ABSTRACT
Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. However, the genetic variants that contribute to temporal control of glucose levels have not been previously examined. Using data from 420,000 individuals from the UK Biobank and replicating our findings in 100,000 individuals from the Estonian Biobank, we show that diurnal serum glucose is under genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B) (rs10830963, P = 1e-22) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1e-16). Furthermore, we show that sleep modulates serum glucose levels and the genetic variants have a separate mechanism of diurnal control. Finally, we show that these variants independently modulate risk of type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight variation at MTNR1B and CRY2 as temporal regulators for glucose levels.
ABSTRACT
Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active 5-h, mid-point most active 10-h, sleep fragmentation, and efficiency) on HbA1c/glucose in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 146,806). Cross-trait linkage disequilibrium score regression was applied to determine genetic correlations across accelerometer-derived, self-reported sleep traits, and HbA1c/glucose. We found no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Phenotypic and genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. These findings suggested accelerometer-derived sleep traits do not affect HbA1c. Accelerometer-derived measures of sleep duration and quality might not simply be 'objective' measures of self-reported sleep duration and insomnia, but rather captured different sleep characteristics.
Subject(s)
Accelerometry , Blood Glucose , Glycated Hemoglobin , Mendelian Randomization Analysis , Sleep , Humans , Glycated Hemoglobin/analysis , Glycated Hemoglobin/metabolism , Sleep/genetics , Sleep/physiology , Blood Glucose/analysis , Male , Female , Middle Aged , Adult , Self Report , Aged , Sleep Initiation and Maintenance Disorders/geneticsABSTRACT
BACKGROUND: Home parenteral nutrition (HPN) is often cycled nocturnally and is expected to result in glucose intolerance and sleep disruption partly due to circadian misalignment. This study aimed to define the metabolic response when HPN is cycled during the daytime compared to overnight. METHODS: This secondary analysis leveraged samples from a clinical trial in adults with short bowel syndrome consuming HPN (ClinicalTrials.gov: NCT04743960). Enrolled patients received 1 week of HPN overnight followed by 1 week of HPN during the daytime. Fasting blood samples were collected following each study period and global metabolic profiles were examined from plasma samples. Differential metabolite abundance was determined from normalized and scaled data using adjusted Linear Models for MicroArray Data models followed by pathway enrichment analysis. RESULTS: Nine patients (mean age, 52.6 years; 78% female; mean BMI 20.7 kg/m2) provided samples. Among 622 identified metabolites, changes were observed in 36 metabolites at Punadj < 0.05 with higher abundance of fatty acids, long-chain and polyunsaturated fatty acids (Dihomo-gamma-linolenic acid, arachidonate (20:4n6), docosahexaenoate (DHA; 22:6n3)) and glycerolipids with daytime infusions. Enrichment analysis identified changes in pathways related to the biosynthesis of unsaturated fatty acids, d-arginine, and d-ornithine metabolism, and linoleic acid metabolism (Punadj<0.05). CONCLUSION: Daytime infusions of HPN may result in changes in circulating lipids and amino acid composing metabolic pathways previously implicated in circadian rhythms. As this is the first untargeted metabolomics study of HPN, larger studies are needed.
Subject(s)
Metabolomics , Parenteral Nutrition, Home , Short Bowel Syndrome , Humans , Female , Male , Middle Aged , Short Bowel Syndrome/therapy , Short Bowel Syndrome/blood , Adult , Circadian Rhythm/physiologyABSTRACT
Infusions of home parenteral nutrition (HPN) are often cycled at night coinciding with sleep episodes. Adult consumers of HPN are known to experience poor sleep attributed to frequent awakenings and long durations of wakefulness after falling asleep. Consequently, most consumers do not meet recommendations for sleep duration and quality or daytime napping. The primary underlying pathophysiology resulting in sleep problems is nocturia; however, other factors also exist, including disruptions caused by medical equipment (ie, pump alarms), comorbid conditions, dysglycemia, and medication use. Early guidance on sleep is imperative because of the central role of sleep in physical health and wellbeing, including mitigating complications, such as infection risk, gastrointestinal problems, pain sensitivity, and fatigue. Clinicians should routinely inquire about the sleep of their patients and address factors known to perturb sleep. Nonpharmacologic opportunities to mitigate sleep problems include education on healthy sleep practices (ie, sleep hygiene); changes in infusion schedules, volumes, rates, and equipment; and, possibly, behavioral interventions, which have yet to be examined in this population. Addressing comorbid conditions, such as mood disorders, and nutrition deficiencies may also help. Pharmacologic interventions and technological advancement in HPN delivery are also needed. Research on sleep in this population is considered a priority, yet it remains limited at this time.
