Simin Liu

Although numerous evidences suggest that zinc may have a beneficial impact on preventing and treating diabetes, findings from the population studies are inconclusive. To address this gap, we conducted a nested case-control study, employing restricted cubic splines and a conditional logistic regression model to explore the association between serum zinc levels and the risk of diabetes. We also assessed potential effect modifications through stratified analyses and examined the mediating effects of metabolic indicators using a multiclass mediation effect model. We measured baseline serum zinc concentrations using Inductively Coupled Plasma Mass Spectrometry in a cohort of 2156 participants, including 1078 individuals with diabetes and 1078 matched controls. Our findings revealed a 51 % increased risk of diabetes when comparing the highest quartile (Q4) to the lowest quartile (Q1) of serum zinc levels …

BACKGROUNDType 2 diabetes mellitus (T2D) confers a two-to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.METHODSFrom 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level …

ObjectiveThe purpose of this study was to determine whether sleep characteristics are associated with incidence of treated diabetes in postmenopausal individuals.MethodsPostmenopausal participants ages 50-79 years reported sleep duration, sleep-disordered breathing, or insomnia at baseline and again in a subsample 3 years later. The primary outcome was self-reported new diagnosis of diabetes treated with oral drugs or insulin at any time after baseline. Multivariable Cox proportional hazards models were used.ResultsIn 135,964 participants followed for 18.1 (± 6.3) years, there was a nonlinear association between sleep duration and risk of treated diabetes. Participants sleeping ≤5 hours at baseline had a 21% increased risk of diabetes compared with those sleeping 7 hours (adjusted hazard ratio [aHR] 1.21; 95% confidence interval [CI], 1.00-1.47). Those who slept for ≥9 hours had a nonsignificant 6 …

INTRODUCTION Alzheimer's disease (AD) and AD‐related dementias (ADRD) are leading causes of death among older adults in the United States. Efforts to understand risk factors for prevention are needed. METHODS Participants (n = 146,166) enrolled in the Women's Health Initiative without AD at baseline were included. Diabetes status was ascertained from self‐reported questionnaires and deaths attributed to AD/ADRD from hospital, autopsy, and death records. Competing risk regression models were used to estimate the cause‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the prospective association of type 2 diabetes mellitus (T2DM) with AD/ADRD and non‐AD/ADRD mortality. RESULTS There were 29,393 treated T2DM cases and 8628 AD/ADRD deaths during 21.6 (14.0–23.5) median (IQR) years of follow‐up. Fully adjusted HRs (95% CIs) of the association with T2DM were 2 …

BackgroundEstimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period.Methods22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 …

BackgroundAlthough gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established.ObjectiveThis study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women.Study DesignThe Women’s Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with …

BackgroundMuch remains unknown regarding the associations of adversities in childhood and adulthood with incident cardiovascular diseases (CVD). We aimed to examine the independent and cumulative relations of adversities in childhood and adulthood with incident CVD and whether these associations can be mitigated by adopting a healthy lifestyle later in life.MethodsWe included 136,073 men and women [38–72 years at baseline] free of diagnosed CVD at baseline who responded to surveys on adversities in childhood and adulthood in the United Kingdom Biobank prospective cohort. They were recruited between 2006 and 2010 and were followed-up until 28 January 2021. Adversities included physical abuse, emotional abuse, sexual abuse, emotional neglect, and physical neglect. Participants were categorised into four groups according to the exposure periods, which were no adversity, childhood …

BackgroundThere is debate over whether the glycaemic index of foods relates to chronic disease. We aimed to assess the associations between glycaemic index (GI) and glycaemic load (GL) and type 2 diabetes, cardiovascular disease, diabetes-related cancers, and all-cause mortality.MethodsWe did a meta-analysis of large cohorts (≥100 000 participants) identified from the Richard Doll Consortium. We searched the Cochrane Library, MEDLINE, PubMed, Embase, Web of Science, and Scopus for cohorts that prospectively examined associations between GI or GL and chronic disease outcomes published from database inception to Aug 4, 2023. Full-article review and extraction of summary estimates data were conducted by three independent reviewers. Primary outcomes were incident type 2 diabetes, total cardiovascular disease (including mortality), diabetes-related cancers (ie, bladder, breast, colorectal …

BackgroundA substantial observational literature relating specific fatty acid classes to chronic disease risk may be limited by its reliance on self-reported dietary data.ObjectivesWe aimed to develop biomarkers for saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acid densities, and to study their associations with cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) in Women’s Health Initiative (WHI) cohorts.MethodsBiomarker equations were based primarily on serum and urine metabolomics profiles from an embedded WHI human feeding study (n = 153). Calibration equations were based on biomarker values in a WHI nutritional biomarker study (n = 436). Calibrated intakes were assessed in relation to disease incidence in larger WHI cohorts (n = 81,894). Participants were postmenopausal women, aged 50–79 when enrolled at 40 United States Clinical Centers (1993 …

