and healthy controls were recruited from the Department of Ophthalmology, Uijeongbu St. Mary's Hospital, Republic of Korea. All subjects gave written informed consent after being informed of the purpose of genetic testing and the blood collection process, and those who refused to participate were excluded. The study was approved by the Institutional Review Board of Uijeongbu St. Mary's Hospital, Republic of Korea (Approval Number: UC16SISE0060) and performed in accordance with the principles of the Declaration of Helsinki. For haplotype analysis, 178 NTG patients recruited from Uijeongbu St. Mary's Hospital and 32,858 controls without glaucoma from the KoGES cohort were used.
의정부성모병원 안과에서 모집한 정상안압 녹내장 환자군은 다음과 같은 과정을 거쳐서 선별되었다. 시신경두 검사를 포함한 철저한 안과 검사가 모든 참가자에게 시행되었다. 포함 기준은 다음과 같다: VCDR ≥0.6을 나타내는 특징적인 녹내장 시신경두를 가진 사람; 확산 또는 초점 신경망막 테두리 얇아짐(예: 시신경의 노칭 또는 후천적 패임) 및/또는 망막 신경 섬유층(RNFL) 결함, 험프리 자동 필드 분석기(Zeiss Humphrey Systems, Dublin, CA)로 측정된 녹내장 시야 결함, 열린 각 구조 및 초기 검사 및 다른 날에 반복 측정시 투약 없이 IO1 ≤21mmHg임.The normal-tension glaucoma patient group recruited from the Department of Ophthalmology, Uijeongbu St. Mary's Hospital was selected through the following process. A thorough ophthalmologic examination including optic nerve head examination was performed on all participants. Inclusion criteria were as follows: patients with a characteristic glaucomatous optic nerve head as indicated by VCDR ≥0.6; diffuse or focal neuroretinal rim thinning (e.g., notching or acquired optic nerve stenosis) and/or retinal nerve fiber layer (RNFL) defects, glaucomatous visual field defects measured by a Humphrey automated field analyzer (Zeiss Humphrey Systems, Dublin, CA), open-angle architecture, and medication-free IO1 ≤21 mmHg at the initial examination and repeat measurements on different days.
녹내장 시야 결손은 확률이 1% 미만인 최소 1개의 포인트가 있는 최소 1개의 반시야에서 패턴 편차 맵에서 확률이 5% 미만이거나 확률이 5% 미만인 3개 이상의 포인트 클러스터로 정의되었으며, 필드 결과는 "외부 녹내장 반시야 테스트에서 정상 한계" 또는 확률이 <5%인 패턴 표준 편차이다.Glaucomatous visual field defect was defined as a cluster of three or more points with a probability <5% or a probability <5% on the pattern deviation map in at least one hemifield with at least one point with a probability <1%, and a field outcome of “normal limits on the external glaucoma hemifield test” or a pattern standard deviation with a probability <5%.
평균 연령 67.15±12.8세의 총 210명의 NTG 환자(남성 80명, 여성 130명)가 포함 기준을 충족했다. 폐쇄각 녹내장, 색소 녹내장, 포도막염 녹내장, 신생혈관 녹내장 또는 외상 병력이 있는 환자는 제외되었다. 대조군 대상자(환자 117명, 남성 46명, 여성 71명, 평균 연령 70.3±10.9세)는 모집 시 다음 기준을 충족했다: 정상 시신경두; 정상 IOP(≤21mmHg); IOP 상승 이력 없음; 녹내장의 가족력이 없음.A total of 210 NTG patients (80 males and 130 females) with a mean age of 67.15±12.8 years met the inclusion criteria. Patients with closed-angle glaucoma, pigmentary glaucoma, uveitic glaucoma, neovascular glaucoma, or a history of trauma were excluded. Control subjects (117 patients, 46 males and 71 females, mean age 70.3±10.9 years) met the following criteria at recruitment: normal optic nerve head; normal IOP (≤21 mmHg); no history of elevated IOP; and no family history of glaucoma.
1.2 샘플 준비 및 대립유전자 판별1.2 Sample preparation and allele determination
MG Blood Genomic DNA Extraction SV kit(MGmed, Seoul, Korea)를 이용하여 혈액에서 Genomic DNA를 분리하였다. APOE에 대한 유전자좌의 각 5개의 SNP(rs449647 포함 4종, 표 1 참조)가 본 발명에서 분석되었다.Genomic DNA was isolated from blood using the MG Blood Genomic DNA Extraction SV kit (MGmed, Seoul, Korea). Five SNPs (four including rs449647, see Table 1) of each gene locus for APOE were analyzed in the present invention.
rs2946370 포함 19종 다형성에 대한 유전자형 분석은 C___2485201_10, C__11916555_30, C__15840320_10, 및 C___2485225_20의 TaqMan SNP Genotyping Assay 분석 ID(Applied Biosystems, Foster City, CA)를 사용하여 각각 QuantStudio 실시간 중합효소 연쇄 반응 시스템(Applied Biosystems)으로 수행되었다.Genotyping for 19 polymorphisms including rs2946370 was performed with the QuantStudio real-time polymerase chain reaction system (Applied Biosystems) using TaqMan SNP Genotyping Assay assay IDs C___2485201_10, C__11916555_30, C__15840320_10, and C___2485225_20 (Applied Biosystems, Foster City, CA), respectively.
KoGES 에서 추출된 대조군의 경우 Axiom Biobank Array version1.1 (Korean-chip Microarray sequencing) 방법 및 NARD2 imputation 까지 완료된 genotype에서 APOE SNP 5개 정보를 대조군 모두에서 추출하여 Haplotype analysis에 활용되었다.For the control group extracted from KoGES, the five APOE SNP information was extracted from all control groups using the Axiom Biobank Array version 1.1 (Korean-chip Microarray sequencing) method and the genotypes that had completed NARD2 imputation were utilized for haplotype analysis.