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Background: Consumers of overnight home parenteral nutrition (HPN) often experience sleep disruption; however, existing healthy sleep recommendations are widely inapplicable to consumers. Objectives: The aim of this mixed-methods, community-based participatory research study was to develop tailored recommendations on healthy sleep practices for HPN consumers. Methods: The multipart study involved the following: 1) an initial draft of sleep recommendations based on the evaluation of existing general sleep hygiene guidelines by an expert panel of clinicians and consumers with lived experience; 2) semi-structured focus groups with consumers and clinicians; 3) pre- and post-knowledge tests completed by consumers, and 4) final approval of the recommendations by the expert panel. Results: The literature synthesis resulted in 51 recommendations evaluated for relevance for HPN consumers. Focus groups with 20 HPN consumers and clinicians contributed additional recommendations based on lived experience. Ultimately, the final resource included recommendations spanning 4 sections: getting ready for bed, preparing the bedroom for sleep, daytime behaviors, and overall strategies for better sleep. Of the 36 recommendations, 58% were derived from existing general sleep hygiene guidelines, and the remaining 42% addressed sleep challenges experienced uniquely by consumers, including nocturnal polyuria, noise/light from medical equipment, and infusion schedules. Knowledge tests completed by 10 additional consumers indicated a modest increase in sleep health knowledge. Conclusions: The curated healthy sleep resource tailored for HPN consumers was facilitated by a multidisciplinary expert panel, a strategic collaboration with members of the HPN community and their clinicians, and in partnership with patient advocacy and support organizations. The wide distribution of these resources may improve the overall well-being of HPN consumers.
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A wealth of data is available from electronic health records (EHR) that are collected as part of routine clinical care in hospitals worldwide. These rich, longitudinal data offer an attractive object of study for the field of circadian medicine, which aims to translate knowledge of circadian rhythms to improve patient health. This narrative review aims to discuss opportunities for EHR in studies of circadian medicine, highlight the methodological challenges, and provide recommendations for using these data to advance the field. In the existing literature, we find that data collected in real-world clinical settings have the potential to shed light on key questions in circadian medicine, including how 24-hour rhythms in clinical features are associated with-or even predictive of-health outcomes, whether the effect of medication or other clinical activities depend on time of day, and how circadian rhythms in physiology may influence clinical reference ranges or sampling protocols. However, optimal use of EHR to advance circadian medicine requires careful consideration of the limitations and sources of bias that are inherent to these data sources. In particular, time of day influences almost every interaction between a patient and the healthcare system, creating operational 24-hour patterns in the data that have little or nothing to do with biology. Addressing these challenges could help to expand the evidence base for the use of EHR in the field of circadian medicine.
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BACKGROUND: Patients receiving home parenteral nutrition (HPN) are known to experience psychological distress and have profoundly disrupted sleep. The aim of this analysis was to examine the relationship between sleep patterns with depressive symptoms and HPN characteristics. METHODS: The study was a secondary analysis of cross-sectional data examining sleep patterns using subjective and objective measures. Sleep was assessed by surveys and 7-day actigraphy. The Patient Health Questionnaire-8 was used to evaluate depressive symptoms. Participants provided information on HPN. Spearman correlations were calculated between sleep measures with depressive symptoms and HPN characteristics. Correlations were further examined in multivariable linear regression models. RESULTS: Thirty-two adults (age = 53 years; 75% female; 94% White) were included. Lower sleep quality (r = 0.54-0.60; P < 0.001) and later sleep timing (r = -0.35; P = 0.049) were correlated with higher depressive symptoms. Sleep patterns were also correlated with several HPN characteristics (r = -0.47 to 0.51). In linear regression models, rate of infusion was associated with sleep duration (ß = -0.004 [0.002] h; P = 0.046) in which each 100 mL/h was associated with 24-min shorter duration. Higher total energy was associated with lower sleep quality (ß = 0.0004 [0.0002] log-unit; P = 0.042), and higher volume was associated with longer sleep onset latency (ß = 0.0006 [0.0003] log-min; P = 0.049). CONCLUSIONS: We provide evidence supporting the link between poor and later sleep with higher depressive symptoms and identify potentially modifiable infusion characteristics (notably, slower rate of infusion and lower total energy and volume) that, on further verification, may support sleep among those receiving HPN.
