Abstract Body: Introduction
DNA methylation (DNAm) predictors of high sensitivity C-reactive protein (CRP) offer a stable and accurate means of assessing chronic inflammation, bypassing the CRP protein fluctuations secondary to acute illness. Poor sleep health is associated with elevated inflammation and blood CRP levels which may explain associations of sleep insufficiency with metabolic, cardiovascular and neurological diseases. Our study aims to characterize the relationships obstructive sleep apnea (OSA)-associated phenotypes and CRP markers —blood, genetic, and epigenetic indicators—within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Methods
Multiple polygenetic risk score (PRS)-CRP scores were evaluated for their association with circulating CRP in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort to select the best-performing PRS-CRP for association analysis in HCHS/SOL. Methylation risk scores (MRS)-CRP and PRS-CRP were constructed separately in HCHS/SOL for each individual as weighted sums of methylation beta values or allele counts, respectively. OSA-related phenotypes were measured using self-reported questionnaires and objective measurements. Survey-weighted linear and logistic regressions estimated the associations between OSA-related phenotypes (apnea-hypopnea index (AHI), minimum oxyhemoglobin saturation during sleep (min SpO2), and excessive daytime sleepiness (EDS)), diabetes and hypertension with CRP markers while adjusting for age, sex, BMI, study center, and the first five principal components of genetic ancestry.

Results
We included 2221 HCHS/SOL participants (age range 37-76 yrs, 65.7% female) in the analysis. Both the MRS-CRP (95% confidence interval (CI): 0.32-0.42, p = 3.3 x 10^-38) and the PRS-CRP (95% CI: 0.15-0.25, p = 1 x 10^-14) were associated with blood CRP level. MRS-CRP was associated with AHI, min SpO2, diabetes and hypertension, while PRS-CRP markers was not. EDS was associated only with circulating CRP levels, while diabetes was associated with both circulating and MRS-CRP. Associations between OSA traits and metabolic comorbidities weakened after adjusting for MRS-CRP, with a strong impact of diabetes.

Conclusions
MRS-CRP is a promising estimate for systemic and chronic inflammation, which either mediates or serves as a common cause of the association between OSA-related phenotypes and related comorbidities, especially diabetes.