초록 ▼

본 연구를 통해 2173명의 아스피린 과민성 천식 코호트를 구축하였으며, 이들로부터 수집한 인체자원을 이용해 GWAS, Exomechip 등으로 전장 유전체 분석을 수행하여 아스피린 과민성 천식 진단후보 SNP을 발굴하고 3차에 걸쳐 validation하였음. 재현성이 확인된 34개 SNP을 통합하여 진단에 활용하는 분석 방법 2종을 개발하여 최종 아스피린 과민성 SNP 진단법을 확립함. 또한 본 연구를 통해 IL-4가 관려하는 아스피린 과민성의 신규 기전을 규명하였으며, RNA-seq과 genomics를 통해 17종의 아스피린 과

본 연구를 통해 2173명의 아스피린 과민성 천식 코호트를 구축하였으며, 이들로부터 수집한 인체자원을 이용해 GWAS, Exomechip 등으로 전장 유전체 분석을 수행하여 아스피린 과민성 천식 진단후보 SNP을 발굴하고 3차에 걸쳐 validation하였음. 재현성이 확인된 34개 SNP을 통합하여 진단에 활용하는 분석 방법 2종을 개발하여 최종 아스피린 과민성 SNP 진단법을 확립함. 또한 본 연구를 통해 IL-4가 관려하는 아스피린 과민성의 신규 기전을 규명하였으며, RNA-seq과 genomics를 통해 17종의 아스피린 과민성 관련 신규 유전자를 발굴하였음.

(출처 : 보고서 요약서 3p)

Abstract ▼

Purpose& Contents
The purpose of the study was to establish SNP marker set for diagnosing aspirin exacerbated respiratory disease (AERD), which is a risk factor for severe refractory asthma, by replicating results from genome-wide and whole-exome association study using large populations. In addi

Purpose& Contents
The purpose of the study was to establish SNP marker set for diagnosing aspirin exacerbated respiratory disease (AERD), which is a risk factor for severe refractory asthma, by replicating results from genome-wide and whole-exome association study using large populations. In addition, we tried to discover novel genes involved in pathogenesis of AERD using functional study.

Results
☐ The 1st Validation of primary SNP set obtained from GWAS
○ 43 among 68 SNPs obtained from previously performed GWAS were replicated in 1440 subjects.
☐ Discovery and secondary SNP set using Exome chip
○ AERD-associated rare variants were discovered using whole-exome association study (241,853 SNP) in 960 subjects.
☐ The 2nd validation of secondary SNP set obtained f개m Exome chip
○ 23 among 29 SNPs and 1 gene among 5 candidate genes obtained from the Exomechip analysis were replicated in 1144 subjects.
☐ The 3rd validation of SNPs obtained from the 1st and 2nd validation analyses to establish a final SNP marker set
○ 48 SNPs among 66 SNPs (43 from the 1st validation and 63 from the 2nd validation) and 8 candidate gene were validated in an independently erolled 731 subjects.
○ Finally 34 SNPs and 11 genes were replicated, which could be contents of the final marker set
☐ Development of final SNP set for diagnosing aspirin hypersensitivity
○ To integrating 34 SNP information of individuals, two different integration methods were developed (combination and odd ratio methods), and diagnosis accuaracies were evaluated.
☐ Evaludation of novel pathway and genes involved in pathogenesis of AERD
○ We observed that aspirin directly induced IL-4 production via MAP-NFAT pathway. The expression of IL-4 by aspirin was higher in PBMC of AERD patients than those of ATA subjects.
○ In addition, we discovered some novel genes invloved in pathophysiology of AERD using genetic study and RNA-seq.

Expected Contribution
☐ We established 2173 AERD cohorts and collected clinical information and biospecimens. These would be an important resource for investigating AERD, especially for integrated omics researches.
☐ We developed statistical methods integrating many SNP information of an individuals. These methods could be applied to other multigenic disease, and would be useful for realizing personalized medicine.
☐ Further researches for prospective validation of the SNP marker set and for developing diagnosis kit using these SNPs should be performed.
☐ Our results suggest that the presence of another pathway of AERD hypersensitivity. The roles of discovered candidate molecules in pathophysiology of AERD should be evaluated in further study.

(출처 : SUMMARY 5p)

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 보고서 요약서 ... 3
• 국문 요약 ... 4
• SUMMARY ... 5
• 목차 ... 6
• 1. 연구개발과제의 개요 ... 7
• 1-1. 연구개발 목적 ... 7
• 1-2. 연구개발의 필요성 ... 7
• 1-3. 연구개발 범위 ... 9
• 2. 국내외 기술개발 현황 ... 11
• 3. 연구수행 내용 및 결과 ... 14
• 4. 목표달성도 및 관련분야 기여도 ... 56
• 4-1. 목표달성도 ... 56
• 4-2. 관련분야 기여도 ... 57
• 5. 연구결과의 활용계획 ... 59
• 6. 연구과정에서 수집한 해외과학기술정보 ... 60
• 7. 연구개발성과의 보안등급 ... 60
• 8. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 60
• 9. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 60
• 10. 연구개발과제의 대표적 연구실적 ... 62
• 11. 기타사항 ... 62
• 12. 참고문헌 ... 63
• 별첨 ... 65
• 끝페이지 ... 94