Subject(s)
Depression , Parenteral Nutrition, Home , Sleep Quality , Sleep , Humans , Female , Cross-Sectional Studies , Middle Aged , Male , Parenteral Nutrition, Home/psychology , Sleep/physiology , Adult , Aged , Actigraphy , Sleep Wake Disorders/psychology , Sleep Wake Disorders/etiology , Surveys and Questionnaires , Linear ModelsABSTRACT
Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, and together may provide a more complete picture of sleep health, while also illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p<8.3e-9), along with 341 previously reported loci (p<5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h2=0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections to behavioral, psychological, and cardiometabolic traits.
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Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on diseases has yet to be fully elucidated. Using the Mass General Brigham Biobank, we aimed to examine the association of multidimensional sleep with health outcomes and investigate whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health outcomes. First, we generated a Polygenic Sleep Health Score using previously identified single nucleotide polymorphisms for sleep health and constructed a Sleep Lifestyle Index using data from self-reported sleep questions and electronic health records; second, we performed phenome-wide association analyses between these indexes and clinical phenotypes; and third, we analyzed the interaction between the indexes on prevalent mental health outcomes. Fifteen thousand eight hundred and eighty-four participants were included in the analysis (mean age 54.4; 58.6% female). The Polygenic Sleep Health Score was associated with the Sleep Lifestyle Index (ß=0.050, 95%CI=0.032, 0.068) and with 114 disease outcomes spanning 12 disease groups, including obesity, sleep, and substance use disease outcomes (p<3.3×10-5). The Sleep Lifestyle Index was associated with 458 disease outcomes spanning 17 groups, including sleep, mood, and anxiety disease outcomes (p<5.1×10-5). No interactions were found between the indexes on prevalent mental health outcomes. These findings suggest that favorable sleep behaviors and genetic predisposition to healthy sleep may independently be protective of disease outcomes. This work provides novel insights into the role of multidimensional sleep on population health and highlights the need to develop prevention strategies focused on healthy sleep habits.
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BACKGROUND: While environmental factors play an important role in weight loss effectiveness, genetics may also influence its success. We examined whether a genome-wide polygenic score for BMI was associated with weight loss effectiveness and aimed to identify common genetic variants associated with weight loss. METHODS: Participants in the ONTIME study (n = 1210) followed a uniform, multimodal behavioral weight-loss intervention. We first tested associations between a genome-wide polygenic score for higher BMI and weight loss effectiveness (total weight loss, rate of weight loss, and attrition). We then conducted a genome-wide association study (GWAS) for weight loss in the ONTIME study and performed the largest weight loss meta-analysis with earlier studies (n = 3056). Lastly, we ran exploratory GWAS in the ONTIME study for other weight loss outcomes and related factors. RESULTS: We found that each standard deviation increment in the polygenic score was associated with a decrease in the rate of weight loss (Beta (95% CI) = -0.04 kg per week (-0.06, -0.01); P = 3.7 × 10-03) and with higher attrition after adjusting by treatment duration. No associations reached genome-wide significance in meta-analysis with previous GWAS studies for weight loss. However, associations in the ONTIME study showed effects consistent with published studies for rs545936 (MIR486/NKX6.3/ANK1), a previously noted weight loss locus. In the meta-analysis, each copy of the minor A allele was associated with 0.12 (0.03) kg/m2 higher BMI at week five of treatment (P = 3.9 × 10-06). In the ONTIME study, we also identified two genome-wide significant (P < 5×10-08) loci for the rate of weight loss near genes implicated in lipolysis, body weight, and metabolic regulation: rs146905606 near NFIP1/SPRY4/FGF1; and rs151313458 near LSAMP. CONCLUSION: Our findings are expected to help in developing personalized weight loss approaches based on genetics. CLINICAL TRIAL REGISTRATION: Obesity, Nutrigenetics, Timing, and Mediterranean (ONTIME; clinicaltrials.gov: NCT02829619) study.