INTRODUCTION Whether apolipoprotein E's (APOE’s) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. METHODS Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low‐density lipoprotein [LDL], high‐density lipoprotein [HDL], non‐HDL cholesterol, total‐to‐HDL, LDL‐to‐HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 postmenopausal women from the Women's Health Initiative Memory Study. We also examined associations of baseline dietary cholesterol and fat with lipids based on APOE status. RESULTS After an average of 11.13 years, less favorable lipid levels related to greater dementia and cognitive impairment risk. Dementia (odds ratio [OR] = 3.13; 95% confidence interval [CI]: 2.31 to 4.24) and cognitive …

Demographic and clinical factors influence the metabolome. The discovery and validation of disease biomarkers are often challenged by potential confounding effects from such factors. To address this challenge, we investigated the magnitude of the correlation between serum and urine metabolites and demographic and clinical parameters in a well-characterized observational cohort of 444 post-menopausal women participating in the Women’s Health Initiative (WHI). Using LC-MS and lipidomics, we measured 157 aqueous metabolites and 756 lipid species across 13 lipid classes in serum, along with 195 metabolites detected by GC-MS and NMR in urine and evaluated their correlations with 29 potential disease risk factors, including demographic, dietary and lifestyle factors, and medication use. After controlling for multiple testing (FDR < 0.01), we found that log-transformed metabolites were mainly associated with age, BMI, alcohol intake, race, sample storage time (urine only), and dietary supplement use. Statistically significant correlations were in the absolute range of 0.2–0.6, with the majority falling below 0.4. Incorporation of important potential confounding factors in metabolite and disease association analyses may lead to improved statistical power as well as reduced false discovery rates in a variety of data analysis settings.

Modest and sustained weight loss has been shown to reduce the need for glucose-lowering medications and improve glycemic control in overweight and obese individuals with type 2 diabetes (1–3). Still, these individuals face challenges in achieving and maintaining weight control due to a plethora of metabolic, psychological, and behavioral factors (4, 5). The use of liquid meal replacements within a structured dietary plan may offer a viable solution. Liquid meal replacements provide a mixture of carbohydrates, fat, and protein, along with added vitamins and minerals, in ready-to-drink form or powder formulas that require mixing. They are frequently used to replace one or two main meals each day, or in some cases, all meals (ie, total diet replacement [TDR]). Current gaps in this area of research include identifying the type of formulations and complimentary aspects of a dietary program that yield long-term weight loss maintenance, reduce cardiometabolic risk, and increase the odds of diabetes remission in overweight and obese patients with type 2 diabetes. In this special issue in the Frontiers of Endocrinology, we comment on three key perspective articles that outline (1) the role for diabetes-specific nutrition formulas (DNSFs) as meal replacements in type 2 diabetes management (6),(2) lessons learned from the Diabetes Remission Clinical Trial (DiRECT) which demonstrated diabetes remission with the use of TDR followed by structured food reintroduction and long-term weight loss maintenance (7), and (3) use of meal replacements as a temporary option to induce weight loss followed by transition to a dietary pattern that aligns with the …

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women’s Health Initiative (n = 85,356) were used to examine the association between personal history of being born preterm (born 1910–1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds …

BackgroundType 2 diabetes is a major public health concern in the United States and worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) are tools that assess dietary inflammation. Previous evidence suggests that obesity can modify the association between inflammation and disease.ObjectiveThe aim of this study was to evaluate the association between the DII/E-DII and incident diabetes in self-identified Hispanic women from the Women’s Health Initiative (WHI). The secondary aim was to evaluate whether obesity modifies the association between the DII/E-DII scores and incident diabetes.DesignParticipants were from the WHI Observational Study and the Clinical Trial Components (except women from the treatment arm in the Dietary Modification Trial) conducted among postmenopausal women in the United States. DII/E-DII scores were calculated from a self-administered food …

Background Cardiometabolic comorbidities have been associated with a higher risk of COVID‐19 severity and mortality, but more investigations are needed to determine which comorbidity is more detrimental. Methods Embase, Emcare, and MEDLINE were searched systematically for prospective and retrospective studies assessing the associations of cardiometabolic risk factors and COVID‐19 outcomes of hospitalization, severity, and mortality among COVID‐19‐diagnosed patients. Literature search was performed from first publication to May 19, 2021. Study quality was assessed by the Newcastle‐Ottawa Scale. Results From the literature search, 301 studies suggested that all included cardiometabolic risk factors were associated with a higher risk of COVID‐19 hospitalization, severity, and mortality, except that overweight was associated with a decreased risk of mortality (relative risk [RR] 0.88; 95% CI, 0.80 …

Background:Sickle cell trait affects∼ 8% of African American individuals, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including end-stage kidney disease. The mechanisms underlying these associations remain poorly understood. We utilized proteomic profiling to gain insight into the pathobiology of sickle cell trait.Methods:We measured proteomics (N= 1,285 proteins assayed by Olink Explore) using baseline plasma samples from 592 African American participants with sickle cell trait and 1: 1 age-matched African American participants without sickle cell trait from the prospective Women’s Health Initiative (WHI) cohort. Age-adjusted linear regression was used to assess the association between protein levels and …

ImportanceNeonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.ObjectiveTo test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Design, Setting, and ParticipantsMendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.ExposuresGenetic scores for BMI, fasting glucose level, type …

