Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence.

Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution.

The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group.

Patients with familial pulmonary fibrosis represent a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making.

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP.

CT Imaging Phenotypes of Pulmonary Fibrosis in the MUC5B Promoter Site Polymorphism.

Background: To determine the effect of the MUC5B promoter polymorphism (rs35705950) on the CT imaging appearance of pulmonary fibrosis.

Methods: High-resolution CT scans of 1,764 subjects were scored as part of a, genomewide association study with institutional review board approval; 1,491 of these had pulmonary fibrosis on CT scans and were included in the study. Two thoracic radiologists independently scored CT scans systematically.

CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis.

Background: The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis.

Methods: The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan.

Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.

Importance: Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials.

Objective: To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF.

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.

High-resolution CT scan findings in familial interstitial pneumonia do not conform to those of idiopathic interstitial pneumonia.

Background: The aim of this study was to describe the high-resolution CT (HRCT) scan features that characterize familial interstitial pneumonia (FIP).

Methods: FIP was defined by the presence of two or more cases of probable or definite idiopathic interstitial pneumonia (IIP) in individuals related within three degrees. The cases were collected consecutively from three centers.

The peripheral blood transcriptome identifies the presence and extent of disease in idiopathic pulmonary fibrosis.

Rationale: Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. We hypothesize that peripheral blood biomarkers will identify disease in its early stages, and facilitate monitoring for disease progression.

A common MUC5B promoter polymorphism and pulmonary fibrosis.

Background: The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk.

Methods: Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families.

A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci.

Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there is strong association between vitiligo and other autoimmune diseases. To map genetic loci that confer susceptibility to generalized vitiligo and perhaps other autoimmune diseases, we performed a genomewide linkage scan in 71 white multiplex families with vitiligo from North America and the United Kingdom.

Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2.

Generalized vitiligo is a common autoimmune disorder in which patchy loss of skin and hair pigmentation results from loss of pigment-forming melanocytes from the involved regions. Vitiligo occurs with a frequency of about 1% in most populations, and is highly associated with other autoimmune disorders, particularly Hashimoto thyroiditis. Most cases of vitiligo are sporadic, although some cases cluster in families, and the disorder is thought to be oligogenic in origin.