초록 ▼

본 과제는 한국전통의학(TKM)의 핵심 컨텐츠인 사상체질의학의 과학화를 목표로,

○ 대규모 통합체질정보은행(KCMS; Korea Constitution Multicenter Bank)을 구축하고
- 14,927 증례 (24개 한방의료기관의 확진자 3,701, 가계증례 328, 코호트증례 7,752, 생리체증례 626, 체질한방검진자료 2,257, 일본, 중국 등 국외 증례 263건),

○ 객관적 체질진단툴(SCAT)을 개발, 자동화된 프로세스로 웹서비스를 통해 확산시키며
- 베타버전 출시 이후 3

본 과제는 한국전통의학(TKM)의 핵심 컨텐츠인 사상체질의학의 과학화를 목표로,

○ 대규모 통합체질정보은행(KCMS; Korea Constitution Multicenter Bank)을 구축하고
- 14,927 증례 (24개 한방의료기관의 확진자 3,701, 가계증례 328, 코호트증례 7,752, 생리체증례 626, 체질한방검진자료 2,257, 일본, 중국 등 국외 증례 263건),

○ 객관적 체질진단툴(SCAT)을 개발, 자동화된 프로세스로 웹서비스를 통해 확산시키며
- 베타버전 출시 이후 3,471건 사용, 체질대표얼굴 학회 인증을 통한 체질임상 표준화

○ 서양의학적 생리, 병리, 유전체 DB에 체질정보를 연결시켜 융합연구를 수행함으로써
- 체질별 대사율 연구, 체질별 심혈관대사질환 위험요인 및 유전인자 연구, GWAS 체질연관 유전인자 및 체질특이 pathway 분석

궁극적으로 전통체질의학을 현대과학적 근거를 갖춘 시스템의학으로 발전시키는 기반연구를 수행하였음.

( 출처 : 요약서 5p )

Abstract ▼

Ⅳ. Results
Section 1. Construction of Constitutional Information Collecting System for Scientification of Constitutional Diagnosis
1. Management and expansion of the clinical research network
A. Oriental medicine hospital and oriental medicine clinic Oriental medicine cooperative network co

Ⅳ. Results
Section 1. Construction of Constitutional Information Collecting System for Scientification of Constitutional Diagnosis
1. Management and expansion of the clinical research network
A. Oriental medicine hospital and oriental medicine clinic Oriental medicine cooperative network consisting of nationwide oriental medicine hospital(13) and clinic (11) is managed. The constitutional clinical data and biological data for the confirmed cases are collecting through the network.

B. Cohort and Physiome institute
Epidemiological studies of relations between constitutions and disease and Relialbility test of Constititon diagnostic tool were done with cohort site as collaboration works.
We collected Korea University’s Ansan cohorts subjects data of ordinary inspection data, constitutional data, body shape measuring and biological factors. In collaboration of Ulsan medical school(Seoul Asan hospital), Constition-physiome studies were carried out. In this study, targeted to healthy subjects, enery metabolite regard to constititutional clinical data and body measurement were collected.

C. Overseas research center
To build up the international constitutional data collaborating with overseas research center, Tohoku medical college in Japan and Joui hospital in China were selected as the overseas cooperation research center. Clinical data and measured data about Japanese and Chinese were collected.

2. Expansion of Clinical Constitution data for subjects
A. Establishment of Korea Constitutional Multicenter Bank, KCMB
The total number of cases which have been collected in KCMB is 14,927 cases. The cases consist of 3,701 for the constitution confirmed cases, 7,752 cohort cases, 626 physiome cases, 2,257 ordinary people's cases, 263 overseas cases, and 328 family cases. (From November, 2006 to May 6th, 2012).

KCMB has questionnaire 16,159 cases, body measurement 15,999 cases, face picture 16,133cases and voice data 15,501 cases. As biological data blood sampe 13,808 cases, DNA 8,787 cases, EVB 3,204 cases and Serum 4,000 cases are possed.

B. The systematic data management of KCMB
The standard operating procedure was developed for the data management of KCMB.
- Running Constitution information analysis room and constitution document repository for safe keeping of KCMB’s data
- We Distributed KCMB’s data 58 times following process of KCMB data usage.
- White paper of KCMB has been published.

