The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS

Am J Respir Crit Care Med. 2020 Mar 1;201(5):540-554. doi: 10.1164/rccm.201904-0769OC.


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

Keywords: SERPINA1; alpha-1 antitrypsin; chronic obstructive pulmonary disease; emphysema; rare variant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Black or African American
  • Female
  • Forced Expiratory Volume
  • Genotype
  • Heterozygote
  • Hispanic or Latino
  • Humans
  • Isoelectric Focusing
  • Lung / physiopathology*
  • Male
  • Maximal Midexpiratory Flow Rate
  • Middle Aged
  • Phenotype
  • Polymorphism, Genetic
  • Pulmonary Disease, Chronic Obstructive / epidemiology
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Pulmonary Emphysema / epidemiology
  • Pulmonary Emphysema / genetics*
  • Pulmonary Emphysema / metabolism
  • Pulmonary Emphysema / physiopathology
  • Smoking / epidemiology*
  • Tomography, X-Ray Computed
  • Vital Capacity
  • White People
  • alpha 1-Antitrypsin / genetics*
  • alpha 1-Antitrypsin / metabolism


  • SERPINA1 protein, human
  • alpha 1-Antitrypsin