초록

본연구에서는 임신성 당뇨병의 원인 유전자 발굴을 위한 전장유전체 연관성 분석을 시행하였으며 임신성 당뇨병 여성의 인슐린 분비능력에 관여하는 유전자를 찾고자함. 아울러 출산후 제2형 당뇨병으로 진행하는 데 관여하는 유전자 변이를 검색함. 전장유전체 연고나성 분석결과 CDKAL1및 MTNR1B 유전자 변이가 임신성 당뇨병의 위험을 유의하게 증가시킴을 밝혀냄. 임신성 당뇨병 여성의 인슐린 분비능력에 관여하는 유전자로 CDKAL1 및 HHEX를 발굴하였으며 이들은 임신성 당뇨병 여성이 제2형 당뇨병으로 진행하는 데도 중요하였음.

Abstract ▼

Gestational diabetes mellitus (GDM) may share similar genetic susceptibillity with type 2 diabetes. However knowledge regarding the genetic risk factor of GDM is still limited. In this study we performed a 2 stage genome-wide association analysis of GDM in Korean women and genetic association study

Gestational diabetes mellitus (GDM) may share similar genetic susceptibillity with type 2 diabetes. However knowledge regarding the genetic risk factor of GDM is still limited. In this study we performed a 2 stage genome-wide association analysis of GDM in Korean women and genetic association study regarding insulin secretion capacity.
GDM was diagnosed according to the criteria of the Third International Workshop-Conference on GDM. The inclusion criteria for control subjects were: female, age <TEX>${\geq}$</TEX> 60 years, no previous history of diabetes, no family history of diabetes and normal glucose tolerance in 75g oral glucose tolerance test. Atotal of 321,654 SNPs were genotyped in stage 1 study(468 cases and 1242 controls). Genotype imputation was used to test for association in more than 2 million SNPs. We selected 10 SNPs for replication in stage 2 study (931 cases and 459 controls). We also investigated the genetic variations that were significantly associated with progression to type 2 diabetes after GDM pregnancy.
In stage 1 genome-wide association study, rs7754840 in CDKAL1 showed the strongest association with GDM (P=2.15×10-11). rs10830962 of MTNR1B and rs1470579 of IGF2BP2 were also highly associated with risk of GDM (P=2.60×10-7 and P=5.80×10-11). Although, variations in IGF2BP2, CDKN2A/2B and IDE were associated with GDM, they did not reach henome-wide significance. None of the genetic variations that were newly discovered to be associated with GDM from the stage 1 genome scan did not have genome wide significance in the joint analysis.
Am ong the 844 GDM women, 105 (12.0%) progressed to diabetes early postpartum. Am ong the 435 women who had normal glucose tolerance at early postpartum and had follow up visit for more than one year, 120 (27.6%) progressed to diabetes. Early converters had higher glucose and lower insulin concentration during diagnostic OGTT performed at pregnancy compared to late converters. The early converters had significantly decreased 1-hour insulinogenic index compared to late converters. Variations in HHEX were significantly associated with early conversion to diabetes and variations in CDKAL1 were significantly associated with late conversion to diabetes. Genetic variations of HHEX, SLC30A8 and CDKAL1 were significantly associated with insulin secretion capacity.
We have confirmed that variations in CDKAL1 and MTNR1B, which are known to modulate type 2 diabetes risk, are also major determinants of genetic susceptibility to GDM. However, we were not albe find additional variations that were specifically associated with risk of GDM.

목차 Contents

• 겉표지 ... 1
• 제출문 ... 3
• 보고서 요약서 ... 4
• 요약문 (한글) ... 5
• 요약문 (영문) ... 6
• 연구 성과 실적 및 향후 계획 ... 7
• 참여연구원 현황표 ... 12
• 연구과제 연구결과 ... 13
• 1. 연구개발과제의 배경 및 필요성 ... 14
• 2. 국내외 기술개발 현황 ... 17
• 3. 연구개발과제의 추진체계 ... 17
• 4. 연구개발수행 내용 및 결과 ... 17
• 5. 목표달성도 및 관련분야 기여도 ... 26
• 6. 향후 연구성과 추진 계획 ... 26
• 7. 연구개발결과의 파급효과 ... 26
• 8. 연구개발결과의 활용계획 ... 28
• 9. 연구개발과정에서 수집한 해외과학기술정보 ... 28
• 10. 참고문헌 ... 28
• 첨부서류 ... 30
• ○. 실적증빙자료 및 첨부서류 목차 ... 31
• 1. 자체평가의견서 ... 32
• 끝페이지 ... 34