American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Mar 2020
The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.
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. ⋯ 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.
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Am. J. Respir. Crit. Care Med. · Mar 2020
Optimizing the Design of Latent Tuberculosis Treatment Trials: Insights from Mathematical Modeling.
Rationale: Noninferiority trials of treatment for latent tuberculosis infection (LTBI) are challenging because of imperfect LTBI diagnostic tests. Objectives: To assess the effect on study outcomes of different enrollment strategies for a noninferiority trial of LTBI treatment. Methods: We mathematically simulated a two-arm randomized clinical trial of LTBI in which the experimental therapy was 50% efficacious and the control was 80% efficacious, with an absolute 0.75% noninferiority margin. ⋯ Enrolling based on no test or regardless of test result led to falsely declaring noninferiority unless LTBI prevalence in the underlying population was higher than 45%. Enrolling based on a mix of TST and IGRA substantially reduced the likelihood of falsely declaring noninferiority over enrolling based on TST alone, even if as many as 70% of participants were enrolled based on positive TST. Conclusions: Noninferiority trials of LTBI should enroll based on the most specific diagnostic tests available (i.e., IGRAs) to avoid misclassifying inferior treatment regimens as noninferior.
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Am. J. Respir. Crit. Care Med. · Mar 2020
Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.
Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. ⋯ Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.