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Type: Journal article
Title: Effect of five genetic variants associated with lung function on the risk of chronic obstructive lung disease, and their joint effects on lung function
Author: Artigas, M.
Wain, L.
Repapi, E.
Obeidat, M.
Sayers, I.
Burton, P.
Johnson, T.
Zhao, J.
Albrecht, E.
Dominiczak, A.
Kerr, S.
Smith, B.
Cadby, G.
Hui, J.
Palmer, L.
Hingorani, A.
Wannamethee, S.
Whincup, P.
Ebrahim, S.
Smith, G.
et al.
Citation: American Journal of Respiratory and Critical Care Medicine, 2011; 184(7):786-795
Publisher: American Thoracic Society
Issue Date: 2011
ISSN: 1073-449X
Statement of
María Soler Artigas, Louise V. Wain, Emmanouela Repapi, Ma’en Obeidat, Ian Sayers, Paul R. Burton, Toby Johnson, Jing Hua Zhao, Eva Albrecht, Anna F. Dominiczak, Shona M. Kerr, Blair H. Smith, Gemma Cadby, Jennie Hui, Lyle J. Palmer, Aroon D. Hingorani, S. Goya Wannamethee, Peter H. Whincup, Shah Ebrahim, George Davey Smith, Inês Barroso, Ruth J. F. Loos, Nicholas J. Wareham, Cyrus Cooper, Elaine Dennison, Seif O. Shaheen, Jason Z. Liu, Jonathan Marchini, Medical Research Council National Survey of Health and Development (NSHD) Respiratory Study Team, Santosh Dahgam, Åsa Torinsson Naluai, Anna-Carin Olin, Stefan Karrasch, Joachim Heinrich, Holger Schulz, Tricia M. McKeever, Ian D. Pavord, Markku Heliövaara, Samuli Ripatti, Ida Surakka, John D. Blakey, Mika Kähönen, John R. Britton, Fredrik Nyberg, John W. Holloway, Debbie A. Lawlor, Richard W. Morris, Alan L. James, Cathy M. Jackson, Ian P. Hall, Martin D. Tobin, and the SpiroMeta Consortium
Abstract: Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 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 FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 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.
Keywords: FEV1; FVC; genome-wide association study; modeling risk
Rights: Copyright American Thoracic Society
DOI: 10.1164/rccm.201102-0192OC
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