TY - JOUR
T1 - Risk loci for chronic obstructive pulmonary disease
T2 - A genome-wide association study and meta-analysis
AU - The NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators
AU - Cho, Michael H.
AU - McDonald, Merry Lynn N.
AU - Zhou, Xiaobo
AU - Mattheisen, Manuel
AU - Castaldi, Peter J.
AU - Hersh, Craig P.
AU - DeMeo, Dawn L.
AU - Sylvia, Jody S.
AU - Ziniti, John
AU - Laird, Nan M.
AU - Lange, Christoph
AU - Litonjua, Augusto A.
AU - Sparrow, David
AU - Casaburi, Richard
AU - Barr, R. Graham
AU - Regan, Elizabeth A.
AU - Make, Barry J.
AU - Hokanson, John E.
AU - Lutz, Sharon
AU - Dudenkov, Tanda Murray
AU - Farzadegan, Homayoon
AU - Hetmanski, Jacqueline B.
AU - Tal-Singer, Ruth
AU - Lomas, David A.
AU - Bakke, Per
AU - Gulsvik, Amund
AU - Crapo, James D.
AU - Silverman, Edwin K.
AU - Beaty, Terri H.
N1 - Funding Information:
This work was supported by the US National Heart, Lung, and Blood Institute ( R01 HL084323, P01 HL083069, P01 HL105339, and R01 HL089856 to EKS; K08 HL097029 and R01 HL113264 to MHC; and R01 HL089897 to JDC ), the Alpha-1 Foundation (funding to MHC), and a Veterans Affairs Research Career Scientist award to DS. The COPDGene study is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, and Sunovion. NETT was supported by the US National Heart, Lung, and Blood Institute ( N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119 ), the Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality. NAS is supported by the Cooperative Studies Program/ERIC of the US Department of Veterans Affairs, and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). The Norway GenKOLS study, the ECLIPSE study, and the ICGN study were funded by GlaxoSmithKline. The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the US National Heart, Lung, and Blood Institute or the National Institutes of Health.
Funding Information:
MHC has received consultancy fees from Merck. CPH has received lecture fees from Novartis and has been a consultant for CSL Behring. RT-S is an employee of GlaxoSmithKline. DAL has received grant support, honoraria, and consultancy fees from GlaxoSmithKline; and is the chair of the GlaxoSmithKline Respiratory Area Therapy Board. EKS has received grant support from GlaxoSmithKline for studies of COPD genetics and honoraria, and consulting fees from AstraZeneca, Merck, and GlaxoSmithKline. The other authors declare that they have no competing interests.
PY - 2014
Y1 - 2014
N2 - Background: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. Methods: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10-7in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5 × 10-8). Findings: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10-14), FAM13A (p=1·12 × 10-14), and HHIP (p=1·57 × 10-12). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10-9). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10-9). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10-9) and TGFB2 (overall joint meta-analysis p=8·3 × 10-9). Interpretation: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. Funding: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.
AB - Background: The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. We sought to identify risk loci for moderate to severe and severe COPD with data from several cohort studies. Methods: We combined genome-wide association analysis data from participants in the COPDGene study (non-Hispanic white and African-American ethnic origin) and the ECLIPSE, NETT/NAS, and Norway GenKOLS studies (self-described white ethnic origin). We did analyses comparing control individuals with individuals with moderate to severe COPD and with a subset of individuals with severe COPD. Single nucleotide polymorphisms yielding a p value of less than 5 × 10-7in the meta-analysis at loci not previously described were genotyped in individuals from the family-based ICGN study. We combined results in a joint meta-analysis (threshold for significance p<5 × 10-8). Findings: Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6·38 × 10-14), FAM13A (p=1·12 × 10-14), and HHIP (p=1·57 × 10-12). We also showed significant evidence of association at a novel locus near RIN3 (p=5·25 × 10-9). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5·4 × 10-9). 3497 individuals were included in our analysis of severe COPD. The effect estimates for the loci near HHIP and CHRNA3 were significantly stronger in severe disease than in moderate to severe disease (p<0·01). We also identified associations at two additional loci: MMP12 (overall joint meta-analysis p=2·6 × 10-9) and TGFB2 (overall joint meta-analysis p=8·3 × 10-9). Interpretation: We have confirmed associations with COPD at three known loci and identified three new genome-wide significant associations. Genetic variants other than in α-1 antitrypsin increase the risk of COPD. Funding: US National Heart, Lung, and Blood Institute; the Alpha-1 Foundation; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; and US Department of Veterans Affairs.
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U2 - 10.1016/S2213-2600(14)70002-5
DO - 10.1016/S2213-2600(14)70002-5
M3 - Article
C2 - 24621683
AN - SCOPUS:84895799527
SN - 2213-2600
VL - 2
SP - 214
EP - 225
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 3
ER -