Tick‐Tock, Tick‐Tock: Clock Gene Expression is Altered in Sleep Apnea
Authors: Holzworth Meaghan , Canales Muna , Berry Richard , Beyth Rebecca , Gumz Michelle L. 
Published: June 2021

IntroductionClock genes play a fundamental role in the maintenance of human body homeostasis. Dysfunctional clock gene expression has been shown to underlie circadian rhythm sleep disorders, but its association with a far more common sleep disorder, sleep apnea (SA), is unclear. The goal of this study is to determine if there is an association between clock gene expression and the presence of SA and related nocturnal hypoxia in a cohort of Veterans with chronic kidney disease (CKD).MethodsA cross‐sectional study of Veterans enrolled in the SNORE Study, a prospective cohort study of 248 Veterans with CKD, was performed. At baseline, all participants underwent a full, unattended sleep study. A subset of 49 consecutive participants provided whole blood samples the morning after sleep study at a consistent time point for this sub‐study; samples were processed the same day to isolate RNA. We determined gene expression (normalized to β‐actin) of Bmal1, Ck1δ, Ck1ɛ, Clock, Cry1, Cry2, NPAS2, Per1, Per2, Per3, Rev‐Erb‐α, RORα, and Timeless using real‐time, quantitative RT‐PCR utilizing the ΔΔCT method. SA was defined by the apnea‐hypopnea index (AHI), measured in events per hour, as follows: none (AHI 0–4.9), mild (AHI 5–14.9), moderate (AHI 15–29.9) and severe (AHI ≥30). We also compared clock gene expression between those with and without nocturnal hypoxia, where nocturnal hypoxia was defined as ≥10% of total sleep time spent at less than 90% oxygen saturation. After excluding outliers (n=7), two‐sided t‐tests were used to compare the fold change in expression between those with no SA and those with varying degrees of SA.ResultsMean age of our cohort was 71 ±11 years and mean BMI was 30 ±5 kg/m2. Mean estimated glomerular filtration rate was 38.2 ±8.6 ml/min/1.73 m2. 51% were diabetic and 88% were hypertensive. Sleep apnea was diagnosed in 71% of our cohort with 31% having mild SA, 16% with moderate SA and 24% with severe SA. 27% met criteria for nocturnal hypoxia. Participants with SA exhibited an average of a 34.9% decrease (P=0.012) in Per3 expression compared to their counterparts without SA. Participants with nocturnal hypoxia demonstrated an average 50.4% (P=0.027), 28.7% (P=0.014), and 31% (P=0.04) decrease in NPAS2, Per1, and Rev‐Erb‐α expression, respectively, compared to those who did not present with nocturnal hypoxia.ConclusionMorning expression of Per3 was significantly down‐regulated in SA. Nocturnal hypoxia was associated with down‐regulation of Per1, NPAS2, and Rev‐Erb‐α expression. These preliminary data suggest that there are meaningful differences in the expression of key clock genes between those with and without SA and related nocturnal hypoxia. Future studies should examine the 24‐hour expression of clock genes as they relate to sleep apnea in individuals with and without CKD. Should SA lead to disruption of circadian clock gene expression, treatment of SA or targeted pharmacotherapy to affect clock gene expression may restore normal rhythms and improve health outcomes for patients with SA.Support or Funding InformationVA CSR&D Career Development Award (CX000533‐01A1) to Dr. Canales; Orlando Aerie of the Fraternal Order of Eagles to Dr. Gumz; Gatorade Trust, Division of Nephrology, Department of Medicine, University of FloridaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.