The Effects of Rare <i>SERPINA1</i> Variants on Lung Function and Emphysema in SPIROMICS

Abstract

<b>Rationale:</b> The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, <i>SERPINA1</i> (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.<b>Objectives:</b> To comprehensively evaluate the effects of rare <i>SERPINA1</i> variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.<b>Methods:</b> 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 <i>SERPINA1</i>.<b>Measurements and Main Results:</b> White PI Z heterozygotes confirmed by sequencing (MZ; <i>n</i> = 74) had lower post-bronchodilator FEV₁ (<i>P</i> = 0.007), FEV₁/FVC (<i>P</i> = 0.003), and greater computed tomography-based emphysema (<i>P</i> = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as V_R. PI Z-containing compound heterozygotes (ZS/ZV_R; <i>n</i> = 7) had lower FEV₁/FVC (<i>P</i> = 0.02) and forced expiratory flow, midexpiratory phase (<i>P</i> = 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 (<i>P</i> = 0.007).<b>Conclusions:</b> In this integrative deep sequencing study of <i>SERPINA1</i> 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 <i>SERPINA1</i> variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of <i>SERPINA1</i> variation associated with respiratory disease in at-risk smokers.