Publications

BACKGROUND: Individuals with an evening chronotype often experience circadian misalignment, which may disrupt health behaviors and cardiometabolic functions.

METHODS: We conducted a prospective study in 322 777 UK Biobank participants aged 39 to 74 years free of known cardiovascular disease (CVD). Chronotype was self-reported using a single representative question. The Life's Essential 8 (LE8) score was calculated from 8 CVD risk factors and ranged from 0 to 100 with higher scores indicating better cardiovascular health. Incident CVD was defined as first myocardial infarction or stroke. Cox proportional hazards models estimated the association between chronotype and CVD risk, adjusted for sociodemographics, shift work, and family history of CVD. We evaluated the role of LE8 in the chronotype-CVD association by decomposing the total effect into natural direct effect (independent of LE8) and natural indirect effect (mediated by LE8).

RESULTS: Participants with a "definite evening" chronotype were associated with 79% higher prevalence of an overall poor LE8 score (<50 points) compared with "intermediate" type (95% CI, 1.72-1.85). Over a median 13.8 years of follow-up, there were 17 584 incident CVD events (11 091 myocardial infarction; 7214 stroke). The hazard ratio (HR) for total CVD was 1.03 (95% CI, 0.998-1.07) for the "definite morning" and 1.16 (95% CI, 1.10-1.22) for "definite evening" compared with "intermediate" chronotype (P-trend: 0.10). LE8 explained 75% of the association between evening chronotype and CVD (natural indirect effect comparing "definite evening" with "intermediate": HR, 1.11 [95% CI, 1.09-1.13]).

CONCLUSIONS: Our findings suggest that individuals with an evening chronotype may particularly benefit from interventions targeting CVD risk factors.

RATIONALE: Obstructive sleep apnoea (OSA) is a prevalent disorder with major health consequences for which there is no approved pharmacological therapy targeting upper airway muscle pathophysiology. A combination of a noradrenergic (atomoxetine) and antimuscarinic (oxybutynin) (AtoOxy) may meaningfully reduce apnoea-hypopnoea index (AHI), but further repeated-dose intervention data are needed.

METHODS: 58 participants with moderate-to-severe OSA were randomised to receive AtoOxy (80/5 mg) and placebo in a 1-month cross-over study. Primary analysis quantified the effect of AtoOxy versus placebo on AHI (percent change from baseline). Individual pathophysiology was characterised at baseline in a stand-alone gold-standard physiology study to determine whether OSA traits (collapsibility per 'Pcrit'; arousal threshold and muscle effectiveness per intraoesophageal catheter; loop gain) modified AtoOxy effectiveness.

RESULTS: AHI was lowered by -23.8 (-35.2, -10.6)%baseline (estimate (95% CI)) with AtoOxy versus by -11.7 (-24.3, 2.9)%baseline with placebo; the treatment difference of -12.1 (-22.4, -0.5)%baseline was significant (p=0.041). Only arousal threshold was a significant modifier of response: AtoOxy treatment effect was greater in high versus low arousal threshold (-25 vs +3 %baseline treatment difference from placebo). Point-estimate treatment differences were observed within low but not high muscle effectiveness (-20 vs -4 %baseline) and mild but not severe collapsibility (-17 vs -7 %baseline). Sensitivity analysis suggested a twofold greater treatment difference using AHI4 (4% hypopnoea criteria).

CONCLUSIONS: AtoOxy reduced AHI over 1 month; although the average response was not clinically meaningful, greater improvements were observed in participants with a higher arousal threshold, lower muscle effectiveness and milder collapsibility, which could enable targeted pharmacological intervention.

RATIONALE: As the global population ages, identifying risk factors for age-related diseases, such as COPD, is crucial for public health. Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mosaicism event, but its relationship with pulmonary health remains undercharacterized.

OBJECTIVES: To examine the association between mLOY and pulmonary outcomes in men.

