Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation, and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for Damage Associated Molecular Patterns (DAMPs) in COPD. Here, we investigated the genetics of CS-induced DAMP release in 28 inbred mouse strains. Subsequently, in lung tissue from a subset of strains the expression of the identified candidate genes was analyzed. We tested whether siRNA-dependent knockdown of candidate genes altered the susceptibility of the human A549 cell line to CS-induced cell death and DAMP release. Furthermore, we tested whether these genes were differentially regulated by CS exposure in bronchial brushings obtained from individuals with a family history indicative of either presence or absence of susceptibility for COPD. We observed that of the 4 DAMPs tested, dsDNA showed the highest correlation with neutrophilic airway inflammation. Genetic analyses identified 11 candidate genes governing either CS-induced or basal dsDNA release in mice. Two candidate genes (Elac2 and Ppt1) showed differential expression in lung tissue upon CS exposure between susceptible and non-susceptible mouse strains. Knockdown of ELAC2 and PPT1 in A549 cells altered susceptibility to CS extract-induced cell death and DAMP release. In bronchial brushings, CS-induced expression of ENOX1 and ARGHGEF11 was significantly different between individuals susceptible or non-susceptible for COPD. Our study shows that genetic variance in a mouse model is associated with CS-induced DAMP release, and that this might contribute to susceptibility for COPD.