Background: Diabesity defines the concurrent manifestation of type 2 diabetes (T2D) and obesity (BMI≥30 kg/m 2 ) in the development of cardiovascular diseases, although the genetic basis for this joint phenotype remain poorly understood. Objective: This study aimed to identify the overlapping genetic patterns for diabesity incidence in 3,231 self-reported African American (AA) and 8,252 European Americans (EA) participated in four cohorts of the Trans-Omics for Precision Medicine (TOPMed) consortium. Methods: Using marker set enrichment analysis (MSEA) of whole genome sequencing data, specific gene sets (pathways) and key driver (KD) genes (important hub genes overrepresented in a network of pathways) were identified for diabesity incidence. Using multi-tissue and multi-species gene expression signatures as molecular indicators of drug functions, their potential drug signatures were also examined. Results: Testing genome-wide significance (P-value < 10 -8 ) identified seven independent loci, six of which were replicated in the T2D Knowledge Portal (https://t2d.hugeamp.org/ )( NPFFR1, TRIO, G6PD, BCL11A, IGF1, and TCF7L2, P<0.05) for diabetes and/or such obesity-related traits as blood pressure, lipids, glucose and insulin levels. One novel variant for diabesity, rs144540309, is an intronic region of GPAT3 (G>A, AA MAF = 0.004, beta=3.66 and P=1.00e-8) whose enzyme plays important roles in dietary lipid absorption, enteric and hepatic lipid homeostasis, and entero-endocrine hormone production, along with 12 KEGG/Reactome/Biocarta pathways enriched for diabesity in AAs and 11 for EAs. In AAs, the top three pathways (ranked by P-value and false discovery rate [FDR]) were mitotic spindle checkpoint, resolution of sister chromatid cohesion, and rho GTPases activate formins, along with six KD genes ( NCKAP1L, CDCA8 , BUB1 , IRF5 , FYB , and C15orf23 ); in EAs, colorectal cancer, prostate cancer, and beta Catenin independent WNT signaling were the top 3 pathways (FDR≤0.25) including LEF1 . Top repositioned drugs derived from diabesity-related gene sets (FDR≤0.25) included Benzbromarone, Fenofibrate, Interleukin-1β, and antihypertensive. Conclusion: Our study supports the notion that both pathway and network-based analytical approaches may identify novel signals from gene sets for highly clustering clinical phenotypes such as diabetes and obesity and improve their target validation for intervention.

Background To investigate the association between walking pace and the risk of heart failure (HF) and HF sub-types. Methods We examined associations of self-reported walking pace with risk of incident HF and HF subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fractions, among 25,183 postmenopausal women, ages 50-79 years. At enrollment into the Women's Health Initiative cohort in 1993-1998, this subset of women was free of HF, cancer, or the inability to walk one block, with self-reported information on walking pace and walking duration. Multivariable Cox regression was used to examine associations of walking pace (casual <2 mph [referent], average 2-3 mph, and fast >3 mph) with incident HF. We also examined the joint association of walking pace and duration with incident HF. Results There were 1455 incident adjudicated acute decompensated HF hospitalization cases during a median of 16.9 years of follow-up. There was a strong inverse association between walking pace and overall risk of HF (HR = 0.73, 95% CI [0.65, 0.83] for average vs. casual walking; HR = 0.66, 95%CI [0.56, 0.78] for fast vs. casual walking). There were similar associations of walking pace with HFpEF (HR = 0.73, 95%CI [0.62, 0.86] average vs. casual; HR = 0.63, 95%CI [0.50, 0.80] for fast vs. casual) and with HFrEF (HR = 0.72, 95%CI [0.57, 0.91] for average vs. casual; HR = 0.74, 95%CI [0.54, 0.99] for fast vs. casual). The risk of HF associated with fast walking with less than 1 h/week walking duration was comparable with the risk of HF among casual and average walkers with more than 2 h/week walking duration. Conclusion Walking pace was inversely associated with risks of overall HF, HFpEF, and HFrEF in postmenopausal women. Whether interventions to increase the walking pace in older adults will reduce HF risk and whether fast pace will compensate for the short duration of walking warrants further study.