1.3 독립적인 단일염기다형성(SNP) 인자 추출1.3 Extraction of independent single nucleotide polymorphism (SNP) factors
정상안압 녹내장의 GWAS(Genome-wide association study)를 참고하여, 게놈 차원의 중요성을 가진 5개의 독립적인 APOE SNP 유전자형을 환자군과 대조군 모두에서 추출하였다. 표 1은 본 발명의 PRS 구성에 사용된 5개의 SNP를 나타낸 것이다.Referring to the genome-wide association study (GWAS) of normal tension glaucoma, five independent APOE SNP genotypes with genome-wide significance were extracted from both patient and control groups. Table 1 shows the five SNPs used in the construction of the PRS of the present invention.
Chr19:44,905,791 - 44,909,393
(서열번호 1)APOE promoter
Chr19:44,905,791 - 44,909,393
(sequence number 1)
Chr19:44,905,791 - 44,909,393APOE promoter
Chr19:44,905,791 - 44,909,393
Chr19:44,905,791 - 44,909,393APOE promoter
Chr19:44,905,791 - 44,909,393
Chr19:44,905,791 - 44,909,393
(서열번호 2)APOE exon
Chr19:44,905,791 - 44,909,393
(sequence number 2)
Chr19:44,905,791 - 44,909,393APOE exon
Chr19:44,905,791 - 44,909,393
실시예 2. 실험 결과Example 2. Experimental Results
아포지질단백질 E(APO E)의 19번 염색체에 위치한 5개의 SNP(3개의 프로모터 SNP rs449647, rs769446, rs405509 및 2개의 엑소닉 SNP(rs429358, rs7412)에 대해 SHE-sis 웹 기반 소프트웨어(Analysis tool for random samples, by YongYong Shi. (bio-x.cn))를 사용하여 일배체형 분석을 수행했다(도 1).Haplotype analysis was performed using SHE-sis web-based software (Analysis tool for random samples, by YongYong Shi. (bio-x.cn)) for five SNPs (three promoter SNPs rs449647, rs769446, rs405509 and two exonic SNPs (rs429358, rs7412) located on chromosome 19 of apolipoprotein E (APO E) (Fig. 1).
대조군의 경우 평균 연령은 53.8±8.0세 였고, 남녀 비율은 여성이 66% 를 차지하였으며, 이는 KoGES 데이터베이스에서 확인 가능하였다. p-값과 함께 5개의 SNP 대립유전자 수, 대립유전자 빈도 및 유전자형 빈도는 rs769446 유전자형이 케이스와 대조군 사이에 상당히 다르다는 것을 보여주었다. 상기 5개의 SNP 중 두 번째 프로모터 SNP rs769446 마이너 대립유전자 C는 정상안압 녹내장에 대한 보호 대립유전자였다(도 2). 사례 및 대조군의 5 APOE SNP 대립유전자 및 유전자형 빈도를 표 2로 나타내었다.In the control group, the mean age was 53.8±8.0 years, and the male-to-female ratio was 66% female, which was confirmed in the KoGES database. The number of alleles, allele frequencies, and genotype frequencies of the five SNPs together with the p-values showed that the rs769446 genotypes were significantly different between the cases and the controls. Among the five SNPs, the second promoter SNP rs769446 minor allele C was a protective allele for normal tension glaucoma (Fig. 2). The allele and genotype frequencies of the five APOE SNPs in the cases and controls are shown in Table 2.
(NTG vs.Control)p-value
(NTG vs.Control)
또한, 일배체형 분석은 일배체형 A-C-G-T-T(보호) 및 A-T-G-T-T(위험)가 통계적으로 유의한 p-값을 가짐을 확인하였다(도 3). 5가지 일배체형은 위에서 언급한 순서대로 있다. SHE-sis 소프트웨어를 활용한 일배체형(Haplotype) 분석 결과를 표 3으로 나타내었다.In addition, haplotype analysis confirmed that haplotypes A-C-G-T-T (protective) and A-T-G-T-T (risk) had statistically significant p-values (Fig. 3). The five haplotypes are in the order mentioned above. The results of haplotype analysis using SHE-sis software are shown in Table 3.
이러한 결과는 정상안압 녹내장에서 APOE SNP의 역할에 대한 새로운 시각을 제시하고 특정 일배체형을 가진 사람들을 위해 미래의 임상 환경에서 5 SNP 일배체형 분석이 사용될 수 있음을 증명하므로, 이러한 특정 일배체형의 보호 효과는 녹내장의 임상 결과 및 위험도를 판별하는데 유용하게 사용될 수 있음을 확인하였다.These results provide new insight into the role of APOE SNPs in normal-tension glaucoma and demonstrate that 5-SNP haplotype analysis could be used in future clinical settings for individuals with specific haplotypes, thereby confirming that the protective effect of these specific haplotypes could be useful in determining clinical outcome and risk of glaucoma.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the specific parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereby. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
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| AL-DABBAGH NAJWA MOHAMMED, AL-DOHAYAN NOURAH, ARFIN MISBAHUL, TARIQ MOHAMMAD: "Apolipoprotein E polymorphisms and primary glaucoma in Saudis", MOLECULAR VISION, vol. 15, 1 May 2009 (2009-05-01), US , pages 912 - 919, XP093292729, ISSN: 1090-0535 * |
| ANNA LIMON-SZTENCEL, LIPSKA-ZIęTKIEWICZ BEATA S., CHMARA MAGDALENA, WASAG BARTOSZ, BIDZAN LESZEK, GODLEWSKA BEATA R., LIMON J: "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, DOI: 10.1186/s13195-016-0187-9 * |
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