COPD (chronic obstructive pulmonary disease) is characterized by irreversible lung airflow obstruction. Cigarette smoke is the major risk factor for COPD development. However, only a minority number of smokers develop COPD, and there are substantial variations in lung function among smokers, suggesting that genetic determinants in COPD susceptibility. During the past decade, genome-wide association studies and exome sequencing have been instrumental to identify the genetic determinants of complex traits, including COPD. Focused studies have revealed mechanisms by which genetic variants contribute to COPD and have led to novel insights in COPD pathogenesis. Through functional investigations of causal variants in COPD, from the proteinase–antiproteinase theory to emerging roles of developmental pathways (such as Hedgehog and Wnt pathways) in COPD, we have greatly expanded our understanding on this complex pulmonary disease. In this review, we critically review functional investigations on roles of genetic polymorphisms in COPD, and discuss future challenges and opportunities in discovering novel mechanisms of functional variants.

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