Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

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 3 10 28 ), 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 25 Mb 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 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P ¼ 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P ¼ 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).

Eosinophil-Associated Lung Diseases. A Cry for Surfactant Proteins A and D Help?

“…In a recent candidate gene association study by Kim and colleagues, SP-D was identified as one of two risk loci for COPD from among circulating COPD biomarkers measured in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study (104). These findings support the relevance of SP-D in the pathogenesis of COPD.…”

Prioritization of COPD protein biomarkers, based on a systematic study of the literature

“…SPD is mainly produced in type II pneumocytes [96,97] and plays an important role in pulmonary immune defense [98] , making it an interesting potential biomarker in COPD. In this respect, polymorphisms in the surfactant protein-D gene (SFTPD) have been shown to be associated with susceptibility to develop COPD and to influence serum concentrations of SPD [22,77] . Furthermore, SPD levels were found to be elevated in COPD patients when compared to healthy smoking controls, although no association with COPD severity [80] nor with the rate of change in FEV 1 [26] was observed.…”

“…CC-16 is predominantly secreted from non-ciliated club cells and is localized in terminal and respiratory bronchial epithelia [99] . Significant associations between several single nucleotide polymorphisms and circulating levels of CC-16 have been identified in genome-wide association studies, however, no strong associations between genotypic variations, circulating CC16 levels and risk for developing COPD were observed [22] . CC-16 is decreased in COPD patients when compared to healthy smoking controls [78] and has been significantly and independently associated with the rate of change in FEV 1 [26] .…”

“…In COPD, the search for circulating blood biomarkers has mainly focused on plasma/serum proteins which are known to be involved in the systemic inflammatory response to smoking and subsequent lung injury repair [8,[15][16][17][22][23][24][25][26] . In general, cytokines, chemokines, metalloproteases (e.g.…”

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

“…Kim and colleagues performed a GWAS for 2 pneumoproteins (clara cell secretory protein, CC16, and surfactant protein D, SP-D) as well as 5 inflammatory biomarkers (fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) in the ECLIPSE study. 62 They identified 1 region of association with Clara cell secretory protein (CC16) levels in COPD individuals near the secretoglobin, family 1A, member 1 (uteroglobin) gene, SCGB1A1, which encodes CC16, and another region of association 20 million base pairs away on the same chromosome. SNPs near the surfactant protein D coding gene, SFTPD, were associated with surfactant protein D (SP-D) levels, but SNPs on 2 other chromosomes were significantly associated as well, suggesting that these other chromosomal regions encode trans-acting regulatory factors.…”