Background The role of sex hormone-binding globulin (SHBG) levels in clinical risk stratification and intervention for coronary heart disease (CHD) remains uncertain. We aimed to examine whether circulating levels of SHBG are predictive of CHD risk in men and women. Methods We investigated the association between SHBG and the risk of incident CHD in 128 322 men and 135 103 women free of CHD at baseline in the prospective United Kingdom Biobank (UKB) cohort. The unconfounded associations were estimated using Mendelian randomization (MR) analysis. We further conducted a meta-analysis to integrate currently available prospective evidence. CHD events included nonfatal and fatal myocardial infarction and coronary revascularization. Results In the UKB, during a median of 11.7 follow-up years, 10 405 men and 4512 women developed …

Background and Objectives The Portfolio Diet is a plant-based dietary pattern of established cholesterol-lowering foods. The diet has been shown to improve a number of cardiovascular disease (CVD) risk factors, including low-density lipoprotein cholesterol (LDL-C), blood pressure, and C-reactive protein (CRP) in clinical trials, and has been associated with lower CVD incidence in a prospective cohort. As yet, there have not been any large prospective studies directly assessing the relation of the Portfolio Diet to total and CVD mortality. Methods We followed 109,445 postmenopausal women initially free of CVD, diabetes, and cancer in the Women's Health Initiative (WHI) Clinical Trials and Observational Study from 1993 to 2021. Adherence to the Portfolio diet was assessed using an a priori diet index based on six food categories (high in plant protein [soy & pulses], nuts, viscous fiber, phytosterols and monounsaturated fat, and low in saturated fat and dietary cholesterol) via a food frequency questionnaire at baseline and year three. Adjusted hazard ratios (HRs) and 95% confidence intervals [CIs] for CVD incidence and death and total mortality were calculated using Cox regressions, adjusted for potential confounders (including age, race/ethnicity, family history, lifestyle and dietary factors, and medication use). Results Over a mean of 17.4 years of follow-up, there were 11,597 cases of incident total CVD, 4,695 cases of coronary heart disease (CHD), 4,215 cases of stroke, 7,624 cases of CVD death, and 28,162 total deaths. Comparing the highest to the lowest quartile in the fully adjusted model, higher adherence to the Portfolio diet was …

INTRODUCTION—Clonal hematopoiesis (CH) refers to a genetically distinct subpopulation of myeloid cells, which share an acquired (ie, not inherited) mutation that distinguishes them from other tissues and unaffected hematopoietic cells. CH may be detected in healthy individuals with few or no hematologic manifestations; although clonality is also a feature of myelodysplastic syndromes, acute leukemias, and myeloproliferative neoplasms, these malignancies are generally associated with substantial hematologic findings.

The assessment of risks associated with environmental exposure to metals/metalloids requires well-established reference values for each population since it varies considerably according to distinct local/regional characteristics. However, very few studies establish baseline values for these elements (essential and toxic) in large population groups, especially in Latin American countries. This study was aimed at establishing urinary reference levels of 30 metals/metalloids: aluminum (Al), antimony (Sb), arsenic (As), barium (Ba), beryllium (Be), cadmium (Cd), cerium (Ce), cesium (Cs), chromium (Cr), cobalt (Co), copper (Cu), lanthanum (La), lead (Pb), lithium (Li), strontium (Sr), manganese (Mn), mercury (Hg), molybdenum (Mo), nickel (Ni), platinum (Pt), rubidium (Rb), selenium (Se), silver (Ag), tin (Sn), tellurium (Te), thallium (Tl), thorium (Th), tungsten (W), uranium (U) and zinc (Zn) in a Brazilian southeast adult …

The assessment of risks associated with environmental exposure to metals/metalloids requires well-established reference values for each population since it varies considerably according to distinct local/regional characteristics. However, very few studies establish baseline values for these elements (essential and toxic) in large population groups, especially in Latin American countries. This study was aimed at establishing urinary reference levels of 30 metals/metalloids: aluminum (Al), antimony (Sb), arsenic (As), barium (Ba), beryllium (Be), cadmium (Cd), cerium (Ce), cesium (Cs), chromium (Cr), cobalt (Co), copper (Cu), lanthanum (La), lead (Pb), lithium (Li), strontium (Sr), manganese (Mn), mercury (Hg), molybdenum (Mo), nickel (Ni), platinum (Pt), rubidium (Rb), selenium (Se), silver (Ag), tin (Sn), tellurium (Te), thallium (Tl), thorium (Th), tungsten (W), uranium (U) and zinc (Zn) in a Brazilian southeast adult population. This pilot study is a cross-sectional analysis conducted with the first wave of the ELSA-Brasil cohort (baseline examination). A total of 996 adults (45.5% men, N= 453, mean age: 50.5, and 54.5% women, N= 543, mean age: 50.6) were included in the study. Sample analyses were performed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Percentiles (2.5, 10, 25, 50, 75, 95 (CI95%), and 97.5) of each element (mu g/g of creatinine) in the study are presented according to sex. Moreover, differences in the mean metal/metalloid urinary levels according to age, education, smoking, and alcohol intake are also presented. Finally, median found values were compared to established values of large human biomonitoring …