METHODS: Leveraging mLOY assessment (cell fraction ≥ 5%) in over 12 000 men, including 5097 from the COPDGene Study and 7235 from six additional cohorts in the Trans-Omics for Precision Medicine program, we investigated mLOY associations with respiratory outcomes and epigenetic aging using multivariable cross-sectional, longitudinal, and prospective models. Primary outcomes included spirometry, CT-based emphysema, and epigenetic pace of aging.

RESULTS: The prevalence of mLOY increased with age. Cross-sectionally, mLOY was associated with airflow obstruction, with reduced FEV1/FVC of 0.018 [95% CI, -0.030 to -0.006] in COPDGene and 0.020 [95% CI, -0.027 to -0.013] in TOPMed. mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Longitudinally, mLOY was associated with faster FEV1 decline (∼55mL/year vs ∼38mL/year). Prospectively, mLOY was associated with higher odds of developing COPD [OR = 1.84, 95% CI, 1.10-3.07] and preserved ratio impaired spirometry (PRISm) [OR = 2.87, 95% CI, 1.09-7.56] among participants with normal lung function at baseline. Associations remained robust after adjusting for clonal hematopoiesis and telomere length.

CONCLUSIONS: mLOY is associated with lower lung function, accelerated lung function decline, higher emphysema, and faster pace of aging, positioning mLOY as a potential biomarker of respiratory aging in men.

UNLABELLED: Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations.

ARTICLE HIGHLIGHTS: We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.

STUDY OBJECTIVES: Sleep is critical for maintaining overall brain health and may influence the trajectory of cognitive impairment. Using a multidimensional conceptualization of sleep, we hypothesized that data-derived multidimensional sleep composites would be associated with cognitive performance.

METHODS: Data from four examinations (2010-2024) in the Multi-Ethnic Study of Atherosclerosis were used to examine cross-sectional and longitudinal associations between multimodal sleep and cognition. Multidimensional sleep composites were derived from 39 objective and subjective sleep variables using principal components analysis (PCA). Cognition was measured using a global cognition composite (GCC), a standardization of total scores across Digit Symbol Coding (DSC), Digit Span (DS), and Cognitive Abilities Screening Instrument (CASI). Linear regression analyzed cross-sectional associations between sleep composites and cognition, and linear mixed-effects models examined associations with within-person cognitive change over time.

RESULTS: In cross-sectional analyses of 1,628 participants (mean age 68.0; 54.9% female), 13 sleep composites explained about 71% of the sample's variance. After adjusting for demographic and lifestyle factors, five sleep composites were associated with GCC cross-sectionally: (1) EEG power spectral density (ß (per SD) = 0.065; 95% CI 0.03-0.10), (2) actigraphy based sleep continuity (ß = 0.049; 0.01-0.08), (3) spindle density (ß = 0.052; 0.02-0.09), (4) spindle-slow oscillation coupling (ß = 0.050; 0.01-0.09), and (5) REM sleep (ß = 0.047; 95% CI 0.01-0.08) In the longitudinal analysis, actigraphy based sleep continuity and variability were associated with cognitive decline, although significance decreased after multiple comparison adjustment.

CONCLUSIONS: EEG-based sleep microstructure and actigraphy-based sleep continuity were associated with cognitive performance cross-sectionally, while actigraphy-based sleep continuity was associated with cognition longitudinally. These findings support a multidimensional framework for understanding sleep-related risk factors for cognitive decline.

BACKGROUND AND OBJECTIVES: Late-life dementia has a strong heritable component. While the APOE ɛ4 allele is the strongest genetic risk factor of Alzheimer disease (AD), polygenic risk factors also play a significant role. Cardiometabolic diseases (CMDs) and their risk factors predict dementia in many cohorts, but how genetic predictors of CMD influence dementia-related outcomes remains unclear. In this study, we examined the associations of polygenic risk scores (PRSs) for major CMDs and the established APOE risk alleles with dementia-related outcomes in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is enriched for Black participants underrepresented in late-life dementia research.