ObjectivesWestudied associations between social support, social network size, social strainor stressful life events and risk of coronary heart disease (CHD) in postmenopausalwomen with type 2 diabetes. Research Designand MethodsFrom the Women’s Health Initiative, 5,262 postmenopausalwomen with type 2 diabetes at baseline were included. Cox proportional hazardsregression models adjusted for demographics, depressive symptom, anthropometricvariables, and lifestyle factors were used to examine associations betweensocial factors and CHD. ResultsAtotal of 672 cases of CHD were observed during an average 12.79 (SD 6.29) yearsof follow-up. There was a significant linear trend toward higher risk of CHD asnumber of stressful life events increased (p for trend=0.01; HR [95% CI] for thethird and fourth quartiles compared with first quartile = 1.27 [1.03-1.56] and1.30 [1.04-1.64]). Being married or in an intimate relationship was related todecreased risk of CHD [HR and 95% CI 0.82 (0.69-0.97)]. ConclusionAmong postmenopausal women with type 2diabetes, higher levels of stressful life events were associated with higher riskof CHD. Experience of stressful life events might be considered as a riskfactor for CHD among women with type 2 diabetes.

Background and Purpose: The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. Methods: Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. Results: Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79x10(-)(6)). Pathway analysis of the top 517 genes (P0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P2.05x10(-7)), several were near, including an intronic variant in LEXM (rs7549251; P=4.08x10(-)(7)) and an exonic variant in TRAPPC11 (rs67383011; P=5.19x10(-)(6)). Conclusions: Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

Study Objectives: Activities throughout the day, including sleep, sedentary behavior (SB), light-intensity physical activity (LIPA), and moderate to vigorous physical activity (MVPA) are independently associated with cardiometabolic health. Few studies have examined interrelationships between sleep and 24-hour activity and associations with cardiometabolic risk. The objective of this study is to understand how replacing time in SB, LIPA, or MVPA with sleep impacts cardiometabolic risk. Methods: Women's Health Initiative OPACH Study participants (N = 3329; mean age = 78.5 +/- 6) wore ActiGraph GT3X+ accelerometers 24 hours/7 days. Adjusted linear regression estimated the relationship between sleep duration and cardiometabolic markers. Separately for shorter (<8 hours) and longer (>= 8 hours) sleepers, isotemporal substitution models estimated the cross-sectional associations with cardiometabolic markers with reallocating time in daytime activities to or from sleep. Results: Longer sleep duration was associated with higher insulin, HOMA-IR, glucose, total cholesterol, and triglycerides (all p < 0.05). The associations between sleep duration and C-reactive protein, waist circumference, and body mass index (BMI) were U-shaped (both p < 0.05). For shorter sleepers, reallocating 33 minutes of MVPA to sleep was associated with higher values of insulin, HOMA-IR, glucose, triglycerides, waist circumference, and BMI (0.7%-11.5%). Replacing 91 minutes of SB time with sleep was associated with lower waist circumference and BMI (-1.3%, -1.8%). For long sleepers, shifting 91 minutes of sleep to SB was associated with higher waist circumference and BMI (1.3%, 1.4%). Conclusions: This is one of the first isotemporal analyses to include objectively measured sleep duration. Results illuminate possible cardiometabolic risks and benefits of reallocating time to or from sleep.

Background: Cerebral small vessel disease accounts for ~25-30% of strokes and is a leading cause of age- and hypertension-related cognitive decline and disability. Specific treatments for cerebral small vessel disease are lacking, and therapeutic options for secondary prevention are limited as compared to other common causes of stroke. Identifying stroke-associated protein coding variants is a promising tool to better understand disease etiology and identify novel targets. Methods: The GEOS Study was initiated as a biracial population-based study of cases with first-ever ischemic stroke 15 to 49 years of age and controls. All participants had prior GWAS and underwent Illumina exome-chip genotyping. Logistic regression analysis was conducted to identify associated variants after accounting for population substructure using Principal Component Analysis based on GWAS array data. Gene-based aggregation testing (SKAT) and meta-analysis were performed using seqMeta with ethnicity-specific GWAS PCs. Covariates for these analyses included age and gender. This was followed by Ingenuity Pathway Analyses on the top genes. Results: Gene-based testing using a filter (cumulative MAC>40, # of SNPs per gene≥2, missingness=0) was performed on 7448 genes in 123 small vessel cases and 727 non-stroke controls. Two genes reached exome wide statistical significance (p<6.7*10 -6 ) in the meta-analyses: FNDC9 (Fibronectin type III domain containing 9, p=9.2*10 -7 ) and ASXL1 (ASXL Transcriptional Regulator 1, p=3.4*10 -7 ). Although no individual SNPs reached genome-wide significance (3x10 -7 ), a rare missense variant in ASXL1 (MAF=0.02, p=3.5*10 -6 ) was near the threshold. ASXL1 SNPs have been associated with an increased risk of CVD. Pathway analyses of the top 438 genes (p<0.05) from the gene-based results identified the nuclear receptor signaling pathway related to lipid/glucose metabolism, and the neurotransmitter glutamate receptor signaling and neurodevelopment notch signaling pathways. Efforts to replicate these findings in independent data sets are ongoing. Conclusion: Exome-based analyses of small vessel young-onset ischemic stroke is a promising methodology to identify novel genetic risk variants, genes and pathways.