Subject(s)
Body Mass Index , Genome-Wide Association Study , Obesity , Weight Loss , Adult , Female , Humans , Male , Middle Aged , Multifactorial Inheritance/genetics , Obesity/genetics , Polymorphism, Single Nucleotide , Weight Loss/geneticsABSTRACT
Importance: Observational studies have associated anorexia nervosa with circadian rhythms and sleep traits. However, the direction of causality and the extent of confounding by psychosocial comorbidities in these associations are unknown. Objectives: To investigate the association between anorexia nervosa and circadian and sleep traits through mendelian randomization and to test the associations between a polygenic risk score (PRS) for anorexia nervosa and sleep disorders in a clinical biobank. Design, Setting, and Participants: This genetic association study used bidirectional 2-sample mendelian randomization with summary-level genetic associations between anorexia nervosa (from the Psychiatric Genomics Consortium) and chronotype and sleep traits (primarily from the UK Biobank). The inverse-variance weighted method, in addition to other sensitivity approaches, was used. From the clinical Mass General Brigham (MGB) Biobank (n = 47â¯082), a PRS for anorexia nervosa was calculated for each patient and associations were tested with prevalent sleep disorders derived from electronic health records. Patients were of European ancestry. All analyses were performed between February and August 2023. Exposures: Genetic instruments for anorexia nervosa, chronotype, daytime napping, daytime sleepiness, insomnia, and sleep duration. Main Outcomes and Measures: Chronotype, sleep traits, risk of anorexia nervosa, and sleep disorders derived from a clinical biobank. Results: The anorexia nervosa genome-wide association study included 16â¯992 cases (87.7%-97.4% female) and 55â¯525 controls (49.6%-63.4% female). Genetic liability for anorexia nervosa was associated with a more morning chronotype (ß = 0.039; 95% CI, 0.006-0.072), and conversely, genetic liability for morning chronotype was associated with increased risk of anorexia nervosa (ß = 0.178; 95% CI, 0.042-0.315). Associations were robust in sensitivity and secondary analyses. Genetic liability for insomnia was associated with increased risk of anorexia nervosa (ß = 0.369; 95% CI, 0.073-0.666); however, sensitivity analyses indicated bias due to horizontal pleiotropy. The MGB Biobank analysis included 47â¯082 participants with a mean (SD) age of 60.4 (17.0) years and 25â¯318 (53.8%) were female. A PRS for anorexia nervosa was associated with organic or persistent insomnia in the MGB Biobank (odds ratio, 1.10; 95% CI, 1.03-1.17). No associations were evident for anorexia nervosa with other sleep traits. Conclusions and Relevance: The results of this study suggest that in contrast to other metabo-psychiatric diseases, anorexia nervosa is a morningness eating disorder and further corroborate findings implicating insomnia in anorexia nervosa. Future studies in diverse populations and with subtypes of anorexia nervosa are warranted.
Subject(s)
Anorexia Nervosa , Sleep Initiation and Maintenance Disorders , Female , Humans , Male , Middle Aged , Anorexia Nervosa/complications , Anorexia Nervosa/epidemiology , Anorexia Nervosa/genetics , Circadian Rhythm/genetics , Genetic Risk Score , Genome-Wide Association Study , Sleep , Adult , AgedABSTRACT
BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN. METHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement. RESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m2 , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL. CONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.
