Hassan S. Dashti

Short Sleep Duration and Dietary Intake: Epidemiologic Evidence, Mechanisms, and Health Implications

Links between short sleep duration and obesity, type 2 diabetes, hypertension, and cardiovascular disease may be mediated through changes in dietary intake. This review provides an overview of recent epidemiologic studies on the relations between habitual short sleep duration and dietary intake in adults from 16 cross-sectional studies. The studies have observed consistent associations between short sleep duration and higher total energy intake and higher total fat intake, and limited evidence for lower fruit intake, and lower quality diets. Evidence also suggests that short sleepers may have irregular eating behavior deviating from the traditional 3 meals/d to fewer main meals and more frequent, smaller, energy-dense, and highly palatable snacks at night. Although the impact of short sleep duration on dietary intake tends to be small, if chronic, it may contribute to an increased risk of obesity and related chronic disease. Mechanisms mediating the associations between sleep duration and dietary intake are likely to be multifactorial and include differences in the appetite-related hormones leptin and ghrelin, hedonic pathways, extended hours for intake, and altered time of intake. Taking into account these epidemiologic relations and the evidence for causal relations between sleep loss and metabolism and cardiovascular function, health promotion strategies should emphasize improved sleep as an additional factor in health and weight management. Moreover, future sleep interventions in controlled studies and sleep extension trials in chronic short sleepers are imperative for establishing whether there is a causal relation between short sleep duration and changes in dietary intake.

CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American

Dysregulation in the circadian system induced by variants of clock genes has been associated with type 2 diabetes. Evidence for the role of cryptochromes, core components of the system, in regulating glucose homeostasis is not supported by CRY1 candidate gene association studies for diabetes and insulin resistance in human, suggesting possible dietary influences. The purpose of this study was to test for interactions between a CRY1 polymorphism, rs2287161, and carbohydrate intake on insulin resistance in two independent populations: a Mediterranean (n = 728) and an European origin North American population (n = 820). Linear regression interaction models were performed in two populations to test for gene–diet interactions on fasting insulin and glucose and two insulin-related traits, homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). In addition, fixed effects meta-analyses for these interactions were performed. Cohort-specific interaction analyses showed significant interactions between the CRY1 variant and dietary carbohydrates for insulin resistance in both populations (p < 0.05). Findings from the meta-analyses of carbohydrate–single nucleotide polymorphism interactions indicated that an increase in carbohydrate intake (% of energy intake) was associated with a significant increase in HOMA-IR (p = 0.011), fasting insulin (p = 0.007) and a decrease in QUICKI (p = 0.028), only among individuals homozygous for the minor C allele. This novel finding supports the link between the circadian system and glucose metabolism and suggests the importance this CRY1 locus in developing personalized nutrition programs aimed at reducing insulin resistance and diabetes risk.

CLOCK 3111 T/C SNP Interacts with Emotional Eating Behavior for Weight-Loss in a Mediterranean Population

Objective The goals of this research was (1) to analyze the role of emotional eating behavior on weight-loss progression during a 30-week weight-loss program in 1,272 individuals from a large Mediterranean population and (2) to test for interaction between CLOCK 3111 T/C SNP and emotional eating behavior on the effectiveness of the weight-loss program. Design and Methods A total of 1,272 overweight and obese participants (BMI: 31±5 kg/m2), aged 20 to 65 years, attending outpatient weight-loss clinics were recruited for this analysis. Emotional eating behavior was assessed by the Emotional Eating Questionnaire (EEQ), a questionnaire validated for overweight and obese Spanish subjects. Anthropometric measures, dietary intake and weight-loss progression were assessed and analyzed throughout the 30-week program. Multivariate analysis and linear regression models were performed to test for gene-environment interaction. Results Weight-loss progression during the 30-week program differed significantly according to the degree of emotional eating behavior. Participants classified as ‘very emotional eaters’ experienced more irregular (P = 0.007) weight-loss, with a lower rate of weight decline (−0.002 vs. −0.003, P<0.05) in comparison with less emotional eaters. The percentage of weight-loss was also significantly higher in ‘non-emotional eaters’ (P = 0.009). Additionally, we identified a significant gene-environment interaction associated with weight-loss at the CLOCK 3111 T/C locus (P = 0.017). By dichotomizing the emotional eating behavior score, linear regression analysis indicated that minor C allele carriers with a high emotional score (> = 11), lost significantly less weight than those C carriers with a low emotional score (<11) (P = 0.005). Conclusions Emotional eating behavior associates with weight-loss pattern, progression and total weight-loss. Additionally, CLOCK 3111 T/C SNP interacts with emotional eating behavior to modulate total weight loss. These results suggest that the assessment of this locus and emotional eating behavior could improve the development of effective, long-tern weight-management interventions.

Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations

BACKGROUND Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized, this has yet to be examined by a genome-wide association (GWA) study. OBJECTIVE The objective was to identify common genetic variants associated with concentrations of circulating phylloquinone, the primary circulating form of vitamin K. DESIGN We conducted a 2-stage GWA meta-analysis of circulating phylloquinone in 2 populations of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Circulating phylloquinone was measured by using reversed-phase high-performance liquid chromatography. Results from adjusted cohort-specific discovery GWA analyses were meta-analyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P < 1 × 10(-6) were then evaluated in a second-stage analysis consisting of one independent cohort (n = 265). RESULTS No significant association was observed for circulating phylloquinone at the genome-wide significance level of 5 × 10(-8). However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P < 1 × 10(-6), including a functional variant previously associated with warfarin dose and altered phylloquinone metabolism. These SNPs are on 5 independent loci on 11q23.3, 8q24.3, 5q22.3, 2p12, and 19p13.12, and they fall within or near the candidate genes APOA1/C3/A4/A5 cluster (involved in lipoprotein metabolism), COL22A1, CDO1, CTNAA2, and CYP4F2 (a phylloquinone oxidase), respectively. Second-stage analysis in an independent cohort further suggests the association of the 5q22.3 locus with circulating phylloquinone (P < 0.05). CONCLUSIONS Multiple candidate genes related to lipoprotein and vitamin K metabolism were identified as potential determinants of circulating phylloquinone. Further investigation with a larger sample is warranted to verify our initial findings and identify other loci contributing to circulating phylloquinone. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits

OBJECTIVE Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations. RESEARCH DESIGN AND METHODS We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. RESULTS We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m2 higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h). CONCLUSIONS Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

Associations of the MCM6-rs3754686 proxy for milk intake in Mediterranean and American populations with cardiovascular biomarkers, disease and mortality: Mendelian randomization.

Controversy persists on the association between dairy products, especially milk, and cardiovascular diseases (CVD). Genetic proxies may improve dairy intake estimations, and clarify diet-disease relationships through Mendelian randomization. We meta-analytically (n ≤ 20,089) evaluated associations between a lactase persistence (LP) SNP, the minichromosome maintenance complex component 6 (MCM6)-rs3754686C>T (nonpersistence>persistence), dairy intake, and CVD biomarkers in American (Hispanics, African-American and Whites) and Mediterranean populations. Moreover, we analyzed longitudinal associations with milk, CVD and mortality in PREDIMED), a randomized Mediterranean diet (MedDiet) intervention trial (n = 7185). The MCM6-rs3754686/MCM6-rs309180 (as proxy), LP-allele (T) was strongly associated with higher milk intake, but inconsistently associated with glucose and lipids, and not associated with CVD or total mortality in the whole population. Heterogeneity analyses suggested some sex-specific associations. The T-allele was associated with higher CVD and mortality risk in women but not in men (P-sex interaction:0.005 and 0.032, respectively), mainly in the MedDiet group. However, milk intake was not associated with CVD biomarkers, CVD or mortality either generally or in sub-groups. Although MCM6-rs3754686 is a good milk intake proxy in these populations, attributing its associations with CVD and mortality in Mediterranean women to milk is unwarranted, as other factors limiting the assumption of causality in Mendelian randomization may exist.

PRKCZ methylation is associated with sunlight exposure in a North American but not a Mediterranean population

