Integrative Metabolomics of Sarcoidosis Diagnosis and Progression

/ABSTRACT Sarcoidosis is a systemic granulomatous disease whose pathogenesis involves both genetic and environmental factors. Diagnosis of sarcoidosis is difficult and often delayed since there is no confirmatory laboratory test. Many sarcoidosis patients develop progressive pulmonary disease, which is associated with a higher mortality rate. However, no reliable biomarkers of diagnosis or prognosis exist to identify patients with disease or at risk of progression. In addition, significant disparities exist in sarcoidosis outcomes, with race and sex differences in lung function and mortality, and African American (AA) women having the worst outcomes. Thus, there is a need for studies focusing on sarcoidosis diagnosis and progression, including a sex and gender-diverse population, with limited studies focusing on gene expression, in our exciting preliminary sarcoidosis metabolomics data at National Jewish Health (NJH). We found the arginine availability index (AAI, Arginine/ [Ornithine+Citrulline]) is lower, and linoleate is higher in sarcoidosis cases vs. controls. We also observed racial and sex differences in the metabolomic profiles: European American sarcoidosis cases have a much lower AAI than AAs; female sarcoidosis cases have much higher linoleate levels than males. These findings support the feasibility of using metabolomics to identify potential blood signatures. Yet, molecular signatures from a single omics type are generally underpowered and may be biased, given disease complexity. Thus a systems biology investigation using multi-omics and advanced machine learning algorithms would be useful to identify molecular signatures of progressive vs. non-progressive pulmonary sarcoidosis. Specifically, this proposal will incorporate single nucleotide polymorphisms (SNPs) and gene expression with plasma metabolomics/lipidomics to construct and validate predictive sarcoidosis diagnosis and progression models. We hypothesize that blood arginine and arginine metabolism pathway-related SNPs and genes are associated with pulmonary sarcoidosis risk and prognosis, and these blood signatures differ by genetic ancestry and sex. Utilizing pre-existing blood samples at NJH as a Discovery Cohort, we will validate the results with prospectively collected blood, lung function, and chest imaging (Validation Cohort) at NJH and Mount Sinai Health System. We proposed the following aims: Aim 1: Determine blood diagnostic signatures associated with pulmonary sarcoidosis vs. healthy controls. Aim 2: Define baseline blood prognostic signatures of progressive pulmonary sarcoidosis integrating clinical, SNP, gene expression, and metabolomic/lipidomic data. Aim 3: Identify the longitudinal blood signature metabolomic/integrative omics dynamics contributing to pulmonary sarcoidosis progression. This will represent the largest integrative metabolomics study in a diverse sarcoidosis population to date, enabling the identification of diagnostic (Aim 1) and prognostic (Aim 2) blood signatures with longitudinal assessment (Aim 3). Ultimately, this study will identify potential candidates for therapeutic targets and biomarkers motivating preventive approaches for sarcoidosis progression in future studies. Project Number: 1R01HL173239-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Shu-Yi Liao | Institution: NATIONAL JEWISH HEALTH, DENVER, CO | Award Amount: $760,374 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-M (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17323901A1