Subject(s)
Actigraphy , Sleep , Adult , Female , Humans , Middle Aged , Actigraphy/methods , Polysomnography/methods , Self Report , Sleep/physiology , Surveys and Questionnaires , MaleABSTRACT
BACKGROUND: Patients with short bowel syndrome (SBS) dependent on home parenteral nutrition (HPN) commonly cycle infusions overnight, likely contributing to circadian misalignment and sleep disruption. METHODS: The objective of this quasi-experimental, single-arm, controlled, pilot trial was to examine the feasibility, safety, and efficacy of daytime infusions of HPN in adults with SBS without diabetes. Enrolled patients were fitted with a continuous glucose monitor and wrist actigraph and were instructed to cycle their infusions overnight for 1 wk, followed by daytime for another week. The 24-h average blood glucose, the time spent >140 mg/dL or <70 mg/dL, and sleep fragmentation were derived for each week and compared using Wilcoxon signed-rank test. Patient-reported quality-of-life outcomes were also compared between the weeks. RESULTS: Twenty patients (mean age, 51.7 y; 75% female; mean body mass index, 21.5 kg/m2) completed the trial. Overnight infusions started at 21:00 and daytime infusions at 09:00. No serious adverse events were noted. There were no differences in 24-h glycemia (daytime-median: 93.00 mg/dL; 95% CI: 87.7-99.9 mg/dL, compared with overnight-median: 91.1 mg/dL; 95% CI: 89.6-99.0 mg/dL; P = 0.922). During the day hours (09:00-21:00), the mean glucose concentrations were 13.5 (5.7-22.0) mg/dL higher, and the time spent <70 mg/dL was 15.0 (-170.0, 22.5) min lower with daytime than with overnight HPN. Conversely, during the night hours (21:00-09:00), the glucose concentrations were 16.6 (-23.1, -2.2) mg/dL lower with daytime than with overnight HPN. There were no differences in actigraphy-derived measures of sleep and activity rhythms; however, sleep timing was later, and light at night exposure was lower with daytime than with overnight HPN. Patients reported less sleep disruptions due to urination and fewer episodes of uncontrollable diarrhea or ostomy output with daytime HPN. CONCLUSIONS: Daytime HPN was feasible and safe in adults with SBS and, compared with overnight HPN, improved subjective sleep without increasing 24-h glucose concentrations. This trial was registered at clinicaltrials.gov as NCT04743960 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04743960).
Subject(s)
Parenteral Nutrition, Home , Short Bowel Syndrome , Adult , Female , Humans , Male , Middle Aged , Glucose , Parenteral Nutrition, Home/adverse effects , Pilot Projects , Short Bowel Syndrome/therapy , SleepABSTRACT
BACKGROUND: Consumers of parenteral nutrition (PN) and their caregivers use social media to seek advice and support from their peers and to share experiences. We aimed to leverage posts from a social media patient community to identify common lived experiences of consumers of PN to prioritize opportunities for support through advocacy, education, and research. METHODS: Anonymous posts with high engagement were collected over 4 months from a PN-focused social media support group platform. No personal information was collected or analyzed. Post content was reviewed for demographic characteristics. Thematic analysis involved inductive coding to identify content-based keywords. Keywords were then used to form major themes and subthemes that were then quantified by post counts. RESULTS: A total of 306 social media posts were analyzed. Most were from adult PN consumers (80.4%) and pertained to home-based PN (82%). Equivalent number of posts (5%) were from new consumers and those who had not yet started or restarting PN. The analysis revealed 12 major themes with 2-11 subthemes each, spanning medical, nutrition, emotional, and social aspects. The most prevalent theme was "Best practices, care, and safety of PN use" (36.9%), covering posts seeking guidance on line care, personal hygiene, equipment use, and vascular access devices. Others included "Symptoms" (23.9%) and "Patient safety concerns of PN handling by healthcare providers" (16.0%). CONCLUSIONS: The identified themes provide a broader understanding of contemporary shared lived experiences and concerns relevant to PN consumers and their caregivers. Given the evolving nature of daily stressors, periodic reanalysis may be necessary.
