초록 ▼

개발성과 요약:
본 연구과제는 약 3.5만 명의 KoGES 코호트 시료를 기반으로 수행된 대규모 대사성질환 유전-환경 상호작용 연구로, 상호작용을 고려하여 대사성질환과 연관성이 높은 새로운 유전변이를 발굴하였으며, 이는 일본 코호트 시료와 병원 코호트 시료에서 일부 검증되었음. 또한 마우스 모델을 이용하여 통계적으로 발굴한 유전-환경 상호작용이 생체내에서도 적용되는 것을 확인하였음. 본 과제를 통하여 대사성질환의 새로운 환경위험 요인을 발굴하였으며, 이를 이용한 risk score system을 개발하였음. 다기관 협력 당뇨병

개발성과 요약:
본 연구과제는 약 3.5만 명의 KoGES 코호트 시료를 기반으로 수행된 대규모 대사성질환 유전-환경 상호작용 연구로, 상호작용을 고려하여 대사성질환과 연관성이 높은 새로운 유전변이를 발굴하였으며, 이는 일본 코호트 시료와 병원 코호트 시료에서 일부 검증되었음. 또한 마우스 모델을 이용하여 통계적으로 발굴한 유전-환경 상호작용이 생체내에서도 적용되는 것을 확인하였음. 본 과제를 통하여 대사성질환의 새로운 환경위험 요인을 발굴하였으며, 이를 이용한 risk score system을 개발하였음. 다기관 협력 당뇨병 코호트인 KNDP 시료의 임상 데이터를 정리하고, 세분화하여 당뇨병 고위험군을 선정하였고, 이를 이용해 당뇨병 유전마커를 발굴하기 위한 genotyping을 수행하여 고위험군 시료의 유전정보를 생산하였음

(출처 : 요약서 3p)

Abstract ▼

Purpose&Contents
The westernization of the Korean diet is driving the increase in the case number of metabolic disorders including diabetes, obesity, and hyperlipidemia. Despite the importance of the gene-environment interaction (GxE) considering such a change in the modern disease, the genetic f

Purpose&Contents
The westernization of the Korean diet is driving the increase in the case number of metabolic disorders including diabetes, obesity, and hyperlipidemia. Despite the importance of the gene-environment interaction (GxE) considering such a change in the modern disease, the genetic factors and the environmental factors had been investigated independently. Our aim is to identify novel genetic factors by investigating the GxE. The first sub-aim is to confirm the GxE by using the clinical cohort as well as the local area cohort, and the second sub-aim is to develop a therapeutic approach by using a mouse model.

Results
1. We obtained large-scale population-based cohort data from KNIH: KARE (n = 8,840), CAVAS (n = 21,000), HEXA (n = 25,000), Japan (RHS, n = 3,200)
2. We calculated genetic risk score (GRS) for type 2 diabetes, hypertension and obesity and analyzed GRS-environment interaction. We identified GRS-TG, GRS-total cholesterol interactions for fasting glucose (P < 0.05). And we developed new GRS index for GxE, interaction genetic risk score (iGRS), and identified iGRS-total calorie intake interaction (P < 0.05)
3. We performed genome-wide interaction study (GWIS) for metabolic disease and related phenotype. (1) We performed GWIS for metabolic disease using KARE and among 64 significant SNPs, 8 SNPs and 13 SNPs were replicated in the RHS Japan cohort and CAVAS (P<0.05), respectively.(2) We performed GWIS for metabolic disease using KARE and CAVAS and performed meta-analysis using the GWIS results of KARE and CAVAS1. And we performed replication analysis using CAVAS2 and HEXA. As the results, 3 and 7 SNPs were replicated in CAVAS2 and HEXA, respectively. (3) We performed alcohol consumption GWIS for DBP using KARE, CAVAS and HEXA, and identified rs1297184-alcohol interaction with meta P-value = 8.94E-8. (4) We performed calcium and iron GWIS using KARE follow-up data, however, we could not find any GxE.
4. We produced Nr3c2 CRIPR/Cas9 knockout mouse model and validated Nr3c2 gene and obesity interaction for blood pressure (BP). The increment of weight for Nr3c2+/+ was higher than Nr3c2+/- irrespective of diet, however, BP of Nr3c2+/+ (high fat diet) was higher than hetero and BP of Nr3c2+/+ (low fat diet) was lower.
5. We summarized phenotype data for type 2 diabetes (T2D) patients cohort (KNDP) and specified the high risk T2D group.
6. We identified new environment risk factors for metabolic disease. (ait pollution was associated with obesity and family history was associated with T2D. Using These results, we developed T2D risk scoring system.
7. We identified the complication of T2D (retinopathy) variants and developed GRS system.
8. We analyzed diabetes association tests using prediabetes and T2D patient, and found 10 loci for follow-up data based GWAS, 9 loci for baseline data based-GWAS and 27 loci for GWIS.
9. We genotyped 578 participants and 48 SNPs using KNDP cohort T2D high risk group and performed replication analysis for preDM-DM GWAS and GWIS. A Total 3 loci were replicated.
10. We published total 9 articles and applied for 1 domestic patent.

Expected Contribution
Once completed, this study is to identify novel genetic factors that have not been discovered by the Genome-Wide Association Study and to provide an explanation for the underlying mechanism of the disorder occurrence and to increase the total explanation power for the occurrence of the disorder, and to provide a target gene for development of a new medicine.
Therefore, this study is to foster the health industry and to provide a preventive medicine for a disease, resulting in a decrease in the occurrence of metabolic disorders and contributing to enhancement of the people health.

(출처 : SUMMARY 5p)

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 보고서 요약서 ... 3
• 국문 요약문 ... 4
• SUMMARY ... 5
• 목차 ... 6
• 1. 연구개발과제의 개요 ... 7
• 1-1. 연구 개발의 개요 ... 7
• 1-2. 연구 개발 대상의 국내외 현황 ... 9
• 1-3. 연구 개발의 중요성 ... 16
• 2. 국내외 기술개발 현황 ... 20
• 3. 연구수행 내용 및 결과 ... 29
• 4. 목표달성도 및 관련분야 기여도 ... 65
• 4-1. 목표달성도 ... 65
• 4-2. 관련분야 기여도 ... 67
• 5. 연구결과의 활용계획 ... 68
• 6. 연구과정에서 수집한 해외과학기술정보 ... 69
• 7. 연구개발성과의 보안등급 ... 71
• 8. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 71
• 9. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 71
• 10. 연구개발과제의 대표적 연구실적 ... 72
• 11. 기타사항 ... 72
• 12. 참고문헌 ... 73
• [별첨2]최종보고서 평가 면제요청서 (매출액 달성) ... 75
• [별첨3]최종보고서 비공개 승인요청서 ... 76
• [별첨4]임상‧오믹스 정보생산 실적서 ... 77
• [별첨5]실적 증빙자료 ... 79
• 끝페이지 ... 104