In summary, we have identified robust evidence of association of COPD with the α-nicotinic receptor (CHRNA 3/5) and HHIP loci. The hedgehog (Hh) gene family encodes signaling molecules that play an important role in regulating morphogenesis and the HHIP locus may play a role lung development. Although there is evidence of association of CHRNA 3/5 locus with nicotine addiction, both this study and recent reports of a lung cancer association [12]–[14] with the same alleles suggest that this region may be involved in more than nicotine addiction, and may potentially have direct functional relevance in the development of COPD, lung cancer, peripheral arterial disease, and other smoking related conditions. The first-degree relatives of both lung-cancer patients and COPD patients have higher rates of impaired forced expiratory flow rates than relatives of patients with non-pulmonary disease [20], suggesting that susceptibility to lung cancer and COPD share common familial components. The association of CHRNA 3/5 locus with COPD, lung cancer, and peripheral arterial disease is powerful enough to make genetic screening of smokers an attractive interventional strategy.