ObjectiveTo examine the associations of dietary and supplemental magnesium (Mg) as assessed by a semi-quantitative food frequency questionnaire with cognitive outcomes among ageing women.DesignThis work conducts a prospective cohort study of participants enrolled in the Women’s Health Initiative Memory Study (WHIMS), which was subsequently extended and named WHIMS-Epidemiology of Cognitive Health.SettingForty clinical centres in the USA.ParticipantsPostmenopausal women aged 65–79 years without dementia on enrolment.Main outcome measuresPhysician-adjudicated mild cognitive impairment (MCI) and/or probable dementia (PD).ResultsParticipants were excluded (n=1006) if they had extreme values of dietary energy intake, had missing or extreme body mass index values, with prevalent MCI/PD at baseline, received only one cognitive assessment or had been followed up for <1 year. During >20 years of follow-up, 765 (11.8%) out of 6473 participants developed MCI/PD. For MCI/PD and MCI, the risks tended to be lower among participants in quintiles Q2–Q5 of Mg consumption compared with those in the lowest quintile. Participants in Q3 had a significantly lower risk of MCI/PD (HR 0.69, 95% CI 0.53 to 0.91) and MCI (HR 0.63, 95% CI 0.45 to 0.87) after multivariate adjustments. No significant association was observed between total Mg intake and PD. The association between total Mg intake, MCI/PD and MCI was non-linear as suggested by the likelihood test.ConclusionsTotal Mg intake between the estimated average requirement and the recommended dietary allowances may associate with a lower risk of MCI/PD and MCI.Trial registration numberNCT00685009.

Background: Sleep, sedentary behavior (SB), and physical activity (PA) are independently associated with cardiometabolic health, but few studies have examined the interrelationships between 24 hour activity and cardiometabolic risk factors. Extending sleep may be a feasible cardiometabolic risk reduction strategy; however, research is needed to understand how replacing time in SB and/or PA with sleep impacts cardiometabolic risk. Methods: Women’s Health Initiative participants in the OPACH Study (N=3329; mean age=78.5±6) wore ActiGraph GT3X+ accelerometers 24 hours/day for up to 7 days. Sleep duration was derived using a validated protocol. Adjusted regression models estimated the relationship between sleep duration and cardiometabolic markers. Separately for shorter (<8 hours) and longer (≥8 hours) sleepers, isotemporal substitution models estimated the change in cardiometabolic risk markers associated with reallocating time in daytime activity (SB, light PA (LIPA), moderate to vigorous (MVPA)) to or from sleep. Results: Longer sleep duration was significantly associated with higher insulin, HOMA-IR, total cholesterol, triglycerides, and Reynolds Risk Score (RRS) (all p < 0.05). For shorter sleepers, reallocating 33 minutes of MVPA to sleep was associated with significantly higher values of insulin, HOMA-IR, triglycerides, waist circumference, and RRS (0.9%-11.4%) (Figure 1). Replacing 91 minutes of SB time with sleep was associated with significantly lower waist circumference (-1%). In longer sleepers, reallocating 74 minutes from sleep to LIPA was associated with significantly lower values of insulin, HOMA-IR, trigylcerides, and waist circumference (-1.4% - -12.3%). Conclusions: This is one of the first isotemporal analysis to include objectively measured sleep duration. Results illuminate possible cardiometabolic risks and benefits of reallocating time to or from sleep duration.

