보고서 정보
주관연구기관 |
한국한의학연구원 Korea Institute of Oriental Medicine |
연구책임자 |
김종열
|
참여연구자 |
정상균
,
김부여
,
송광훈
,
차성원
,
김근호
,
도준형
,
진희정
,
김효정
,
구임회
,
조려화
,
이선화
,
이선영
,
유현주
,
오수아
,
박아연
,
변혜진
,
유성곤
,
이영신
,
김봉화
,
권철홍
|
보고서유형 | 2단계보고서 |
발행국가 | 대한민국 |
언어 |
한국어
|
발행년월 | 2012-07 |
과제시작연도 |
2011 |
주관부처 |
교육과학기술부 Ministry of Education and Science Technology(MEST) |
등록번호 |
TRKO201700010023 |
과제고유번호 |
1345146247 |
사업명 |
바이오의료기술개발 |
DB 구축일자 |
2017-11-04
|
키워드 |
사상의학.체질.진단.심혈관대사질환.유전체학.후보유전자 접근법.Sasang constitutional medicine.constitution.diagnosis.cardiometabolic disease.genomics.candidate gene approach.
|
DOI |
https://doi.org/10.23000/TRKO201700010023 |
초록
▼
○ 비침습적 방법, 대량의 데이터,정량적 변수,자동 변수 추출 알고리즘,다양한 전문가 의견을 바탕으로 웹기반 체질 진단툴을 개발함으로써 실용화 수준의 체질진단툴을 확보하였음.
○ 안면,음성,체형,성격에서 다른 체질과의 비교를 통해 희귀체질로 알려진 태양인의 정량적 체질지표를 발굴하였음
○ 체질진단툴의 결과와 전문가들의 견해를 기반으로 체질별 대표 얼굴을 생성하여 체질별 안면 특성의 차이를 직관적으로 사실적으로 표현하였음
○ 체질확진자 대상 비만,고혈압,지질이상혈증 등과 같은 심혈관대사질환에 체질
○ 비침습적 방법, 대량의 데이터,정량적 변수,자동 변수 추출 알고리즘,다양한 전문가 의견을 바탕으로 웹기반 체질 진단툴을 개발함으로써 실용화 수준의 체질진단툴을 확보하였음.
○ 안면,음성,체형,성격에서 다른 체질과의 비교를 통해 희귀체질로 알려진 태양인의 정량적 체질지표를 발굴하였음
○ 체질진단툴의 결과와 전문가들의 견해를 기반으로 체질별 대표 얼굴을 생성하여 체질별 안면 특성의 차이를 직관적으로 사실적으로 표현하였음
○ 체질확진자 대상 비만,고혈압,지질이상혈증 등과 같은 심혈관대사질환에 체질 특이적으로 연관된 유전인자를 코호트에서 재현성을 검증하였고,복부비만 표현형에 대한 체질특이 유효 유전인자 세트의 체질별 효과크기를 측정하였음
○ 체질별 림프세포주에 세 개의 약물을 처리하여 microarray로 발현을 분석하고, 체질별로 약재에 유의적인 발현차이를 보이는 유전자, pathway 및 관련 후보 중심 단백질을 발굴함
○ Genomcis 분석을 통해 체질연관 유전인자 및 기능단위 pathway를 규명하였고, HOX 및 segmentation 유전자들 대상으로 4개의 체질연관 유전인자를 발굴하는 한편,체형 연관 유전인자는 림프세포주에서 발현 조절 양상을 분석함
( 출처 : 요약서 3p )
Abstract
▼
Ⅳ. Results
1. Integrated analysis of constitutional information
A. Development of SCAT
- Automatic constitutional diagnosis was developed using feature extraction algorithms of face and voice.
- An objective constitutional diagnosis algorithm was developed using experts opinion and non-i
Ⅳ. Results
1. Integrated analysis of constitutional information
A. Development of SCAT
- Automatic constitutional diagnosis was developed using feature extraction algorithms of face and voice.
- An objective constitutional diagnosis algorithm was developed using experts opinion and non-invasive information, such as face, voice, body shape and questionnaire.
B. Development of web-based SCAT in level of practical use
- A practical level of diagnosis tool was secured by the web-based SCAT developed with the constitutional diagnosis algorithm.
- The web-based SCAT has been used by 9 institute and 3,471 people. Its diagnosis results was agreed to experts by 70% or more when applied to clinical test.
C. Applying SCAT to cooperation research institutes
- SCAT was applied to cohort, physiology study and other institutes. A scientific evidence was provided by applying SCAT to the various studies, such as relationship between constitution and cardiometabolic diseases, and constitutional physiology.
