Development and validation of a metabolite index for obstructive sleep apnea across race/ethnicities

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. Studying metabolomic associations with OSA in a diverse community-based cohort may provide insights into the pathophysiology of OSA. We aimed to develop and replicate a metabolite index for OSA and identify individual metabolites associated with OSA. We studied 219 metabolites and their associations with the apnea hypopnea index (AHI) and with moderate-severe OSA (AHI ≥ 15) 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 jointly associated with OSA, which was used to develop a metabolite index for OSA. Results were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) (n = 475). When assessing the associations with individual metabolites, we identified seven metabolites significantly positively associated with OSA in HCHS/SOL (FDR p < 0.05), of which four associations-glutamate, oleoyl-linoleoyl-glycerol (18:1/18:2), linoleoyl-linoleoyl-glycerol (18:2/18:2) and phenylalanine, were replicated in MESA (one sided-p < 0.05). The OSA metabolite index, composed of 14 metabolites, was associated with a 50% increased risk for moderate-severe OSA (OR = 1.50 [95% CI 1.21-1.85] per 1 SD of OSA metabolite index, p < 0.001) in HCHS/SOL and 55% increased risk (OR = 1.55 [95% CI 1.10-2.20] per 1 SD of OSA metabolite index, p = 0.013) in MESA, both adjusted for demographics, lifestyle, and comorbidities. Similar albeit less significant associations were observed for AHI. Replication of the metabolite index in an independent multi-ethnic dataset demonstrates the robustness of metabolomic-based OSA index to population heterogeneity. Replicated metabolite associations may provide insights into OSA-related molecular and metabolic mechanisms.