RATIONALE: A genome-wide association study (GWAS) for circulating 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, interleukin-6, interleukin-8, and tumor necrosis factor-alpha) in 1951 COPD subjects. For genome-wide significant SNPs (p < 1 x10-8), association with COPD susceptibility was tested in 2939 COPD cases and 1380 smoking controls. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. 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 ~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 values 0.009-0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (p values 0.001-0.049), although these COPD associations were not replicated in two additional cohorts. CONCLUSION: Distant genetic loci as well as 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.