D. Seeking an index for Taeyangin
- An index for Taeyangin was derived by comparing to other constitutions in face, voice, body shape and character categories. The quantitative characteristics of the diagnosis index was analyzed.
E. Generating a representative face model for each constitution
- A representative face model for each constitution was generated and the face appearance differences between each constitution was intuitively and easily understood since the face model represent qualitative but realistic face appearance.
- Representative face model for each constitution was approved in the conference of Sasang constitutional medicine and it is helpful for educational activities in oriental hospitals, clinics and medical centers.
2. Identification of constitution-specific genetic variants on chronic metabolic diseases
A. Identification of constitution-specific genetic variants in the constitution-confirmed population (Total, 2,269; TE(Tae-eum), 914; SY(Soyang), 774; SE(Soeum), 581)
- After association analyses on cardiometabolic diseases with all 71 genetic variants(obesity, 20; hypertension, 10; dyslipidemia, 9; hematological dysfunction, 17; muscloskeletal disease, 15), we identified 7 TE-specific variants, 15 SY-specific variants, and 9 SE-specific variants, of which the genetic effects had a tendency to be enriched in each constitution compared to those in total population.
B. Identification of constitution-specific genetic variants in the cohort (Total, 3,472; TE,1,882; SY, 1,277; SE, 313)
- With the same association analyses on cardiometabolic diseases used in the constitution-confirmed population, we identified 14 TE-specific variants, 9 SY-specific variants, and 4 SE-specific variants, of which the genetic effects had a tendency to be enriched in each constitution compared to those in total population.
- We found the all 10 genetic variants presenting reproducibility for the associations in the constitution-confirmed population: 5 TE-specific variants, 2 SY-specific variants, and 0 SE-specific variants, and 3 non-specific variants.
C. Profiling and analyzing the effects of abdomen-associated genetic variants in each constitutional type
- We selected 57 genetic variants associated with abdominal traits, a pivotal risk factor for cardiometabolic disease, in subjects with Affymetrix SNP(single nucleotide polymorphism) genotype.
- We constructed the genetic variants presenting both constitution-specificity and effectivity on abdominal traits such that we identified 8 genetic variants in TE type, 9 genetic variants in SY type, and 11 genetic variants in SE type.
- We found that the increased number of risk variants on abdominal obesity in the right constitutional type had a tendency to increase the risks on abdominal obesity after estimating the combined effect sizes of effective genetic variants on abdominal traits in each constitution, but no effects in the other constitutional types.
3. Establishment of research basis for constitution-based medical remedy
A. Construction of the stable culture system for the constitution-specific lymphocyte cell line
- Constitution-specific EBV-transformed lymphoblastoid cell line was constructed and stably maintained.
- The constitution-specific lymphocyte was free of Mycoplasm contamination as examined by polymerase chain reaction method.
B. Genomic analysis of drug responses on lymphocyte according to constitution types
- Microarray analysis was performed using the constitution-specific lymphocyte cell lines treated with 3 different drugs (aspirin, ibuprofen, simvastin), in which diverse genes and pathways were significantly associated with both constitution type and treated drugs.
- Using differently expressed genes among constitution types by treatment with drugs, core-proteins interacting with many other proteins were identified in silico analysis. These core-proteins could be key components responsible for constitution-specific drug metabolism.
4. Identification of the constitution-associated genetic variations
A. Identification of genetic elements associated with constitution using genomic approach
- By implementing family-based linkage analysis using SNP4Linkage and Merlin program, the locations of genetic elements were identified to be strongly associated with constitution.
- Through Genome-Wide Association Study (GWAS) of 1,222 people, individual SNPs associated with constitution types were identified with statistical significance.
- Functionally related genes was identified (GPM6A, SYT4 and GRIK1 for TE, DRGX and AKAP11 for SE, ZFP42, CDH22, ALDH1A2, OTX2 and EN2 for SY) by text mining analysis of constitution-associated SNPs.
- Pathway analysis based on GWAS indicates that cytoskeleton-related pathways were enriched in TE type, melanoma-related pathways in SY type and cardio-related pathways and amino-acid metabolism pathways in SE type.
