Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol

Abstract

Sarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation with tremendous clinical heterogeneity and uncertain pathobiology and lacking in clinically useful biomarkers. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study is an observational cohort study designed to explore the role of the lung microbiome and genome in these two diseases. This article describes the design and rationale for the GRADS study sarcoidosis protocol. The study addresses the hypothesis that distinct patterns in the lung microbiome are characteristic of sarcoidosis phenotypes and are reflected in changes in systemic inflammatory responses as measured by peripheral blood changes in gene transcription. The goal is to enroll 400 participants, with a minimum of 35 in each of 9 clinical phenotype subgroups prioritized by their clinical relevance to understanding of the pathobiology and clinical heterogeneity of sarcoidosis. Participants with a confirmed diagnosis of sarcoidosis undergo a baseline visit with self-administered questionnaires, chest computed tomography, pulmonary function tests, and blood and urine testing. A research or clinical bronchoscopy with a research bronchoalveolar lavage will be performed to obtain samples for genomic and microbiome analyses. Comparisons will be made by blood genomic analysis and with clinical phenotypic variables. A 6-month follow-up visit is planned to assess each participant's clinical course. By the use of an integrative approach to the analysis of the microbiome and genome in selected clinical phenotypes, the GRADS study is powerfully positioned to inform and direct studies on the pathobiology of sarcoidosis, identify diagnostic or prognostic biomarkers, and provide novel molecular phenotypes that could lead to improved personalized approaches to therapy for sarcoidosis.

Clinical phenotyping: role in treatment decisions in sarcoidosis

“…The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study developed a phenotype proposal predicting prognosis for patients in whom multiple specimens had been obtained [14]. This study promises to provide detailed genetic information regarding these different phenotypes.…”

IFN-γ–Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells

“…A total of 35 patients with sarcoidosis and 18 healthy control subjects were enrolled in the U.S. cohort. Patients with sarcoidosis had pulmonary disease (Table 2) and met criteria for chronic disease (lack of disease resolution by 2 yr after diagnosis [27]). There were no significant differences in sex between groups; however, the control population was younger, on average.…”

Transcriptome profiles in sarcoidosis and their potential role in disease prediction

“…The main limitations of most of the published transcriptomics studies are a) limited sample size, less than 20 patients in most studies, b) the lack of African Americans participants, c) the absence of time course data and d) the use of cellular admixtures as input samples. The recently completed Genomics Research in Alpha-1 Antitrypsin and Sarcoidosis (GRADS) study used a multi ‘omics’ approach in analysis of three compartments (blood, BAL, stool), and included a large sample size with multiethnic participants, and proteomics, metabolomics and microbiomics but did not include prospective time course analysis and cellular subpopulations [30]. Thus, future studies should include cutting-edge technologies that identify changes in specific cell subpopulations, potentially at the level of the single cells, and should provide prospective follow up and repeated sampling to address disease dynamics and heterogeneity.…”