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P< 5× 10− 8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry …

Results: Plasma TMAO concentrations were (median [IQR]) 1.65 (1.12–2.44) μmol/L at age 1 year and 1.91 (1.32–2.70) μmol/L at age 2 years. TMAO concentrations did not differ by age, sex, or ethnicity. Plasma TMAO concentrations were unrelated to usual and recent egg and fish intakes. At age 1 year, TMAO concentrations were positively associated with usual intakes of phosphocholine (ρ= 0.205; P= 0.036) and sphingomyelin (ρ= 0.199; P= 0.042). At age 2 years, TMAO concentrations were positively associated with recent intakes of total choline (ρ= 0.210; P= 0.039) and phosphatidylcholine (ρ= 0.316; P= 0.002). TMAO concentrations were not associated with plasma choline metabolites.Conclusions: TMAO concentrations were not associated with egg or fish intake in toddlers. Positive associations between dietary choline intakes and TMAO concentrations were found, but were inconsistent among choline forms. Additional research is needed to confirm these findings in larger pediatric populations.

Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions …

Trivalent chromium is an essential micronutrient that participates in the regulation of insulin receptor signal transduction as well as carbohydrate and lipid metabolism. 1 Circulating levels of chromium decrease with age, 2 and in patients with insulin resistance and type 2 diabetes (T2D). 3 Previous studies have shown that intravenous chromium infusion can reduce insulin requirement and improve hyperglycemia in patients with severe insulin resistance. 4 However, findings from randomized controlled trials (RCTs) investigating the efficacy of oral chromium supplementation in reducing cardiometabolic risk factors have been inconsistent. To reconcile the inconsistencies in the literature regarding the role of chromium in the development of health outcomes and the contradictory recommendations for the optimal intake of chromium, we conducted a systematic review and meta-analysis of relevant RCTs via a novel …

Few studies have demonstrated reproducible gene–diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient–glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate …

OBJECTIVE A plant-based dietary pattern, the Portfolio Diet, has been shown to lower LDL cholesterol and other cardiovascular disease risk factors. However, no study has evaluated the association of this diet with incident type 2 diabetes. RESEARCH DESIGN AND METHODS This analysis included 145,299 postmenopausal women free of diabetes at baseline in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study from 1993 to 2021. Adherence to the diet was assessed with a score based on six components (high in plant protein [soy and pulses], nuts, viscous fiber, plant sterols, and monounsaturated fat and low in saturated fat and cholesterol) determined from a validated food-frequency questionnaire. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association of the Portfolio Diet, alongside the Dietary …

PurposePrenatal exposure to famine has been linked to increased diabetes risk in adulthood. However, one fundamental issue to be addressed is that the reported famine-diabetes relation may be confounded by the age differences between the exposed and non-exposed groups. We aimed to determine the association between prenatal exposure to the Chinese famine of 1959–1962 and risk of diabetes by applying age well-controlled strategies.MethodsAmong 20,535 individuals born in 1955–1966 who participated in the China Health and Nutrition Survey from 1997 to 2015, we constructed age-matched exposed vs. non-exposed groups to investigate the role of prenatal exposure to the Chinese famine of 1959–1962 in relation to diabetes. We also built a hierarchical age-period-cohort (HAPC) model to specifically examine the relation of famine to diabetes risk independent of age.ResultsCompared to the age …

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare “clumping-and-thresholding” (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity …

BackgroundThe Women’s Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here, we use WHI observational data for further insight into the chronic disease implications of adopting this type of low-fat dietary pattern.ObjectivesWe aimed to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction, to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error, and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately.MethodsProspective disease association results are presented using WHI cohorts of postmenopausal …

OBJECTIVE Observational studies have indicated that cocoa flavanol supplementation may be a promising strategy for type 2 diabetes (T2D) prevention. We aimed to directly evaluate its clinical efficacy in a large randomized clinical trial (RCT). RESEARCH DESIGN AND METHOD The Cocoa Supplement and Multivitamin Outcomes Study (COMSOS) was a 2 × 2 factorial RCT performed from June 2015 to December 2020 that tested cocoa extract and a multivitamin for the prevention of cardiovascular disease (CVD) and cancer. A total of 21,442 U.S. adults free of CVD and recent cancer, including 12,666 women aged ≥65 years and 8,776 men aged ≥60 years, were randomly assigned to receive cocoa extract [500 mg/day cocoa flavanols, including 80 mg (−)-epicatechin] or placebo. In this study, we included 18,381 participants without diabetes at enrollment and examined the …

BackgroundOver the past decade, DNA methylation (DNAm)-based deconvolution methods that leverage cell-specific DNAm markers of immune cell types have been developed to provide accurate estimates of the proportions of leukocytes in peripheral blood. Immune cell phenotyping using DNAm markers, termed immunomethylomics or methylation cytometry, offers a solution for determining the body’s immune cell landscape that does not require fresh blood and is scalable to large sample sizes. Despite significant advances in DNAm-based deconvolution, references at the population level are needed for clinical and research interpretation of these additional immune layers. Here we aim to provide some references for immune populations in a group of multi-ethnic post-menopausal American women.ResultsWe applied DNAm-based deconvolution to a large sample of post-menopausal women enrolled in the …

Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor …

As of April 2023, there have been six successful PDS releases of Mars 2020 data. The imaging data included in these releases are discussed.