3. Analysis and a follow-up survey for clinical constitution data of a family
A. Collecting the cases of a family study and a follow-up survey.
- Cooperation institutions collected the family information about three generations on the basis of the subject(first generation: parents, second generation: the subject, third generation: children), who are related to each other by blood, and a follow-up survey was conducted.
- Through the follow-up survey, the total 462 people which constitute 53 families as parents-the subject-children were observed.

B. Upgrading of family constitution diagnosis
- Three body constitution specialists classified large family A and B class which are in accord with the constitutional diagnosis. Excepting the cases, they reinvestigated and adjusted 39 cases of C, D and F class which are not in accord with the constitutional diagnosis. And finally the family constitution class was upgraded as 87 for A class, 45 for B class.

C. The result on the family constitution heredity analysis
- According to the result on heredity analysis of family data, sons' personality and body shape related to obesity generally correlate the maternal heredity,and the shape of the face is related to the paternal side. For daughters' case,their personality is related to the paternal side, but their body shape and appearance are related to the maternal line.

4. Study on the correlation of Constitution-Disease
A. In retropective case-control study of stroke, for weight and weight of skeletal muscle, taeeumin was much heavier than soeumin. For LDL(Low Density Lipoprotein), the result of soyangin was much higher than taeeumin's and soeumin's.

B. According to the result of cerebral infraction, the weight of taeeumin and soyangin was much heavier than soeumin, and for the weight of skelectal muscle and BMI,taeeumin was much higher than soeumin. For total cholesterol and LDL, the result from soyangin was much higher than the one from taeeumin and soeumin, and besides, the rate of non-smoker in soeumin was higher than any other constitutions.

C. The purpose of the analysis is to prepare the basis of the hypothesis that the constitution of taeyangin is correlated to ALS. For the analysis, body constitution specialists collected the constitutional factors such as demographic information, face and voice characteristics and physical shape about ALS patients, and then investigated the constitutional diagnosis with them.

D. It suggested that ALS patients have relatively large upper body shape and portion of Taeyang-in and Soyang-in is higher than healthy person in same age.

5. Expansion of the KCMB and improvement of eCRF
A. eCRF is upgraded and reconstructed in accordance with the article 28 in KGCP.
B. Log function of editing history, Data query function, and DB Locking function has been added to eCRF system.

Section 2. Development of SCAT(Sansang Constitutional Analysis Tool)
1. Survey of non-invasive components for constitutional characteristics
A. Non-invasive components
- Subject feels less uncomfortable and experts diagnosis is guided by obtaining and analysing the information related to constitution before actual treatment.

B. Literature evidence for constitutional characteristics of individual diagnosis component
- Constitutional characteristics of each individual diagnosis component, face, voice, body shape, and questionnaire, were surveyed.

2. Development of constitutional diagnosis algorithm
A. Selecting candidates of quantitative features
- Based on the literature survey of the individual diagnosis component, a set of candidate features, which can be represented by quantitative form, was determined. Automatic feature extraction methods on face and voice were implemented.
- An age normalization method was applied for each variable to compensate the effect of age by normalizing with its average and standard deviation at each age.

B. Development of constitutional diagnostic model
- Multivariate logistic regression model was used for generating individual diagnostic model, which generates predicted probability for each constitution.
- By applying a weight factor to each individual diagnosis, integrative constitutional score was calculated.

C. Analysis results of constitutional diagnostic model
- Data were divided into two groups, training group and test group. The constitutional diagnostic model was generated by using training group, and the test group was used for verification.
- As the integrative constitutional score went higher, diagnosis accuracy also went higher.

3. Development and application of web-based SCAT for practical use
A. Design and implementation of web-based SCAT
- Subject’s primary information was filled in the system when visiting a hospital.
Then face, voice information was uploaded and questionnaire, body shape information was filled in. The information transferred to KIOM server and the analysed result was displayed.

B. Application of web-based SCAT to oriental hospital
- The web-based SCAT has been used by 9 institute and 3,471 people.
- The results was agreed to experts by 70% or more. The higher the constitutional score was, the higher agreement ratio to expert was.

4. Application of SCAT to cooperative research institute
A. Research institute
- The developed SCAT was applied to cohort, physiology study, regular health check, Japan, and China. The constitutional diagnosis results were successfully derived.

B. Meaning of cooperation
- Many studies including relation between constitution and chronic diseases, investigation of physiological mechanism for each constitution is going on.

5. Deriving 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.

6. Generating representative face model for each constitution
A. Generating method
- A typical set of faces were collected by the result of SCAT and the experts’ common opinion. The selected faces were synthesized for each gender and age group.