Background: The genetic architecture of ischemic stroke (IS) is poorly understood and may differ by age of onset. To identify stroke susceptibility variants, genes and pathways for IS in young adults, we genotyped participants in the Genetics of Early-Onset Stroke (GEOS) with an exome array to interrogate the protein-coding portion of genes. Methods: The GEOS Study was initiated as a biracial population-based study of cases with first-ever ischemic stroke 15 to 49 years of age (n=828) and controls (n=850). All participants had prior GWAS and underwent Illumina exome-chip genotyping. Mixed model regression in EMMAX was conducted to calculate variant-specific associations using pooled European-Caucasians (EUR) and African-Americans (AA) samples, with population structure controlled by kinship matrix relationships using GWAS data. Gene-based burden testing and meta-analysis were performed using seqMeta with ethnicity-specific GWAS PCs. In both analyses covariates included age and gender. This was followed by Ingenuity Pathway Analyses on the top genes. Results: While no individual SNPs reached chip-wide significance (3x10 -7 ), several were near, including one exonic variant in TRAPPC11 (rs67383011, p=1.7*10 -6 ). Gene-based burden testing using a filter (cumulative MAC>40, # of SNPs per gene≥2, missingness=0) was performed on 6934 genes in EURs and 9423 genes in AAs. While several interesting genes were identified, notably in methylation pathways, none reached statistical significance in the ethnicity-stratified (p=3.3*10 -4 ) or meta-analyses (p=1.1*10 -4 ). Pathway analyses on the top 448 genes (p<0.05) from the gene-based results identified several metabolism and signaling pathways, including: (1) those implicated in the risk for vascular diseases: glucose metabolism, lipid metabolism, and inflammation (leukocyte extravasation, IL-17A); (2) neurotrophic signaling: CTNF and NGF, and; (3) neurotransmitter and neuroactive compound signaling: GABA receptor signaling and tryptophan degradation pathways. Efforts in additional data sets to replicate these findings are ongoing. Conclusion: Exome-based analyses in the setting of early-onset stroke is a promising methodology to identify novel genetic risk variants, loci and pathways.

ABSTRACT Purpose Leisure-time physical activity (LTPA) is a well-established modifiable lifestyle determinant for multiple cardiometabolic outcomes. However, current understanding of the genetic architecture that may determine LTPA remains very limited. Therefore, we aimed to examine the role of genetic factors in affecting LTPA, which has yet to be investigated comprehensively and in-depth. Methods We conducted a genomewide analysis using 1000 Genomes Project imputed data from the Women’s Health Initiative ( n = 11,865), the Jackson Heart Study ( n = 3015), and the Framingham Heart Study ( n = 7339). A series of secondary analyses, including candidate gene analysis, sequence kernel association tests, pathway analysis, functional annotation, and expression quantitative trait loci analysis, were performed to follow-up on the primary findings. Results Ethnicity-specific genetic signals were investigated, respectively, for African Americans and European Americans. Two variants, rs116550874 (meta-analysis: P = 1.63 × 10 −7 ) and rs3792874 (meta-analysis: P = 8.33 × 10 −7 ), were associated with LTPA in African Americans; rs28524846 (meta-analysis: P = 1.30 × 10 −6 ) was identified for EA. We also replicated four previously reported loci ( GABRG3 , CYP19A1 , PAPSS2 , and CASR ; P for lead single nucleotide polymorphisms < 0.005). Further fine-mapping and functional annotation suggested that several identified loci (novel and replicated) are involved in 1) the homeostatic drive coupled with the reward system and 2) the development and regulation of the capacity to perform LTPA. Conclusions To our knowledge, our analysis is the first to comprehensively investigate the genomewide signals for LTPA in multiple ethnicities. These findings support the notion that genetic predisposition plays a critical role in determining LTPA, of which the biological and clinical implications warrants further investigation.

Sucrose nonfermenting-related kinase (SNRK) is a member of the AMPK-related kinase family, and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white adipose tissue (WAT) and brown adipose tissue (BAT), but SNRK expression diminishes in adipose tissue in obesity. In this study we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival; SNRK globally deficient pups die within 24 h after birth. Heterozygous mice are characterized by inflamed WAT and less BAT. Adipocyte-specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impaired adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, higher body weight, and insulin resistance. We further confirm the significant association of common variants of the SNRK gene with obesity risk in humans. Through applying a phosphoproteomic approach, we identified eukaryotic elongation factor 1δ and histone deacetylase 1/2 as potential SNRK substrates. Taking these data together, we conclude that SNRK represses WAT inflammation and is essential to maintain BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated metabolic disorders.

Limited evidence suggests that hyperinsulinemia may contribute to the risk of breast, endometrial, and, possibly, ovarian cancer. The aim of this study was to assess the association of serum glucose and insulin with risk of these cancers in postmenopausal women, while taking into account potential confounding and modifying factors. We studied 21103 women with fasting baseline insulin and glucose measurements in a subsample of the Women's Health Initiative. The subsample was composed of four studies within Women's Health Initiative with different selection and sampling strategies. Over a mean of 14.7 years of follow-up, 1185 breast cancer cases, 156 endometrial cancer cases, and 130 ovarian cancer cases were diagnosed. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) by quartile of glucose or insulin. Serum insulin was positively associated with breast cancer risk (multivariable-adjusted HR for highest vs. lowest quartile 1.41, 95% CI: 1.16-1.72, P-trend<0.0003), and glucose and insulin were associated with roughly a doubling of endometrial cancer risk (for glucose: HR: 2.00, 95% CI: 1.203.35, P-trend=0.01; for insulin: HR: 2.39, 95% CI: 1.32-4.33, P-trend=0.008). These associations remained unchanged or were slightly attenuated after mutual adjustment, adjustment for serum lipids, and assessment of possible reverse causation. Glucose and insulin showed no association with ovarian cancer. Our findings provide support for a role of insulin-related pathways in the etiology of cancers of the breast and endometrium. However, because of the unrepresentative nature of the sample, our results need confirmation in other populations. Copyright (c) 2018 Wolters Kluwer Health, Inc. All rights reserved.

