Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

被引：263

作者：

Cho, Michael H. ^{[1
,2
]}

McDonald, Merry-Lynn N. ^{[1
]}

Zhou, Xiaobo ^{[1
,2
]}

Mattheisen, Manuel ^{[1
,3
]}

Castaldi, Peter J. ^{[1
]}

Hersh, Craig P. ^{[1
,2
]}

DeMeo, Dawn L. ^{[1
,2
]}

Sylvia, Jody S. ^{[1
]}

Ziniti, John ^{[1
]}

Laird, Nan M. ^{[3
]}

Lange, Christoph ^{[3
]}

Litonjua, Augusto A. ^{[1
,2
]}

Sparrow, David ^{[4
,5
,6
]}

Casaburi, Richard ^{[7
]}

Barr, R. Graham ^{[8
,9
]}

Regan, Elizabeth A. ^{[10
,11
]}

Make, Barry J. ^{[10
]}

Hokanson, John E.

Lutz, Sharon ^{[12
]}

Dudenkov, Tanda Murray ^{[13
]}

Farzadegan, Homayoon ^{[13
]}

Hetmanski, Jacqueline B. ^{[13
]}

Tal-Singer, Ruth ^{[14
]}

Lomas, David A. ^{[15
]}

Bakke, Per ^{[16
,17
]}

Gulsvik, Amund ^{[16
,17
]}

Crapo, James D. ^{[10
]}

Silverman, Edwin K. ^{[1
,2
]}

Beaty, Terri H. ^{[13
]}

机构：

[1] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[4] Boston Univ, Sch Publ Hlth, Boston, MA USA

[5] Boston Univ, Sch Med, Boston, MA 02118 USA

[6] Vet Adm Boston Healthcare Syst, Boston, MA USA

[7] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA

[8] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA

[9] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA

[10] Natl Jewish Hlth, Denver, CO USA

[11] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA

[12] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Bioinformat & Stat, Aurora, CO USA

[13] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA

[14] GlaxoSmithKline Res & Dev Ltd, King Of Prussia, PA USA

[15] UCL, London, England

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

[17] Haukeland Hosp, Dept Thorac Med, N-5021 Bergen, Norway

来源：

LANCET RESPIRATORY MEDICINE | 2014年 / 2卷 / 03期

基金：

美国医疗保健研究与质量局;

关键词：

HEDGEHOG-INTERACTING PROTEIN; MATRIX METALLOPROTEINASE-12; GENETIC EPIDEMIOLOGY; CIGARETTE-SMOKING; COMMON VARIANTS; LUNG-FUNCTION; COPD; SUSCEPTIBILITY; ONSET; EMPHYSEMA;

D O I：

10.1016/S2213-2600(14)70002-5

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

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 5x10(-7) in 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<5x10(-8)). Findings Analysis of 6633 individuals with moderate to severe COPD and 5704 control individuals confirmed association at three known loci: CHRNA3 (p=6.38x10(-14)), FAM13A (p=1.12x10(-14)), and HHIP (p=1.57x10(-12)). We also showed significant evidence of association at a novel locus near RIN3 (p=5.25x10(-9)). In the overall meta-analysis (ie, including data from 2859 ICGN participants), the association with RIN3 remained significant (p=5.4x10(-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=2.6x10(-9)) and TGFB2 (overall joint meta-analysis p=8.3x10(-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 alpha-1 antitrypsin increase the risk of COPD.

引用

页码：214 / 225

页数：12

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