The Influence of Circadian-Related Genes, Sleep, and Seasonality on Dietary Intake and Cardiometabolic Traits.
The circadian clock governs numerous aspects of human physiology including sleep/wake
cycle, eating behavior, and metabolism. This autonomous system is entrainable by
external cues including light exposure and dietary intake. Circadian-related genetic
polymorphisms and short sleep duration have been associated with increased risk for
cardiometabolic diseases. Objectives:... read moreTo first explore the associations between sleep
measures and dietary intake, and potential modification by CLOCK genetic variants (Aim
1). Next, to investigate whether the associations between known circadian-related
genetic polymorphisms and cardiometabolic traits may be modified by lifestyle (Aim 2).
Finally, to elucidate the independent effects of daylight duration, environmental
temperature, and clock genes on cardiometabolic traits and DNA methylation (Aim 3).
Methods: We investigated the associations between actigraphic sleep measures and dietary
intake in the Rotterdam Study (n =439), using multivariable linear regression models
(Aim 1). Next, we conducted inverse-variance weighted, fixed-effect meta-analyses of
results of adjusted associations and interactions between self-reported sleep duration
and selected variants on dietary intake (Aim 1), then self-reported sleep duration or
dietary intake and selected variants on cardiometabolic traits (Aim 2), from
population-based cohort studies (up to n =28,190) from the CHARGE Consortium.
Furthermore, we examined whether daylight duration or environmental temperature on the
day of participants' assessment and clock genes associate with cardiometabolic traits
and CD4+ T-cells DNA methylation using adjusted linear regression models in the
family-based GOLDN cohort (n =821) (Aim 3). Results: In the Rotterdam Study, we observed
associations between higher sleep fragmentation with lower relative carbohydrate intake,
and both lower sleep efficiency and very short sleep duration (<5 h) with higher
total energy intake. In our meta-analysis, we observed associations between longer
self-reported sleep duration and lower BMI, and sex- and age- specific macronutrient
composition, as well as nominal interactions (P <0.01) between sleep duration and
CLOCK variant on relative polyunsaturated fatty acid and protein intakes (Aim 1). We
also observed nominal interactions between sleep duration and CRY2-rs11605924 for HDL-C;
and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI. As for
dietary intake, higher relative carbohydrate intake was significantly associated with
higher insulin resistance among individuals homozygous for the minor C allele at the
CRY1-rs2287161 locus in two independent populations (Aim 2). Each additional 1oC
increase in environmental temperature was associated with lower systolic and diastolic
blood pressure (BP) in the GOLDN cohort. Also, clock genes collectively explained a
significant proportion of the variance in systolic BP. We also observed an
epigenome-wide significant association between daylight duration and methylation status
at cg26930596, a CpG site located in PRKCZ, a gene involved in the circadian entrainment
pathway (Aim 3). Conclusions: Our results indicate that improved overall sleep
associates with lower BMI and favorable dietary behaviors. Additionally, the influence
of obesity-associated CLOCK variants on the association between sleep duration and
macronutrient intake suggests that longer habitual sleep duration may ameliorate genetic
predisposition to obesity via a favorable dietary profile (Aim 1). Our results further
suggest that normal sleep duration and lower carbohydrate intake may ameliorate
cardiometabolic abnormalities conferred by common circadian-related genetic variants
(Aim 2). Until further mechanistic examination of these interactions is conducted,
recommendations applicable to the general population regarding diet and normal sleep
duration should continue to be emphasized among individuals with the investigated
circadian-related genetic polymorphisms. Furthermore, our findings provide evidence for
the importance of the circadian pathway underlying cardiac physiology (Aim 3). Whether
seasonally induced methylation changes at PRKCZ mediate seasonal variation in
cardiometabolic traits requires further
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: José Ordovas.
Committee: Paul Jacques, Stefania Lamon-Fava, and Frank Scheer.
Keywords: Nutrition, Genetics, and Epidemiology.read less