Studies have found an inverse relationship between the risk of heart failure hospitalization and physical activity. This study aims at exploring the association between walking pace (speed), walking frequency and duration and the risk of acute hospitalized HF (HHF). Study participants were women 50

Purpose of Review Physical activity (PA) is a well-established modifiable lifestyle determinant for multiple cardio-metabolic outcomes. While many psychosocial and environmental correlates of PA have been identified, current understanding of the genetic architecture that contributes to PA is still very limited, especially when compared to other phenotypes such as obesity and diabetes. Recent Findings This review systematically and comprehensively assesses available evidence from animal experiments, family studies, population-based candidate gene analyses, and genome-wide association studies (GWAS) studying the genetics of physical activity patterns. It discusses the scientific evolution in the field of PA genetics, including the recognition of increased sample sizes, the shift from early family-based approaches to association-based design, and the rapidly advancement of enabling genotyping and sequencing technologies. In addition, this review points to the gaps in the current knowledge base, including the general lack of GWAS and whole-genome sequence analyses particularly understudied populations, and the need for large-scale collaborative effort in both observational and experimental settings. In this review, we also call for research utilizing systems biology strategies for PA genetic research and accounting for complex gene-environment interactions that may vary by race/ethnicity. Summary The epidemic of physical inactivity has been a public health nemesis, encompassing a large burden of diseases and high societal costs. A better understanding of the genetic basis of PA can inform public health policies for the prevention, control, and treatment of many chronic diseases related to physical inactivity.

Introduction: Leisure time physical activity (LTPA) has been associated with high-density lipoprotein (HDL) cholesterol and cardiometabolic health, but whether it is related to HDL subspecies remai...

BackgroundLow circulating levels of sex hormone-binding globulin (SHBG) have been shown to be a direct and strong risk factor for type 2 diabetes, cardiovascular diseases, and hormone-dependent cancers, although the relationship between various aspects of dietary carbohydrates and SHBG levels remains unexplored in population studies. MethodsAmong postmenopausal women with available SHBG measurements at baseline (n=11159) in the Women's Health Initiative, a comprehensive assessment was conducted of total dietary carbohydrates, glycemic load (GL), glycemic index (GI), fiber, sugar, and various carbohydrate-abundant foods in relation to circulating SHBG levels using multiple linear regressions adjusting for potential covariates. Linear trend was tested across quartiles of dietary variables. Benjamini and Hochberg's procedure was used to calculate the false discovery rate for multiple comparisons. ResultsHigher dietary GL and GI (both based on total and available carbohydrates) and a higher intake of sugar and sugar-sweetened beverages were associated with lower circulating SHBG concentrations (all P-trend< 0.05; Q-values= 0.04,0.01, 0.07, 0.10, 0.01, and <0.0001, respectively). In contrast, women with a greater intake of dietary fiber tended to have elevated SHBG levels (P-trend=0.01, Q-value=0.04). There was no significant association between total carbohydrates or other carbohydrate-abundant foods and SHBG concentrations. ConclusionsThe findings suggest that low GL or GI diets with low sugar and high fiber content may be associated with higher serum SHBG concentrations among postmenopausal women. Future studies investigating whether lower GL or GI diets increase SHBG concentrations are warranted.

Globally, individuals with chronic diseases now consume over 80% of all healthcare resources. Set against this depressing projection is decades of epidemiologic work demonstrating that 80%-90% of cardiovascular disease can be prevented via lifestyle and dietary interventions. How can we reconcile such contrasting views toward the future of cardiovascular health in human populations? Herein, we review available sources of evidence that can be used to answer these challenging questions of how and why. In particular, we submit that analytical framework incorporating the 6P (prediction, precision, personalization, prevention, population, and policy)-3G (good food, good environment, and good behavior)-4I (interpretation, integration, implementation, and innovation) will allow us to focus resource towards the development of multi-level approaches for the betterment of population