Triangulating causal effects of sleep, inflammation, and cardiometabolic disease

Significance. Sleep problems, including short sleep duration and sleep disorders, elevate risk of a numerous chronic diseases, particularly cardiometabolic diseases (CMDs), and contribute to racial and ethnic health disparities. One possible mechanism linking sleep problems to CMDs is chronic, low-grade inflammation. However, existing evidence on sleep, chronic low-grade inflammation, and CMDs has primarily focused on non- specific inflammatory biomarkers that are less likely to be causal. Because upstream regulation of inflammation is mainly dictated by polyunsaturated fatty acids and their oxylipin derivatives (“oxylipins”), these molecules afford novel insights into the role of inflammation in sleep and CMDs. Oxylipins are also amenable to treatment. However, very few studies have examined the relationship between sleep problems, oxylipins, and CMDs. The handful of studies that are available are small or did not measure a comprehensive set of oxylipins. While research on oxylipins and CMDs is more abundant, these studies have lacked diversity, did not prioritize which of the highly correlated oxylipins are most likely causal, and are limited by confounding and reverse causation. Specific aims. The proposed research aims to triangulate causal and mediating effects of ~130 oxylipins with sleep problems, including insomnia, sleep apnea, and short sleep duration, and CMDs to identify shared and distinct inflammatory pathways in the well-characterized Hispanic Community Health Study/Study of Latinos (n=16,415). Aim 1 will identify oxylipins associated with insomnia symptoms, a common (prevalence=10-30%) threat to sleep health using tailored statistical methods that accommodate highly correlated data and protect against reverse causation and residual confounding. Aim 2 will extend aim 1 to include sleep apnea and short sleep duration, enabling the applicant to examine the consistency of oxylipins across sleep problems. Finally, integration of CMDs (hypertension, type 2 diabetes, and obesity), again using models that accommodate highly correlated data and protect against residual confounding and reverse causation, will provide some of the first insights into inflammatory pathways linking sleep problems and CMDs. Fellowship information. The applicant, Ms. Sarah Koenigsberg, is an epidemiology PhD student at the University of North Carolina at Chapel Hill with a background in biochemistry, cardiometabolic disease, and population-level research. The proposed research and training plan would occur under the guidance of Ms. Koenigsberg's mentorship team, which consists of experts in molecular, cardiometabolic, and sleep epidemiology, biostatistics, and large-scale computation. Under this award, Ms. Koenigsberg would receive training on sleep epidemiology and evidence triangulation methods to complement her existing skill set, as well as engage in professional development activities that would equip her to achieve her long-term goal of becoming an independent investigator at the intersection of cardiometabolic, molecular, and sleep epidemiology. Project Number: 1F31HL177899-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Sarah Koenigsberg | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $41,700 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F18-E (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17789901