The second replication cohort included 389 non-Hispanic white COPD cases from the U.S. National Emphysema Treatment Trial (NETT) [24] and 472 non-Hispanic white control subjects from the Normative Aging Study (NAS) [25]. Subjects in NETT had severe COPD (FEV1 ≤45% predicted) and bilateral emphysema on chest CT; all NETT subjects were former smokers. Control subjects from the NAS had normal spirometry and at least 10 pack-years of cigarette smoking history. Subjects from extended pedigrees in the Boston Early-Onset COPD (BEOCOPD) study were used as an additional family-based replication cohort. BEOCOPD subjects were recruited through COPD probands with age <53 years, FEV1 <40% predicted, and without severe α1-antitrypsin deficiency [26]. The BEOCOPD analysis included 949 individuals from 127 pedigrees.
