0030 Development and Validation of a Metabolomic Risk Score for Obstructive Sleep Apnea across Race/Ethnicities
Authors: Zhang Ying , Ngo Debby , Yu Bing , Shah Neomi , Chen Han , Ramos Alberto , Zee Phylis , Kaplan Robert , Rotter Jerome , Clish Clary , Gerszten Robert , Kristal Bruce , Gharib Sina , Redline Susan , Sofer Tamar 
Published: May 2022

Abstract

Introduction
Obstructive sleep apnea (OSA) is a common disorder characterized by recurrent episodes of upper airway obstruction during sleep resulting in oxygen desaturation and sleep fragmentation, and associated with increased risk of adverse health outcomes. Metabolites are being increasingly used for biomarker discovery and evaluation of disease processes and progression. We aimed to develop a metabolomic risk score (MRS) for OSA and identify individual metabolites associated with OSA to provide insights into the pathogenesis of OSA.

Methods
We studied 219 metabolites and their associations the apnea hypopnea index (AHI) and with OSA, defined as AHI , in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n=3507) using two methods: (1) association analysis of individual metabolites, and (2) least absolute shrinkage and selection operator (LASSO) regression to identify a subset of metabolites that are jointly associated with OSA, and develop an MRS. We then validated the results in Multi-Ethnic Study of Atherosclerosis (MESA) (n=475), an independent dataset.

Results
HCHS/SOL participants were 41.72 years old on average, 50.7% female, and 10.2% had OSA. MESA individuals were 68.45 years old on average, 56.2% females, and 46.7% had OSA. When assessing the associations between OSA/AHI and individual metabolites, we identified seven metabolites significantly and positively associated with OSA in HCHS/SOL (FDR p&lt;0.05), of which four associations - glutamate, oleoyl-linoleoyl-glycerol (18:1/18:2) (DAG(36:3)), linoleoyl-linoleoyl-glycerol (18:2/18:2) (DAG(36:4)) and phenylalanine, replicated in MESA (one sided-p value&lt;0.05). The OSA-MRS, composed of 14 metabolites, was associated with 52% increase of risk for moderate to severe OSA (OR=1.52 [95% CI: 1.23-1.87] per 1 SD of OSA-MRS, p&lt;.001) in the discovery dataset of HCHS/SOL and 44% increased risk (OR=1.44 [95% CI: 1.03-2.03] per 1 SD of OSA-MRS, p=0.034) in the validation dataset of MESA, both adjusted for demographic, lifestyle, and comorbidities. Similar albeit less significant associations were observed for AHI modeled continuously.

Conclusion
We developed an MRS that replicated in an independent multi-ethnic dataset, demonstrating the robustness of metabolomic-based OSA risk score to population heterogeneity. Replicated metabolite associations may provide insights into OSA-related molecular and metabolic mechanisms.

Support (If Any)
Support for metabolomics data was graciously provided by the JLH Foundation (Houston, Texas). The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. The authors thank the staff and participants of HCHS/SOL for their important contributions. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. MESA Family is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, and by the National Center for Research Resources, Grant UL1RR033176. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). ). Metabolomics for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416) was performed at Broad Institute and Beth Israel Metabolomics Platform (HHSN268201600038I). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This study was supported by NHLBI grant R35HL135818.