BACKGROUND Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS Participants from the UK Biobank and Women’s Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause …

Background: Diabesity defines the concurrent manifestation of type 2 diabetes (T2D) and obesity (BMI≥30 kg/m2) 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 …

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called “PRSsum”, forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type …

OBJECTIVE Whether and how dietary protein intake is linked to type 2 diabetes (T2D) remains unclear. The aim of this study was to investigate the associations of protein intake with development of T2D and the potential mediating roles of T2D biomarkers. RESEARCH DESIGN AND METHODS We included 108,681 postmenopausal women without T2D at baseline from the Women’s Health Initiative (WHI) (primary cohort) and 34,616 adults without T2D from the U.K. Biobank (UKB) (replication cohort). Cox proportional hazard models were used for estimation of protein-T2D associations. Mediation analysis was performed to assess the mediating roles of biomarkers in case-control studies nested in the WHI. RESULTS In the WHI, 15,842 incident T2D cases were identified during a median follow-up of 15.8 years. Intake of animal protein was associated with …

Much remains unknown about the role of added sugar in relation to cardiovascular disease (CVD) and the relative contributions of sugar-sweetened beverages (SSB) or artificially sweetened beverages (ASB) to CVD risk. Among the 109,034 women who participated in Women’s Health Initiative, we assessed average intakes of added sugar, SSB and ASB, and conducted Cox regression to estimate the hazard ratios (HRs) and their 95% confidence intervals for CVD risk. The consistency of findings was compared to a network meta-analysis of all available cohorts. During an average of 17.4 years of follow-up, 11,597 cases of total CVD (nonfatal myocardial infarction, coronary heart disease (CHD) death, stroke, coronary revascularization, and/or incident heart failure) were confirmed. Added sugar as % energy intake daily (%EAS) at ≥15.0% was positively associated with total CVD (HR = 1.08 [1.01, 1.15]) and CHD (HR = 1.20 [1.09, 1.32]). There was also a higher risk of total CVD associated with ≥1 serving of SSB intake per day (HR = 1.29 [1.17, 1.42]), CHD (1.35 [1.16, 1.57]), and total stroke (1.30 [1.10, 1.53]). Similarly, ASB intake was associated with an increased risk of CVD (1.14 [1.03, 1.26]) and stroke (1.24 [1.04, 1.48]). According to the network meta-analysis, there was a large amount of heterogeneity across studies, showing no consistent pattern implicating added sugar, ASB, or SSB in CVD outcomes. A diet containing %EAS ≥15.0% and consuming ≥1 serving of SSB or ASB may be associated with a higher CVD incidence. The relative contribution of added sugar, SSB, and ASB to CVD risk warrants further investigation.

ObjectiveThe aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality.MethodsIn an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were …

Background Early-life exposures play key roles in the development of metabolic diseases. Whether such effects exist beyond one generation remains unclear. This study aimed to determine the transgenerational association of early-life exposure to the Chinese famine of 1959 to 1962 with the trajectories of body mass index (BMI), waist circumference (WC), and blood pressure (BP) in 2 consecutive generations. Methods We included 21 106 F1 observations born between 1954 and 1967 (median age: 45 years) and 1926 F2 observations (median age: 23 years) from the longitudinal household-based China Health and Nutrition Survey from 1993 to 2015. Trajectories of BMI, WC, systolic BP, and diastolic BP were fitted and compared between groups using linear mixed effect models. Results Early-life exposure to famine was associated with increased BMI, WC, and BP in 2 consecutive generations with sex and …

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10−9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for …

The situation in China is very challenging. These past few months have seen multiple COVID-19 outbreaks ripping through communities from north to south in the country. Most Chinese people in the mainland have never been infected by SARS-CoV-2, the virus that causes COVID-19, thanks to the zero COVID policy implemented uniformly with mass PCR testing and strict lockdowns of millions of people throughout the country since SARS-CoV-2 was first identified early 2020 in Wuhan. Using publicly available data released by the Shanghai government as of 4/29/2022, we calculated the ratio of asymptomatic positive to symptomatic positive cases to be> 10, with a case fatality rate (CFR) of 0.73% and infection fatality rate (IFR) of 0.066% during the lockdown in Shanghai (daily downloaded from https://wsjkw. sh. gov. cn/yqtb/index. html)(Commission, SMH, 2022). Even considering differences in the definitions of …

Background Racial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk. Methods Plasma metabolomic profiles were analyzed using liquid chromatography-tandem mass spectrometry in the WHI-OS (Women’s Health Initiative-Observational Study; 138 Black and 696 White women), WHI-HT trials (WHI-Hormone Therapy; 156 Black and 1138 White women), MESA (Multi-Ethnic Study of Atherosclerosis; 114 Black and 219 White women), JHS (Jackson Heart Study; 1465 Black women with 107 incident …