B. Generating results
- Constitutional characteristics were represented by qualitative and realistic way.
The difference between each constitution was easily and intuitively understood.

C. Approval
- The Representative face model for each constitution was approved in the conference of Sasang constitutional medicine. The process in research and the reliability of the results was approved.

Section 3. Genetic research of constitution and the related diseases
1. Identification of constitution-specific genetic variants on metabolic diseases
A. Identification of constitution-specific genetic variants in the constitution-confiremd population (Total, 2,269; TE, 914; SY, 774; SE, 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 the effects in total population.

B. Replication of constitution-specific genetic variants in the cohort (Total, 3,472 TE, 1,882; SY, 1,277; SE, 313)
- We found all 10 genetic variants presenting reproducibility for the associations shown 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 constructed the set of genetic variants presenting both constitutionspecificity and effectivity on abdominal traits such that we identified 8 genetic variants in TE type, 9 in SY type, and 11 in SE type.
- We found that the increased number of abdominal obesity-risk variants specific for a certain constitution group had a tendency to increase the risk (combined effect sizes) on abdominal obesity in the right constitution type, but no effects in the other constitutional types.

3. Establishment of resear 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 types and treated drugs.
- Using differently expressed genes among constitution types by treatment with drugs, core-proteins interacting with many other proteins, key components responsible for constitution-specific drug metabolism, were identified in silico analysis.

4. Identification of the constitution-associated genetic variations
A. Identification of constitution-associated genetic elements using genomic approach
- By implementing family-based linkage analysis using SNP4Linkage and Merlin program, the genomic loci strongly associated with constitution were identified.
- Through Genome-Wide Association Study (GWAS) of 1,222 people, individual SNPs associated with constitution types were identified with statistical significance.
- Functionally related genes (GPM6A, SYT4 and GRIK1 for TE, DRGX and AKAP11 for SE, ZFP42, CDH22, ALDH1A2, OTX2 and EN2 for SY) were identified by text mining analysis of constitution-associated SNPs.
- Pathway analysis based on GWAS indicated 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
- Make-up of a gene list for 38 HOX and 109 segmentation genes and selection of SNPs with more than 10% of MAF based on the phased haplotype structures
- Identification of 4 constitution-associated SNPs by analysing the individual genotypes for the candidate SNPs selected with RFLP-MAAQ method

C. Identification of body build-associated genetic variation
- Analysis of the association of individual genotypes with body sizes in each gender population and the identification of 3 SNPs that exhibit a significant association with one or three variables

D. Analysis of regulatory effect of the identified variations on gene transcription
- Since a SNP on HoxA locus exhibiting an association with body sizes is placed near a well conserved sequences between species, allele expression was measured to find imbalanced expressions using the available lymphocytes of family members that were heterozygotes for the given SNP.
- No synchronous regulation for the genes on the same chromosome including mono-allelic expression was evident while HOX gene expression regulation in the lymphocytes appears not to be tight or delicate.

Section 4. Recruitment of additional cases to evaluate the Sasang constitutional medicine in a large community based prospective cohort study
1. Relations between disease and body shape
- To reveal relations between body shape and prevalence of disease, 8 part body(circumferences which cross head, neck, arm pit, chest, lower rib, waist, iliac and pubic) measuring was done. Measured length was divided into tertiles to find out relations to hypertension, diabetes, metabolic syndrome. Therefore hypertension is related to circumferences of neck, arm pit, chest, lower rib, and waist. In case of diabetes, these are neck, chest, lower rib. Finally, metabolic syndrome is related to neck, chest and lower rib.

2. Relations between Constitution and chronic disease
A. Cardiovascular and metabolic diseases are related to constitutions.
- It was revealed that relations between diabetes and Taeum, Soeum of Sasang Constitution, adjusting gender, age and body mass index regard to Ansan cohort study.

B. Chronic metabolic diseases are related to constitutions.
- In males, the prevalence of diabetes and hypertension were higher in Taeum and Soyang compared to Soeum. In female, Taeum’s prevalence is higher than Soeum regard to Ansung cohort study. Prevalence of osteoporosis is higher in Taeum and Soyang compared to Soeum in women subjects. Metabolic syndrome is shown in high frequent among Taeum(Male :18.61, Female:7.38) and Soyang(Male: 4.55, Female: 1.79) than Soeum, in both genders.
- Regard to analysis of risk factors depends on constitution, in males Taeum, it was identified that body fat, waist circumference, diastolic blood pressure, total cholesterol, triglyceride, AST, ALT, beta-cell function, FVC, FVC%, and FEV1 was independently associated with diabetes mellitus. However, in females, no obesity variables or lung function was associated with diabetes mellitus but diastolic blood pressure, HDL, triglyceride, total caloric intake was independently associated with diabetes mellitus.

