MicroRNAs as Biomarkers for Obstructive Sleep Apnea

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ABSTRACT Identification of biomarkers of the severity of sleep-related conditions and the effectiveness of therapies was recently presented as the number one critical opportunity in the 2021 Sleep Research Plan from the National Institutes of Health and National Center on Sleep Disorders Research (NCSDR). While obstructive sleep apnea (OSA) is common, there are limited biomarkers for identification and management of the condition. Specific use cases for an OSA biomarker include: (i) improving case identification, (ii) monitoring efficacy of therapy, and (iii) providing prognostic value with respect to who will get particular consequences or how individuals respond to continuous positive airway pressure (CPAP) treatment. While different approaches can be used to define biomarkers, this project will focus on microRNAs, which have very recently been shown to be promising biomarkers in OSA. MicroRNAs are small non-coding RNAs that alter the translation of protein coding RNA. Their expression is dynamic and altered by many challenges, such as hypoxia. Expression of all microRNAs in blood can be assessed by sequencing all short RNAs. Prior studies, albeit with small sample sizes, suggest differences in microRNA expression between OSA cases and controls and that differences in microRNA expression can identify individuals with OSA who will show larger blood pressure responses to CPAP treatment. Using complementary sequencing approaches and clinically-feasible quantitative PCR (qPCR), we propose to validate and extend these initial observations. First, we will seek biomarkers that are specific to OSA by evaluating differences in microRNA profiles between cases with OSA and controls without OSA matched for age, sex, and body mass index and without other underlying conditions that could independently affect microRNA expression. While identifying microRNAs specific to OSA is important, it is also useful to determine microRNAs useful for improving OSA case identification beyond known clinical risk factors. Thus, this project will enroll a larger case-control sample with minimal exclusion criteria in which to assess the predictive value of differences in microRNA expression. To understand the utility of microRNAs as treatment-related biomarkers, cases with OSA will be studied before and after 6 months of CPAP. We anticipate that some microRNAs specific to OSA will normalize with CPAP treatment, thus providing an objective measure of effectiveness. In all OSA cases, we will assess 24-hour ambulatory blood pressure to validate and extend recent reports of a microRNA signature that predicts blood pressure response to CPAP. We will conduct robust validation for all biomarkers. First, using the same samples sequenced in discovery analyses, we will perform analytical validation via clinically-feasible qPCR techniques. Independent validation of microRNA signatures will be done in new samples, including cases and controls from Project 01. Moreover, the relative utility of microRNAs and other signatures developed in the Program, such as polygenic risk scores, will be assessed. Overall, this Project is directly aligned with the stated research objectives of the NCSDR and the specific goals of this Program Project.