Background In response to the COVID-19 pandemic, public health measures, including stay-at-home orders, were widely instituted in the United States by March 2020. However, few studies have evaluated the impact of these measures on continuity of care among older adults living with chronic diseases. Methods Beginning in June 2020, participants of the national Women’s Health Initiative (WHI) (N = 64 061) were surveyed on the impact of the pandemic on various aspects of their health and well-being since March 2020, including access to care appointments, medications, and caregivers. Responses received by November 2020 (response rate = 77.6%) were tabulated and stratified by prevalent chronic diseases, including hypertension, type 2 diabetes, and cardiovascular disease (CVD). Results Among 49 695 respondents (mean age = 83.6 years), 70 …

Background The cholesterol content of circulating triglyceride-rich lipoproteins is characterized as remnant cholesterol, although little is known about its role in the development of cardiovascular disease (CVD) outcomes, all-cause mortality or transplant failure in kidney transplant recipients (KTRs). Our primary aim was to investigate the prospective association of remnant cholesterol and the risk of CVD events in renal transplant recipients with secondary aims evaluating remnant cholesterol and renal graft failure and all-cause mortality among participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial. Methods Among 4110 enrolled participants, 98 were excluded for missing baseline remnant cholesterol levels and covariates. Nonfasting remnant cholesterol levels were calculated based on the lipid profiles in 3812 FAVORIT trial participants …

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 …

Studies have suggested that adults with gallbladder disease have increased risk of type 2 diabetes. This prospective cohort study assessed the risk of type 2 diabetes in postmenopausal women with gallbladder disease. Data from women enrolled in the Women’s Health Initiative from 1993 to 2005, aged 50–79 years (mean = 63.2; standard deviation, 7.2), were analyzed. Cox proportional hazards regression models were used to estimate the risk of type 2 diabetes associated with gallbladder disease. There were 8,896 new cases of type 2 diabetes after 1,025,486 person-years of follow-up. Gallbladder disease was significantly associated with type 2 diabetes (hazard ratio = 1.52; 95% confidence interval (CI): 1.38,1.67). The observed risk of type 2 diabetes in women with both gallbladder disease and central obesity was 37% higher than expected (relative excess risk due to interaction = 0.37, 95% CI: 0.11,0 …

Objective:To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history.Summary of Background Data:Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women.Methods:This was a post-hoc analysis of Women’s Health Initiative participants who were beneficiaries of Medicare Parts A&B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017.Results:Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced …

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score …

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for …

An increasing body of evidence implicates high levels of selenium intake in the development of diabetes, although prospective studies remain sparse. We conducted a nested case-control study of 622 diabetes incident cases and 622-age, sex, and follow-up time-matched controls in the prospective Jinchang cohort of 48,001 participants with a median of 5.8 years of follow-up. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure all 622 case-control pairs' baseline serum levels of selenium (Se), which were then categorized into quartiles based on the frequency distribution among the controls. Multivariable adjusted conditional logistic regression and restricted cubic splines (RCS) models were applied to evaluate independent odds ratios (OR) as estimates for relative risks (RR) of diabetes according to quartiles (Q) of selenium levels. Compared to the lowest quartile (Q1 as reference …

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation …

The understanding of the impact of prenatal exposure to metal mixtures on birth weight is limited. We aimed to identify metal mixture components associated with birth weight and to determine additional pairwise interactions between metals showing such associations. Concentrations of 18 metals were measured using inductively coupled plasma mass spectrometry in urine samples collected in the 3rd trimester from a prenatal cohort (discovery; n = 1849) and the Healthy Baby Cohort (replication; n = 7255) in Wuhan, China. In the discovery set, we used two penalized regression models, i.e., elastic net regression for main effects and a lasso for hierarchical interactions, to identify important mixture components associated with birth weight, which were then replicated. We observed that 8 of the 18 measured metals were retained by elastic net regression, with five metals (vanadium, manganese, iron, cesium, and …

Aims Much remains unknown about the role of prenatal exposure to environmental stressors in the development of cardiovascular diseases (CVD). The current study aimed to investigate whether exposure to famine early in life was associated with a higher risk of CVD in adulthood. Methods and results Among 71 667 men and women participated in the Patient-centred Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project in southern China, specific years of birth were used to define two cohorts: the exposed group (born during the famine of 1959–62) and the non-exposed group [born before the famine (1949–58) or after the famine (1963–72)]. Multivariable-adjusted generalized linear models were used to examine the associations of famine exposure with the risk of developing CVD, as well as with the 10-year CVD risk defined by well-established risk …

Aims/hypothesisType 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.MethodsWe conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes …

Background and Purpose:Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).Methods:Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we …

BackgroundThe associations of red and processed meat with chronic disease risk remain to be clarified, in part because of measurement error in self-reported diet.ObjectivesWe sought to develop metabolomics-based biomarkers for red and processed meat, and to evaluate associations of biomarker-calibrated meat intake with chronic disease risk among postmenopausal women.MethodsStudy participants were women who were members of the Women's Health Initiative (WHI) study cohorts. These participants were postmenopausal women aged 50–79 y when enrolled during 1993–1998 at 40 US clinical centers with embedded human feeding and nutrition biomarker studies. Literature reports of metabolomics correlates of meat consumption were used to develop meat intake biomarkers from serum and 24-h urine metabolites in a 153-participant feeding study (2010–2014). Resulting biomarkers were used in a …

