Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function

被引：119

作者：

Artigas, Maria Soler ^{[2
]}

Wain, Louise V. ^{[2
]}

Repapi, Emmanouela ^{[2
,3
]}

Obeidat, Ma'en ^{[4
]}

Sayers, Ian ^{[4
]}

Burton, Paul R. ^{[2
]}

Johnson, Toby ^{[5
]}

Zhao, Jing Hua ^{[6
]}

Albrecht, Eva ^{[7
]}

Dominiczak, Anna F. ^{[8
]}

Kerr, Shona M. ^{[9
]}

Smith, Blair H. ^{[10
]}

Cadby, Gemma ^{[11
,12
]}

Hui, Jennie ^{[13
,14
,15
,16
]}

Palmer, Lyle J. ^{[11
,12
]}

Hingorani, Aroon D. ^{[17
]}

Wannamethee, S. Goya ^{[18
]}

Whincup, Peter H. ^{[19
]}

Ebrahim, Shah ^{[20
]}

Smith, George Davey ^{[21
]}

Barroso, Ines ^{[22
,23
]}

Loos, Ruth J. F. ^{[6
]}

Wareham, Nicholas J. ^{[6
]}

Cooper, Cyrus ^{[24
]}

Dennison, Elaine ^{[24
]}

Shaheen, Seif O. ^{[25
]}

Liu, Jason Z. ^{[26
]}

Marchini, Jonathan ^{[26
]}

Dahgam, Santosh

Naluai, Asa Torinsson ^{[28
]}

Olin, Anna-Carin

Karrasch, Stefan ^{[29
,30
]}

Heinrich, Joachim ^{[31
]}

Schulz, Holger ^{[31
]}

McKeever, Tricia M. ^{[32
,33
]}

Pavord, Ian D. ^{[34
]}

Heliovaara, Markku ^{[35
]}

Ripatti, Samuli ^{[35
,36
]}

Surakka, Ida ^{[35
,36
]}

Blakey, John D. ^{[4
]}

Kahonen, Mika ^{[37
,38
]}

Britton, John R. ^{[32
,33
]}

Nyberg, Fredrik ^{[39
]}

Holloway, John W. ^{[40
,41
]}

Lawlor, Debbie A. ^{[21
]}

Morris, Richard W. ^{[18
]}

James, Alan L. ^{[14
,42
]}

Jackson, Cathy M. ^{[43
]}

Hall, Ian P. ^{[4
]}

Tobin, Martin D. ^{[1
,2
]}

机构：

[1] Univ Leicester, Genet Epidemiol Grp, Dept Hlth Sci, Leicester LE1 7RH, Leics, England

[2] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[3] Univ Oxford, Ludwig Inst Canc Res, Oxford, England

[4] Univ Nottingham Hosp, Div Therapeut & Mol Med, Nottingham Resp Biomed Res Unit, Nottingham NG7 2UH, England

[5] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[6] MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England

[7] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[8] Univ Glasgow, Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland

[9] Univ Edinburgh, Mol Med Ctr, Edinburgh, Midlothian, Scotland

[10] Univ Aberdeen, Ctr Acad Primary Care, Aberdeen AB9 1FX, Scotland

[11] Ontario Inst Canc Res, Toronto, ON, Canada

[12] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[13] PathW Lab Med, Mol Genet, Nedlands, WA, Australia

[14] Sir Charles Gairdner Hosp, Busselton Populat Med Res Fdn, Nedlands, WA 6009, Australia

[15] Univ Western Australia, Sch Populat Hlth, Perth, WA 6009, Australia

[16] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia

[17] UCL, Dept Epidemiol & Publ Hlth, London, England

[18] UCL, Dept Primary Care & Populat Hlth, London, England

[19] St Georges Univ London, Div Community Hlth Sci, London, England

[20] London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Unit, Dept Epidemiol & Populat Hlth, London WC1, England

[21] Univ Bristol, MRC Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol, Avon, England

[22] Wellcome Trust Sanger Inst, Cambridge, England

[23] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England

[24] Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England

[25] Barts & London Queen Marys Sch Med & Dent, Ctr Hlth Sci, London, England

[26] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[27] Univ London Imperial Coll Sci Technol & Med, MRC HPA Hlth Protect Agcy Ctr Environm & Hlth, London, England

[28] Univ Gothenburg, Dept Microbiol & Immunol, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden

[29] Univ Munich, Inst Occupat Social & Environm Med, Munich, Germany

[30] Univ Munich, Outpatient Clin Occupat Social & Environm Med, Munich, Germany

[31] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany

[32] Univ Nottingham, Div Epidemiol & Publ Hlth, Sch Community Hlth Sci, City Hosp, Nottingham NG7 2RD, England

[33] Univ Nottingham, Nottingham Resp Biomed Res Unit, Nottingham NG7 2RD, England

[34] Univ Hosp Leicester Natl Hlth Serv Trust, Glenfield Hosp, Inst Lung Hlth, Leicester, Leics, England

[35] Natl Inst Hlth & Welf, Helsinki, Finland

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

[37] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland

[38] Tampere Univ Hosp, Tampere, Finland

[39] AstraZeneca Res & Dev, Molndal, Sweden

[40] Univ Southampton, Southampton Gen Hosp, Sch Med, Div Human Genet, Southampton, Hants, England

[41] Univ Southampton, Southampton Gen Hosp, Sch Med, Infect Inflammat & Immun Div, Southampton, Hants, England

[42] Sir Charles Gairdner Hosp, Dept Pulm Physiol, W Australian Sleep Disorders Res Inst, Nedlands, WA 6009, Australia

[43] Univ St Andrews, St Andrews, Fife, Scotland

来源：

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE | 2011年 / 184卷 / 07期

关键词：

FEV(1); FVC; genome-wide association study; modeling risk; PULMONARY-DISEASE; REFERENCE VALUES; COMMON VARIANTS; SUSCEPTIBILITY; METAANALYSIS; SAMPLE; COHORT;

D O I：

10.1164/rccm.201102-0192OC

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Rationale: Genomic loci are associated with FEV(1) or the ratio of FEV(1) to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied. Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP. Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD. Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10-12 risk alleles was associated with a reduction in FEV(1) (beta = -72.21 ml, P = 3.90 x 10(-4)) and FEV(1)/FVC (beta = -1.53%, P = 6.3 x 10(-6)), and with COPD (odds ratio 1.63, P = 1.4 x 10(-5)). Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

引用

页码：786 / 795

页数：10

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