METHODS: We constructed PRSs for AD and related dementias (ADRDs) and CMDs, including stroke, coronary artery disease, venous thromboembolism, type 2 diabetes, atrial fibrillation, blood pressure (systolic blood pressure, diastolic blood pressure, and pulse pressure), and circulating lipid levels (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides), using lead genome-wide significant genetic variants from the latest genome-wide association studies. We evaluated the predictive performance of each PRS on their primary end point and tested their associations with incident cognitive impairment (ICI), assessed using the 6-item screener and enhanced cognitive battery, and dementia as a contributing cause of death (DCCD). In addition, we explored the impact of APOE variants and, based on previous reports, local genetic ancestry at the APOE locus on these dementia-related outcomes.

RESULTS: Up to 8,818 participants were analyzed (mean age 63.7 years; 58.9% female; 83.3% Black). For CMD PRS, we identified a significant association between PRS for pulse pressure and DCCD (hazard ratio [HR] 1.16, 95% CI 1.06-1.28, p < 1.76 × 10-3). We observed that the PRS for ADRD was associated nominally with DCCD (HR 1.12, 95% CI 1.00-1.25), but not with ICI among REGARDS participants, suggesting heterogeneity in associations across different cognitive-related end points. Furthermore, we identified a nominally significant (p < 0.1) attenuated effect of APOE risk alleles on ICI among those with African ancestry at the APOE locus, similar to previous reports.

DISCUSSION: Higher PRS for pulse pressure was associated with increased DCCD risk, supporting shared genetic underpinnings between CMD and dementia.

AIMS: To determine whether baseline atherosclerotic cardiovascular disease (ASCVD) modifies the blood pressure (BP) response to mandibular advancement device (MAD) vs. continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA).

METHODS AND RESULTS: This prespecified secondary analysis of the CRESCENT randomized controlled trial included adults with moderate-to-severe OSA and elevated cardiovascular risk, randomized 1:1 to MAD or CPAP. Outcomes were evaluated according to ASCVD status. The primary outcome was the between-group difference in 24-h ambulatory BP at 6 months. Analyses used ANCOVA models adjusted for baseline BP, with treatment-by-ASCVD interaction testing. Secondary outcomes included excessive daytime sleepiness and circulating cardiovascular biomarkers. Among the 220 participants (median age 61 years, 85.5% male), 145 (66%) had ASCVD. In the ASCVD group, MAD was associated with greater reductions than CPAP in 24-h systolic BP (-3.41 mmHg; 95% CI -6.56 to -0.27; P = 0.028), 24-h mean BP (-2.50 mmHg; 95% CI -4.90 to -0.11; P = 0.040), asleep systolic BP (-5.13 mmHg; 95% CI -9.36 to -0.91; P = 0.018), and asleep mean BP (-3.97 mmHg; 95% CI -7.31 to -0.62; P = 0.021). No significant between-treatment differences were observed in the non-ASCVD group. A significant treatment-by-ASCVD interaction was observed for asleep systolic BP (P = 0.034). Treatment effects on daytime sleepiness and cardiovascular biomarkers were similar across ASCVD subgroups and across treatment groups.

CONCLUSION: In patients with OSA and ASCVD, MAD was associated with greater reductions in ambulatory BP than CPAP. Formal evidence of differential treatment effect by ASCVD status was strongest for asleep systolic BP. These findings suggest that patients with OSA and ASCVD may derive greater BP benefit from MAD compared with CPAP.

Bioactive fatty acid-derived oxylipin molecules play key roles mediating inflammation and oxidative stress. Circulating levels of fatty acids and oxylipins are influenced by environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biology. We performed a genome-wide association study (GWAS) of 81 fatty acids and oxylipins in 11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years (standard deviation 13.8)). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Thirty-three of the 81 oxylipins and fatty acids were significantly heritable (heritability range: 0-32.7%). Forty (49.4%) oxylipins and fatty acids had at least one genome-wide significant (p < 6.94E-11) variant resulting in 19 independent genetic loci. Six loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including desaturase-encoding FADS and OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with two or more fatty acids and oxylipins. At several of these loci, there was evidence of colocalization of the top variant across fatty acids and oxylipins. The remaining loci were only associated with one oxylipin or fatty acid and included several CYP loci. We also identified an additional rare variant (MAF = 0.002) near CARS2 in two-degree-of-freedom tests. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating work to characterize these compounds and elucidate their roles in disease.