B. Candidate gene approach
- Screening the constitution-associated variations by analyzing the genotype frequencies in the constitution-matched DNA pools that are constructed with genomic DNAs from the subjects with known constitutions
- Make up of a gene list for HOX and segmentation genes and selection of SNPs with more than 10% of MAF(minor allele frequency) based on the phased haplotype structures
- Identification of 4 constitution-associated SNPs by analysing the individual genotypes for the candidate SNPs using consitution-identified gDNAs
C. Identification of body build-associated genetic variation
- Constitution association of the body build-related variables is expected from the functional features of the HOX genes, leading to association analysis of the SNPs on HOX loci with body build-related variables
- Determination of individual genotype from the subjects (n=~2700) and analysis of their association with body sizes, which resulted in the identification of 3 SNPs that exhibit a certain level of association with one or three variables
D. Analysis of regulatory effect of the identified variations on gene transcription
- A SNP on HoxA locus exhibits a certain level of association with body sizes and is placed near a sequences that are well conserved between species, raising a possibility of being a regulatory variation
- Using the available lymphocytes of family members that are heterozygotes for the given SNP, allele expression was measured to find imbalanced expressions including mono-allelic expression found in the lymphocytes obviously with non-genetic causes
- No synchronous regulation for the genes on the same chromosome was evident while HOX gene expression regulation in the lymphocytes appears not to be tight or delicate
( 출처 : SUMMARY 11p )
목차 Contents
- 표지 ... 1제 출 문 ... 2보고서 요약서 ... 3요 약 문 ... 4SUMMARY ... 9CONTENTS ... 15목차 ... 18제 1 장 연구개발과제의 개요 ... 21 제 1 절 연구개발의 필요성 ... 21 1. 연구개발의 목적 ... 21 2. 연구개발의 과학기술, 사회경제적 중요성 ... 21 제 2 절 연구개발의 범위 ... 23 1. 체질정보 통합 분석 ... 23 2. 체질특이 질병 유전인자 발굴 ... 23 3. 체질 약물연구 기반 구축 ... 24 4. 체질인자 발굴 ... 24제 2 장 국내외 기술개발 현황 ... 25 제 1 절 국내외 동향 ... 25 1. 체질정보 통합 분석 ... 25 2. 질병 유전체 연구 ... 25 3. 약물 효능 연구 ... 25제 3 장 연구개발수행 내용 및 결과 ... 27 제 1 절 체질정보 통합 분석 ... 27 1. 개요 ... 27 2. 비침습적 요소의 체질 특성 자료 조사 ... 27 3. 체질진단툴(SCAT) 개발 ... 31 4. 실용화를 위한 웹 기반 체질진단툴 개발 및 활용 ... 48 5. 체질진단툴의 협력 연구기관 적용 ... 57 6. 태양인 체질 특성 지표 발굴 ... 64 7. 체질별 대표 얼굴 생성 ... 69 제 2 절 체질특이 질병 유전인자 규명 ... 71 1. 체질확진자 대상으로 체질질병 유전인자 규명 ... 71 2. 안산·안성 코호트 집단 대상으로 체질확진자의 체질질병 유전인자 연관성 검증 ... 79 3. 복부표현형 관련 유전인자의 체질별 프로파일링 및 영향력 분석(2012년 특허출원) ... 82 제 3 절 체질 약물 연구 기반 구축 ... 87 1. 체질 약물연구 기반 구축 ... 87 제 4 절 체질연관 유전인자의 발굴 ... 98 1. 체질인자 발굴 ... 98 2. 체질인자 발굴을 위한 후보유전자 접근방식 ... 107 3. 체격형성과 연관된 유전인자의 발굴 ... 115 4. 주요 인자의 유전자 발현 영향 분석 ... 119제 4 장 목표달성도 및 관련분야에의 기여도 ... 125 제 1 절 목표달성도 ... 125 제 2 절 관련 분야에의 기여도 ... 125제 5 장 연구개발결과의 활용계획 ... 127 제 1 절 추가연구의 필요성 ... 127 1. 실용화 수준의 체질진단툴의 기능 및 성능 개선 ... 127 2. 체질 질병 연구 ... 127 3. 체질연관유전자의 발굴 ... 127 제 2 절 활용계획 ... 128 1. 체질진단툴의 활용 ... 128 2. 체질 질병 유효 유전인자의 활용 ... 128 3. 체질 유전인자의 활용 ... 129 4. 체질 약물연구에의 활용 ... 129제 6 장 연구개발과정에서 수집한 해외과학기술정보 ... 130 1. 대사성 질환 연구의 최신 동향 파악 ... 130제 7 장 연구시설·장비 현황 ... 131제 8 장 참고문헌 ... 132별첨 1. Questionnaire for Sasang Typology (QST) ... 135끝페이지 ... 138
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