Biomarkers for Obstructive Sleep Apnea

The overall goal of this project is to address the postulate that the optimal molecular
signature for the common disorder obstructive sleep apnea (OSA) is change in relevant
biomarkers during the sleep period. In sleep apnea, events lead to sleep fragmentation and
cyclical deoxygenation/reoxygenation. It is proposed that these changes will lead to
molecular consequences can be detected by assessing biomarkers in blood. To determine which
changes are due to OSA and which to circadian/sleep mechanisms, studies will be done in
patients with OSA before and after effective treatment with Continuous Positive Airway
Pressure (CPAP) and also in controls of similar visceral adiposity without OSA. Multiple
assessments of biomarkers will be made before, during and after sleep. Since it is proposed
that the magnitude of these dynamic changes across the sleep period will be affected by
degree of visceral obesity and be greater in OSA subjects with cardiovascular comorbidities,
studies will be done in 4 groups of subjects: lean and obese with and without such
morbidities. In assessing biomarkers the primary outcome variables will be: urinary
isoprostanes (oxidative stress); plasma tumor necrosis factor alpha (TNFα) (inflammation);
plasma norepinephrine (sympathetic activation); and free fatty acids. Secondary biomarkers
will be: Interleukin 6 (IL-6), urinary norepinephrine; urinary normetanephrine; glucose,
Intercellular Adhesion Molecule (ICAM), leptin. To complement assessment of circulating
biomarkers, an approach utilizing a cellular window will be used. Monocytes will be
separated from each blood sample (before, during and after sleep) and RNA extracted.
Expression of key genes will be assessed by RT-PCR and microarray studies will be performed
in a subset of subjects to assess changes in expression of all genes as a result of OSA. A
particular focus will be investigating differences between individuals with OSA with and
without cardiovascular comorbidities. Three aspects will be evaluated: a)whether individuals
with comorbidities have more oxidative stress and inflammatory change for equivalent degrees
of OSA than individuals without such comorbidities; b) whether individuals with
comorbidities have lower levels of protective mechanisms—melatonin (an anti-oxidant secreted
during sleep), IL-10 (antiinflammatory); c) different gene variants based on a genetic
association study using a recently developed CV SNP array. Finally, data will be used to
determine whether there is a diagnostic urine and/or blood test for OSA.

Inclusion Criteria:

- able to read and write in English

- if female, not pregnant

- goes to bed between 9:30pm-12:30am and sleeps minimum of 7 hours/night

- has telephone access

- BMI < 40

Exclusion Criteria:

- shift worker, irregular schedule

- previous diagnosis of sleep disorder other than OSA

- previous treatment with CPAP, BiPAP, oxygen, surgery for OSA

- current kidney disease, anemia, depression,

- substance abuse/dependence

- BMI > 40

- visual/hearing/cognitive impairments

- smoker who's not willing to refrain from all nicotine during study

- not willing to try CPAP treatment