Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.

OBJECTIVES: We used high-density single nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.

METHODS: On chromosome 12p, we genotyped 1387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial (NETT) and 424 control smokers from the Normative Aging Study (NAS). SNPs with significant associations were then tested in the BEOCOPD Study and the International COPD Genetics Network (ICGN). Based on the human results, we assessed histology and gene expression in the lungs of Sox5(-/-) mice.

MEASUREMENTS AND MAIN RESULTS: In the case-control analysis, 27 SNPs were significant at p≤0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (NETT-NAS p=6.0x10(-4), BEOCOPD p=1.5x10(-5), combined p=1.7x10(-7)), located 3' to the gene SOX5 (sex determining region Y-box 5). Association with rs11046966 was not replicated in the ICGN. Sox5(-/-) mice showed abnormal lung development, with a delay in maturation prior to the saccular stage, as early as E16.5. Lung pathology in Sox5(-/-) lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.

CONCLUSIONS: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.