Genetic Associations and Architecture of Asthma-COPD Overlap

被引：19

作者：

John, Catherine ^{[1
]}

Guyatt, Anna L. ^{[1
]}

Shrine, Nick ^{[1
]}

Packer, Richard ^{[1
]}

Olafsdottir, Thorunn A. ^{[2
]}

Liu, Jiangyuan ^{[3
,4
]}

Hayden, Lystra P. ^{[3
,4
]}

Chu, Su H. ^{[3
,4
]}

Koskela, Jukka T. ^{[5
]}

Luan, Jian'an ^{[6
]}

Li, Xingnan ^{[7
]}

Terzikhan, Natalie ^{[8
]}

Xu, Hanfei ^{[9
]}

Bartz, Traci M. ^{[10
,11
]}

Petersen, Hans ^{[12
]}

Leng, Shuguang ^{[13
]}

Belinsky, Steven A. ^{[12
]}

Cepelis, Aivaras ^{[14
]}

Cordero, Ana I. Hernandez ^{[15
]}

Obeidat, Ma'en ^{[15
]}

Thorleifsson, Gudmar ^{[2
,16
]}

Meyers, Deborah A. ^{[7
]}

Bleecker, Eugene R. ^{[7
]}

Sakoda, Lori C. ^{[17
]}

Iribarren, Carlos ^{[17
]}

Tesfaigzi, Yohannes ^{[4
,18
]}

Gharib, Sina A. ^{[19
,20
]}

Dupuis, Josee ^{[10
,11
]}

Brusselle, Guy ^{[8
,21
]}

Lahousse, Lies ^{[8
,22
]}

Ortega, Victor E. ^{[23
]}

Jonsdottir, Ingileif ^{[2
,16
]}

Sin, Don D. ^{[15
]}

Bosse, Yohan ^{[24
]}

van den Berge, Maarten ^{[25
,26
]}

Nickle, David ^{[27
,28
]}

Quint, Jennifer K. ^{[29
]}

Sayers, Ian ^{[30
,31
,32
]}

Hall, Ian P. ^{[30
,31
]}

Langenberg, Claudia ^{[6
]}

Ripatti, Samuli ^{[5
,33
]}

Laitinen, Tarja ^{[34
,35
]}

Wu, Ann C. ^{[4
,36
,37
,38
]}

Lasky-Su, Jessica ^{[3
,4
]}

Bakke, Per ^{[39
]}

Gulsvik, Amund ^{[39
]}

Hersh, Craig P. ^{[3
,4
]}

Hayward, Caroline ^{[40
]}

Langhammer, Arnulf ^{[14
]}

Brumpton, Ben ^{[41
,42
]}

机构：

[1] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England

[2] deCODE Genet Amgen, Reykjavik, Iceland

[3] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[4] Harvard Med Sch, Boston, MA 02115 USA

[5] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[6] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge, England

[7] Univ Arizona, Dept Med, Div Genet Genom & Precis Med, Tucson, AZ USA

[8] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[9] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[10] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[11] Univ Washington, Dept Biostat, Seattle, WA USA

[12] Lovelace Resp Res Inst, Albuquerque, NM USA

[13] Univ New Mexico, Dept Internal Med, Div Epidemiol Biostat & Prevent Med, Albuquerque, NM 87131 USA

[14] Norwegian Univ Sci & Technol NTNU, Fac Med & Hlth Sci, Dept Publ Hlth & Nursing, Levanger, Norway

[15] Univ British Columbia, Ctr Heart Lung Innovat, Vancouver, BC, Canada

[16] Univ Iceland, Iceland Fac Med, Sch Hlth Sci, Reykjavik, Iceland

[17] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA

[18] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA

[19] Univ Washington, Computat Med Core, Ctr Lung Biol, Seattle, WA 98195 USA

[20] Univ Washington, Med, UW Med Sleep Ctr, Seattle, WA 98195 USA

[21] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium

[22] Univ Ghent, Dept Bioanal, Ghent, Belgium

[23] Wake Forest Sch Med, Dept Med, Winston Salem, NC 27101 USA

[24] Laval Univ, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada

[25] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands

[26] GRIAC Res Inst, Groningen, Netherlands

[27] Univ Washington, Global Hlth, Seattle, WA 98195 USA

[28] Gossamer Bio, San Diego, CA USA

[29] Imperial Coll London, Natl Heart & Lung Inst, London, England

[30] Univ Nottingham, Div Resp Med, Nottingham, England

[31] Univ Nottingham, NIHR Nottingham Biomed Res Ctr, Nottingham, England

[32] Univ Nottingham, Biodiscovery Inst, Nottingham, England

[33] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[34] Turku Univ Hosp, Div Med, Dept Pulm Dis, Turku, Finland

[35] Univ Turku, Dept Pulm Dis & Clin Allergol, Turku, Finland

[36] Harvard Pilgrim Hlth Care Inst, Ctr Healthcare Res Pediat CHeRP, Boston, MA USA

[37] Harvard Pilgrim Hlth Care Inst, PRecis Med Translat Res PROMoTeR Ctr, Boston, MA USA

[38] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA

[39] Univ Bergen, Dept Clin Sci, Bergen, Norway

[40] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Canc, Edinburgh, Midlothian, Scotland

[41] Norwegian Univ Sci & Technol NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway

[42] Trondheim Reg & Univ Hosp, St Olavs Hosp, Clin Thorac & Occupat Med, Trondheim, Norway

[43] Leicester NIHR Biomed Res Ctr, Leicester, Leics, England

来源：

CHEST | 2022年 / 161卷 / 05期

基金：

英国科研创新办公室;

关键词：

asthma; COPD; epidemiology; genome-wide association study; spirometry; OBSTRUCTIVE PULMONARY-DISEASE; GENOME-WIDE ASSOCIATION; BLOOD EOSINOPHIL COUNT; HAY-FEVER; RISK; LOCI; EXACERBATIONS; HERITABILITY;

D O I：

10.1016/j.chest.2021.12.674

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 x 10(-6)) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 x 10(-8)) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

引用

页码：1155 / 1166

页数：12

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