Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease

Deog Kyeom Kim, Michael H. Cho, Craig P. Hersh, David A. Lomas, Bruce E. Miller, Xiangyang Kong, Per Bakke, Amund Gulsvik, Alvar Agustí, Emiel Wouters, Bartolome Celli, Harvey Coxson, Jørgen Vestbo, William MacNee, Julie C. Yates, Stephen Rennard, Augusto Litonjua, Weiliang Qiu, Terri H. Beaty, James D. CrapoJohn H. Riley, Ruth Tal-Singer, Edwin K. Silverman

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-a) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10-8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levelswere significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001-0.049), although these COPD associations were not replicated in two additional cohorts. Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Original languageEnglish (US)
Pages (from-to)1238-1247
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number12
DOIs
StatePublished - Dec 15 2012

Fingerprint

Genome-Wide Association Study
Chronic Obstructive Pulmonary Disease
Biomarkers
Single Nucleotide Polymorphism
Pulmonary Surfactant-Associated Protein D
Disease Susceptibility
Genome
Sputum
Uteroglobin
Chromosomes, Human, Pair 16
Messenger RNA
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 6
Genetic Loci
Quantitative Trait Loci
Interleukin-8
C-Reactive Protein
Fibrinogen
Genes
Interleukin-6

Keywords

  • Biomarker
  • Chronic obstructive pulmonary disease
  • Genomewide association study

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Kim, D. K., Cho, M. H., Hersh, C. P., Lomas, D. A., Miller, B. E., Kong, X., ... Silverman, E. K. (2012). Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 186(12), 1238-1247. https://doi.org/10.1164/rccm.201206-1013OC

Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. / Kim, Deog Kyeom; Cho, Michael H.; Hersh, Craig P.; Lomas, David A.; Miller, Bruce E.; Kong, Xiangyang; Bakke, Per; Gulsvik, Amund; Agustí, Alvar; Wouters, Emiel; Celli, Bartolome; Coxson, Harvey; Vestbo, Jørgen; MacNee, William; Yates, Julie C.; Rennard, Stephen; Litonjua, Augusto; Qiu, Weiliang; Beaty, Terri H.; Crapo, James D.; Riley, John H.; Tal-Singer, Ruth; Silverman, Edwin K.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 186, No. 12, 15.12.2012, p. 1238-1247.

Research output: Contribution to journalArticle

Kim, DK, Cho, MH, Hersh, CP, Lomas, DA, Miller, BE, Kong, X, Bakke, P, Gulsvik, A, Agustí, A, Wouters, E, Celli, B, Coxson, H, Vestbo, J, MacNee, W, Yates, JC, Rennard, S, Litonjua, A, Qiu, W, Beaty, TH, Crapo, JD, Riley, JH, Tal-Singer, R & Silverman, EK 2012, 'Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, vol. 186, no. 12, pp. 1238-1247. https://doi.org/10.1164/rccm.201206-1013OC
Kim, Deog Kyeom ; Cho, Michael H. ; Hersh, Craig P. ; Lomas, David A. ; Miller, Bruce E. ; Kong, Xiangyang ; Bakke, Per ; Gulsvik, Amund ; Agustí, Alvar ; Wouters, Emiel ; Celli, Bartolome ; Coxson, Harvey ; Vestbo, Jørgen ; MacNee, William ; Yates, Julie C. ; Rennard, Stephen ; Litonjua, Augusto ; Qiu, Weiliang ; Beaty, Terri H. ; Crapo, James D. ; Riley, John H. ; Tal-Singer, Ruth ; Silverman, Edwin K. / Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. In: American Journal of Respiratory and Critical Care Medicine. 2012 ; Vol. 186, No. 12. pp. 1238-1247.
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AU - Cho, Michael H.

AU - Hersh, Craig P.

AU - Lomas, David A.

AU - Miller, Bruce E.

AU - Kong, Xiangyang

AU - Bakke, Per

AU - Gulsvik, Amund

AU - Agustí, Alvar

AU - Wouters, Emiel

AU - Celli, Bartolome

AU - Coxson, Harvey

AU - Vestbo, Jørgen

AU - MacNee, William

AU - Yates, Julie C.

AU - Rennard, Stephen

AU - Litonjua, Augusto

AU - Qiu, Weiliang

AU - Beaty, Terri H.

AU - Crapo, James D.

AU - Riley, John H.

AU - Tal-Singer, Ruth

AU - Silverman, Edwin K.

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