Sunlight exposure has been shown to alter DNA methylation patterns across several human cell-types, including T-lymphocytes. Since epigenetic changes establish gene expression profiles, changes in DNA methylation induced by sunlight exposure warrant investigation. The purpose of this study was to assess the effects of sunlight exposure on CD4+ T-cell methylation patterns on an epigenome-wide scale in a North American population of European origin (n = 991). In addition, we investigated the genetic contribution to epigenetic variation (methylQTL). We used linear regression to test the associations between methylation scores at 461 281 cytosine-phosphate-guanine (CpG) sites and sunlight exposure, followed by a genome-wide association analysis (methylQTL) to test for associations between methylation at the top CpG locus and common genetic variants, assuming an additive genetic model. We observed an epigenome-wide significant association between sunlight exposure and methylation status at cg26930596 (p = 9.2 × 10−8), a CpG site located in protein kinase C zeta (PRKCZ), a gene previously shown to be entrained by light. MethylQTL analysis resulted in significant associations between cg26930596 and two intergenic single nucleotide polymorphisms on chromosome 3, rs4574216 (p = 1.5 × 10−10) and rs4405858 (p = 1.9 × 10−9). These common genetic variants reside downstream of WWTR1, a transcriptional co-activator of PRKCZ. Associations observed in the North American population, however, did not replicate in an independent Mediterranean cohort. Our preliminary results support the role of sunlight exposure in epigenetic processes, and lay the groundwork for future studies of the molecular link between sunlight and physiologic processes such as tumorigenesis and metabolism.

A Multinational Arab Genome-Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis.

Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome‐wide association study (GWAS) was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab‐specific genetic loci.

Actigraphic sleep fragmentation, efficiency and duration associate with dietary intake in the Rotterdam Study.

Short self‐reported sleep duration is associated with dietary intake and this association may partly mediate the link between short sleep and metabolic abnormalities. Subjective sleep measures, however, may be inaccurate and biased. The objective of this study was to evaluate the associations between actigraphic measures of sleep fragmentation, efficiency and duration and energy and macronutrient intakes. We used data from a subgroup of 439 participants of the population‐based cohort, Rotterdam Study. Sleep was assessed using 7‐day actigraphy and sleep diaries, and dietary data with a validated food frequency questionnaire. We assessed the associations of actigraphic sleep parameters with dietary intake using multivariable linear regression models. Higher sleep fragmentation was associated with 4.19 g lower carbohydrate intake per standard deviation of fragmentation {β [95% confidence interval (CI) = −4.19 (−8.0, −0.3)]; P = 0.03}. Each additional percentage increase in sleep efficiency was associated with 11.1 kcal lower energy intake [β (95% CI) = −11.1 (−20.6, −1.7); P = 0.02]. Furthermore, very short sleep duration (<5.5 h) was associated with 218.1 kcal higher energy intake [β (95% CI = 218.06 (33.3, 402.8), P = 0.02], relative to the reference group (≥6.5 to <7.5 h). We observed associations between higher sleep fragmentation with lower carbohydrate intake, and both lower sleep efficiency and very short sleep duration (<5 h) with higher energy intake. The association between sleep and higher energy intake could mediate, in part, the link between short sleep or sleep fragmentation index and metabolic abnormalities.

Macronutrient Intakes in Infancy Are Associated with Sleep Duration in Toddlerhood

BACKGROUND Dietary composition has been associated with sleep indexes. However, most of the evidence is based on cross-sectional data, and studies in young children are lacking. OBJECTIVE The aim of this study was to explore the longitudinal associations of macronutrient composition of the diet with sleep duration and consolidation (number of awakenings) in infancy and early childhood. METHODS The study was performed in 3465 children from the Generation R Study, a population-based cohort study in the Netherlands. Mothers reported their childs food intake at 13 mo of age by using a validated food-frequency questionnaire and their childs sleep patterns at 2 and 3 y of age. We used nutrient substitution models to assess the associations of relative macronutrient intakes with sleep indexes and adjusted the models for sociodemographic and lifestyle factors. RESULTS Isocaloric substitution of fat intake by protein or carbohydrate in infancy was associated with longer total sleep duration at 2 but not 3 y of age. For each 5% increase in energy intake of either protein or carbohydrate at the expense of fat, sleep duration at 2 y of age was longer by 6 min (95% CI: 0.4, 12 min) and 4 min (95% CI: 2, 6 min), respectively. Further exploration of macronutrient subtypes indicated no consistent differences between saturated or unsaturated fat and that intake of plant compared with animal protein or Trp did not explain the association of higher total protein intake with longer sleep duration at 2 y of age. Replacing unsaturated with saturated fat was associated with 7 min (95% CI: -13, -1 min) shorter total sleep duration at 3 y of age. Macronutrient intakes were not associated with sleep consolidation. CONCLUSIONS Our results suggest that the macronutrient composition of the diet is associated with sleep duration in young children. Future research should further study the causality of this association and explore the underlying mechanisms.