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BACKGROUND: Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. METHODS AND RESULTS: We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6-9 hours), short (<6 hours), and long (>9 hours), and compared these with a nonsleepy, normal-sleep-duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2-sample Mendelian randomization for each outcome. Compared with healthy sleep, long-sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21-2.77]) during 8.2-year median follow-up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long-sleep EDS subtype in MI (inverse-variance weighted ß=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). CONCLUSIONS: Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long-sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.
Subject(s)
Cardiovascular Diseases , Disorders of Excessive Somnolence , Myocardial Infarction , Stroke , Humans , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Disorders of Excessive Somnolence/diagnosis , Disorders of Excessive Somnolence/epidemiology , Disorders of Excessive Somnolence/genetics , Sleep , Myocardial Infarction/epidemiology , Myocardial Infarction/genetics , Myocardial Infarction/complications , Stroke/diagnosis , Stroke/epidemiology , Stroke/geneticsABSTRACT
Background: Continuous glucose monitors (CGMs) provide high-frequency information regarding daily glucose variation and are recognised as effective for improving glycaemic control in individuals living with diabetes. Despite increased use in individuals with non-diabetic blood glucose concentrations (euglycemia), their utility as a health tool in this population remains unclear. Objectives: To characterise variation in time in range (TIR) and glycaemic variability in large populations without diabetes or impaired glucose tolerance; describe associations between CGM-derived glycaemic metrics and metabolic and cardiometabolic health traits; identify key diet and lifestyle factors associated with TIR and glycaemic variability. Design: Glycaemic variability (coefficient of variation) and time spent in both the ADA secondary target range (TIRADA; 3.9-7.8 mmol/L) and a more stringent range (TIR3.9-5.6; 3.9-5.6 mmol/L) were calculated during free-living in PREDICT 1, PREDICT 2, and PREDICT 3 euglycaemic community-based volunteer cohorts. Associations between CGM derived glycaemic metrics, markers of cardiometabolic health, diet (food frequency questionnaire and logged diet records), diet-habits, and lifestyle were explored. Results: Data from N=4135 participants (Mean SD; Age: 47 12 y; Sex: 83% Female, BMI: 27 6 kg/m2). Median glycaemic variability was 14.8% (IQR 12.6-17.6%), median TIRADA was 95.8% (IQR 89.6-98.6%) and TIR3.9-5.6 was 75.0% (IQR 64.6-82.8%). Greater TIR3.9-5.6 was associated with lower HbA1c, ASCVD 10y risk and HOMA-IR (all p < 0.05). Lower glycaemic variability was associated with lower % energy derived from carbohydrate (rs: 0.17, p < 0.01), ultra-processed foods (NOVA 4, % EI; rs: 0.12, p = 0.01) and a longer overnight fasting duration (rs: -0.10, p = 0.01). Conclusions: A stringent TIR target provides sensitivity to detect changes in HOMA-IR, ASCVD 10 y risk and HbA1c that were not detected using ADA secondary targets. Associations among TIR, glycaemic variability, dietary intake (e.g. carbohydrate and protein) and habits (e.g. nocturnal fasting duration) highlight potential strategic targets to improve glycaemic metrics derived from continuous glucose monitors.
ABSTRACT
This review explores the criteria used for the selection of genetic instruments of sleep traits in the context of Mendelian randomisation studies. This work was motivated by the fact that instrument selection is the most important decision when designing a Mendelian randomisation study. As far as we are aware, no review has sought to address this to date, even though the number of these studies is growing rapidly. The review is divided into the following sections which are essential for genetic instrument selection: 1) Single-gene region vs polygenic analysis; 2) Polygenic analysis: biologically-vs statistically-driven approaches; 3) P-value; 4) Linkage disequilibrium clumping; 5) Sample overlap; 6) Type of exposure; 7) Total (R2) and average strength (F-statistic) metrics; 8) Number of single-nucleotide polymorphisms; 9) Minor allele frequency and palindromic variants; 10) Confounding. Our main aim is to discuss how instrumental choice impacts analysis and compare the strategies that Mendelian randomisation studies of sleep traits have used. We hope that our review will enable more researchers to take a more considered approach when selecting genetic instruments for sleep exposures.