C. Reliability test of Sasang Constitution diagnostic tool
1,356 subjects were recruited to perform reliability test of Sasang diagnostic tool, then Kappa test was carried out. Kappa value was 0.714, which indicate that reliability of the Sasang diagnostic model is "substantially reliable".
However, diagnostic tool suggested different constitutions on same subject when it needs to re-diagnose due to low-accuracy of Constitution diagnose result. In this case, it need to reveal reasons from either consitutional changes of subjects or accuracy of diagnostic tool.

Section 5. Constitutional Study of physiologic-metabolic factors
626 cases of physiologic-metabolic data were collected during 3 years. Male subjects were 331, female subjects were 295, respectively. Statistically significant differences were observed in most parameters, depending heavily on gender, also Constitutions.
Following parameters were statistically significant in each constitution.

1. Body index
- Weight, Body surface area, Intra/extra cellular fluid, body water, muscle weight, body fat, BMI, blood pressure, body measurement

2. Basal metabolic rate related parameters
- Respiratory quotient, oxygen consumption, carbon dioxide production, BMR,BMR/weight, BMR/BSA, BMR/BW, BMR/MW, BMR/BF, BMR/BMI,BMR/Volume, BMR/Density, BMR/LBM

3. Respiration
- In case of Taeum-in, VC, IC, and FVC are larger than the other constitutions’one. However, maximum oxygen uptake was not statistically significant. In case of men, FEV1 was longer in Taeum than the other constitution, therefore Taeum-in’s respiratory muscle functional capacity is weaker than other constitution.

4. Blood pressure, Heart rate, O2, CO2 changes during exercise stress test
- In case of man, total, mean and maximum value of perspiration are bigger than other constitution and the perspiration time are fastest in Taeum-in. These factors are smallest and slowest in Soeum-in. In case of women, no parameters are different in each constitution. Differentiations of norepinephrine, epinephrine,T3, T4, TSH, cortisol changes due to exercise stress test, are found between genders, not in constitutions. During exercise stress test, SBP, DBP, O2 consumption, CO2 production, and HR are statistically significant in each constitution.

5. Muscle power test
- Knee extensor and flexor power are different in each constitution, hence there must be differences in gate of each constitution. In case of man, the left grasping power is statistically different in each constitution.

6. OGTT and Blood cytology
- The changes of blood glucose and insulin are different in each constitution.
OGTT, HDL, LDL, TC, TG, GOT and GPT are different in each constitution.
Only Hematocrit among blood cytology factors was different in each constitution unless gender were not considered.

( 출처 : SUMMARY 20p )

목차 Contents

• 표지 ... 1제 출 문 ... 3보고서 요약서 ... 5요 약 문 ... 7SUMMARY ... 18CONTENTS ... 31목차 ... 33제1장 연구개발과제의 개요 ... 35 1. 연구개발의 목적 ... 35 2. 연구개발의 필요성 ... 35 3. 연구개발의 범위 ... 36제2장 국내외 기술개발 현황 ... 38 1. 지금까지의 연구개발 실적 ... 38 2. 현 기술상태의 취약성 ... 39 3. 앞으로의 전망 ... 40제3장 연구개발수행 내용 및 결과 ... 41 제1절 체질진단 과학화를 위한 체질정보 수집 체계 구축 ... 41 제2절 체질진단툴(SCAT) 개발 ... 53 제3절 체질 질병 유전성 연구 ... 60 제4절 대규모 일반인구 집단에서의 사상체질 증례 ... 72 제5절 생리-대사 지표를 활용한 체질 연구 ... 83제4장 목표달성도 및 관련분야에의 기여도 ... 91 1. 연구개발 목표의 달성도 ... 91 2. 관련분야 기술발전에의 기여도 ... 92제5장 연구개발결과의 활용계획 ... 93 1. 추가연구의 필요성 ... 93 2. 타 연구에의 응용 및 활용계획 ... 93제6장 연구개발과정에서 수집한 해외과학기술정보 ... 95제7장 연구시설ㆍ장비 현황 ... 96제8장 참고문헌 ... 97끝페이지 ... 100