The Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS.

The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. To comprehensively evaluate the effects of rare variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of . White PI Z heterozygotes confirmed by sequencing (MZ;  = 74) had lower post-bronchodilator FEV ( = 0.007), FEV/FVC ( = 0.003), and greater computed tomography-based emphysema ( = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as V. PI Z-containing compound heterozygotes (ZS/ZV;  = 7) had lower FEV/FVC ( = 0.02) and forced expiratory flow, midexpiratory phase ( = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease ( = 0.007). In this integrative deep sequencing study of with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of variation associated with respiratory disease in at-risk smokers.