BACKGROUND: Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep-related phenotypes and blood metabolites.

METHODS: Utilising data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep-related phenotypes, grouped in several domains (sleep disordered breathing (SDB), sleep duration, sleep timing, self-reported insomnia symptoms, excessive daytime sleepiness (EDS), and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualise and interpret the associations between sleep phenotypes and metabolites.

FINDINGS: The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, primary bile acid metabolism showed the highest cumulative percentage of statistically significant associations across all sleep phenotype domains except for SDB and EDS phenotypes. Several metabolites were associated with multiple sleep phenotypes, from a few domains. Glycochenodeoxycholate, vanillyl mandelate (VMA) and 1-stearoyl-2-oleoyl-GPE (18:0/18:1) were associated with the highest number of sleep phenotypes, while pregnenolone sulfate was associated with all sleep phenotype domains except for sleep duration. N-lactoyl amino acids such as N-lactoyl phenylalanine (lac-Phe), were associated with sleep duration, SDB, sleep timing and heart rate during sleep.

INTERPRETATION: This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.

FUNDING: R01HL161012, R35HL135818, R01AG80598.

IMPORTANCE: Apolipoprotein B (apoB) distribution and its implications as an atherosclerotic cardiovascular disease (ASCVD) risk-enhancing factor among individuals of diverse Hispanic or Latino backgrounds have not been described.

OBJECTIVE: To describe the distribution of apoB in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort and to characterize associations of baseline sociodemographic and clinical variables with apoB and self-identified Hispanic or Latino background.

DESIGN, SETTING, AND PARTICIPANTS: The HCHS/SOL was a prospective, population-based cohort study of diverse Hispanic or Latino adults living in the US who were recruited and screened between March 2008 and June 2011. Sampling weights were used to generate a population-based sample of Hispanic or Latino participants aged 18 to 74 years who resided in 4 US metropolitan areas (Bronx, New York; Chicago, Illinois; Miami, Florida; and San Diego, California). ApoB concentration was measured in participants from the HCHS/SOL, and apoB tertiles were compared across demographic groups, including self-identified Hispanic or Latino background. Median percentage continental genetic ancestry (West African, Amerindian, and European) was compared across apoB tertiles.

EXPOSURE: ApoB measured in mg/dL from serum or plasma using an immunoturbidimetric assay.

MAIN OUTCOMES AND MEASURES: ApoB tertiles were determined, and traditional lipids were evaluated across apoB tertiles. ApoB and traditional lipid measurements were assessed across ASCVD risk categories. Additionally, scatterplots were created to observe correlations between apoB and low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol.

RESULTS: Overall mean (SD) apoB concentration was 99.8 (0.4) mg/dL, with male participants displaying significantly higher mean levels than female participants (102.4 vs 97.4 mg/dL, respectively). Mean (SD) participant age was 41.1 (0.8) years, and 8376 participants (51.9%) were female. ApoB levels were higher among older age groups. There was significant heterogeneity in mean apoB concentrations across self-identified Hispanic or Latino background groups, ranging from 95.1 mg/dL in Dominican individuals to 104.8 mg/dL in Cuban individuals. The prevalence of elevated apoB (≥130 mg/dL) was greater across higher predicted ASCVD risk categories. Among participants with a 10-year predicted ASCVD risk of 7.5% or higher, 26.5% had an elevated apoB. Median West African ancestry was lower across higher tertiles of apoB.

CONCLUSIONS AND RELEVANCE: In this cohort study among participants from the HCHS/SOL, elevated apoB was present in one-quarter of a diverse cohort study of Hispanic or Latino individuals who were at intermediate or high predicted ASCVD risk. Differences in apoB distribution among Hispanic or Latino individuals may have important implications for apoB's use in ASCVD risk assessment.