Background Low heart rate variability (HRV), a measure of autonomic imbalance, is associated with increased risk of coronary heart disease (CHD) and heart failure (HF). However, its relationship with HF subtypes; heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) has not been studied prior. Methods and findings We conducted a longitudinal study in Women’s Health Initiative study cohort to investigate the association of baseline quartiles of resting heart rate (rHR) and HRV measures; SDNN (SD of normal-to-normal RR interval) and RMSSD (root mean square of successive difference of RR interval) measured by twelve-lead electrocardiogram (ECG) on enrollment, with the risk of hospitalized HF and its subtypes. Total of 28,603 post-menopausal women, predominantly non-Hispanic whites (69%), with a mean (SD) age of 62.6 (7.1) years, free of baseline CHD and HF were included. In a fully adjusted cox-proportional hazards regression model which adjusted for age, race, BMI, alcohol intake, education, physical activity, hyperlipidemia, hypertension, left ventricular hypertrophy, use of beta-blocker, calcium-channel blocker, hormone therapy, and time-varying incident CHD, the hazard ratios of lowest quartile of HRV (Q1) with HF risk were significant (Q1 SDNN compared to Q4 SDNN: 1.22, 95% CI 1.07, 1.39; Q1 RMSSD compared to Q4 RMSSD: 1.17, 95% CI 1.02, 1.33). On subgroup analysis of HF subtypes, low HRV was associated with elevated HFpEF risk (Q1 vs Q4 SDNN: 1.22, 95% CI 1.02, 1.47) but not with HFrEF (Q1 vs Q4 SDNN: 1.19, 95% CI 0.95, 1.50; Q1 RMSSD: 1.13, 95 …

BackgroundThe genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized.MethodsWe measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women’s Health Initiative and applied a phenome-wide association study framework to assess associations between the PRS and a broad range of blood biomarkers, clinical measurements, and health outcomes.ResultsPolygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the …

Background Healthy dietary patterns are rich in micronutrients, but their influence on cardiovascular disease (CVD) risks has not been systematically quantified. Objectives The goal of this study was to provide a comprehensive and most up-to-date evidence-based map that systematically quantifies the impact of micronutrients on CVD outcomes. Methods This study comprised a systematic review and meta-analysis of randomized controlled intervention trials of micronutrients on CVD risk factors and clinical events. Results A total of 884 randomized controlled intervention trials evaluating 27 types of micronutrients among 883,627 participants (4,895,544 person-years) were identified. Supplementation with n-3 fatty acid, n-6 fatty acid, l-arginine, l-citrulline, folic acid, vitamin D, magnesium, zinc, α-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin showed moderate- to high …

ObjectivesTo assess the association of the plant-based cholesterol-lowering diet, the Portfolio Diet, with incident type 2 diabetes in women.MethodsWe followed 147,732 postmenopausal women initially free of diabetes in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study from 1993 through 2017. Adherence to the Portfolio Diet was assessed using an a priori diet index based on six food categories (high in plant protein [soy & pulses], nuts, viscous fiber, plant sterols and monounsaturated fat, and low in saturated fat) that were previously found to lower cardiovascular risk factors in the Portfolio Diet trials. We used Cox proportional-hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of the association of adherence to a Portfolio Diet score with incident type 2 diabetes, adjusting for potential confounders (demographics, lifestyle behaviors, and medical history). The …

Background Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women’s Health Initiative (WHI) and the TwinsUK cohort. Design The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models …

Introduction Recent studies suggest that both sex‐specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis. Methods We performed both single‐variant and gene‐based genome‐wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia‐related tissues and samples was gathered for each locus. Results Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's …

Reproductive longevity is essential for fertility and influences healthy ageing in women,, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we …

ImportanceSome prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps.ObjectiveTo investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women’s Health Initiative (WHI).Design, Setting, and ParticipantsIn 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF …

Background Pancreatic cancer risk is increasing in countries with high consumption of Western dietary patterns and rising obesity rates. We examined the hypothesis that specific dietary patterns reflecting hyperinsulinemia (empirical dietary index for hyperinsulinemia; EDIH), systemic inflammation (empirical dietary inflammatory pattern; EDIP), and postprandial glycemia [glycemic index (GI); glycemic load (GL)] are associated with pancreatic cancer risk, including the potential modifying role of type 2 diabetes (T2D) and body mass index (BMI). Methods We calculated dietary scores from baseline (1993–1998) food frequency questionnaires among 129,241 women, 50–79 years-old in the Women's Health Initiative. We used multivariable-adjusted Cox regression to estimate HRs and 95% confidence intervals (95% CI) for pancreatic cancer risk. Results …

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95 …

BACKGROUND The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. METHODS We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause …

Background The plant‐based Dietary Portfolio combines established cholesterol‐lowering foods (plant protein, nuts, viscous fiber, and phytosterols), plus monounsaturated fat, and has been shown to improve low‐density lipoprotein cholesterol and other cardiovascular disease (CVD) risk factors. No studies have evaluated the relation of the Dietary Portfolio with incident CVD events. Methods and Results We followed 123 330 postmenopausal women initially free of CVD in the Women's Health Initiative from 1993 through 2017. We used Cox proportional‐hazard models to estimate adjusted hazard ratios (HRs) and 95% CI of the association of adherence to a Portfolio Diet score with CVD outcomes. Primary outcomes were total CVD, coronary heart disease, and stroke. Secondary outcomes were heart failure and atrial fibrillation. Over a mean follow‐up of 15.3 years, 13 365 total CVD, 5640 coronary heart disease …

BackgroundThe difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.ResultsWe identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E−03 and …

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10−8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a …

ObjectiveFew studies have prospectively examined the associations of lipoprotein(a) [Lp(a)] levels with the risk of abdominal aortic aneurysm (AAA), especially in women. Accounting for commonly recognized risk factors, we investigated the baseline Lp(a) levels and the risk of AAA among postmenopausal women participating in the ongoing national Women's Health Initiative.MethodsWomen's Health Initiative participants with baseline Lp(a) levels available who were beneficiaries of Medicare parts A and B fee-for-service at study enrollment or who had aged into Medicare at any point were included. Participants with missing covariate data or known AAA at baseline were excluded. Thoracic aneurysms were excluded owing to the different pathophysiology. The AAA cases and interventions were identified using the International Classification of Diseases, 9th and 10th revision, codes and Current Procedural …

ObjectiveTo evaluate the association between pasta meal intake and long-term risk of developing diabetes or atherosclerotic cardiovascular disease (ASCVD, including coronary heart disease (CHD) and stroke) in postmenopausal women.Design

ObjectiveTo investigate sex and race differences in the association between fasting blood glucose (FBG) and risk of ischemic stroke (IS).MethodsThis prospective longitudinal cohort study included adults age ≥45 years at baseline in the Reasons for Geographic And Racial Differences in Stroke Study, followed for a median of 11.4 years. The exposure was baseline FBG (mg/dL); suspected IS events were ascertained by phone every 6 months and were physician-adjudicated. Cox proportional hazards were used to assess the adjusted sex/race-specific associations between FBG (by category and as a restricted cubic spline) and incident IS.ResultsOf 20,338 participants, mean age was 64.5 (SD 9.3) years, 38.7% were Black, 55.4% were women, 16.2% were using diabetes medications, and 954 IS events occurred. Compared to FBG <100, FBG ≥150 was associated with 59% higher hazards of IS (95% confidence …

Background More women than men are affected by Alzheimer’s disease (AD). However, risk factors for cognitive impairment (CI) among older women by race/ethnicity are not completely understood. The well‐characterized Women’s Health Initiative Memory Study (WHIMS) has followed for more than 25 years postmenopausal women to assess cognitive and brain outcomes. WHIMS provides a unique opportunity to determine the extent to which risk factors for CI vary between White and Black women. Due to the high‐dimensional nature of this problem we based our analyses on machine learning methods. Method To investigate signatures of predictors of incident CI (either mild cognitive impairment or probable dementia) in women, we included 6778 women (503 Black and 6275 White) with up to 25 years of follow‐up including annual cognitive assessments. Mild cognitive impairment and probable dementia …

BackgroundRecent experimental work has shown that phthalates may increase inflammation. Prior research has not examined the role of exposure to phthalates in relation to inflammatory status among postmenopausal women who are at higher risk of developing inflammation-related chronic disorders.ObjectivesWe aimed to examine the associations of urinary phthalate biomarker concentrations with circulating levels of c-reactive protein [CRP] and interleukin-6 [IL-6] among 443 postmenopausal women selected into a breast cancer case-control study nested within the Women's Health Initiative (WHI).MethodsA total of 13 phthalate metabolites were measured in urine samples provided at WHI enrollment from 1993 to 1998. We also measured baseline levels of CRP and IL-6 in these women's serum or plasma samples. Multivariable linear models were used to investigate the role of each phthalate biomarker in …

OBJECTIVE The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk. RESEARCH DESIGN AND METHODS We calculated dietary scores from baseline (1993–1998) food frequency questionnaires among 73,495 postmenopausal women in the Women’s Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression …

The potential role of nutritional factors in the development of peripheral arterial disease (PAD) remains poorly understood. We evaluated multiple recommended eating patterns as reflected by predefined diet quality indices in relation to long-term risk of PAD. We included 138 506 US postmenopausal women in the Women’s Health Initiative who had no known PAD at baseline (1993–1998). Four diet quality indices, including alternate Mediterranean diet index, alternate Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension diet index, and Healthy Eating Index-2015, were derived using dietary information collected by a validated food frequency questionnaire at baseline. Incident cases of symptomatic PAD in the lower extremities were ascertained and adjudicated through March 2019 via medical record review. During a median 18.6 years of follow-up, 1036 incident PAD cases were identified. After …

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p=2.06 × 10−8), which replicated in independent studies of African ancestry (p = 6.26 × 10−23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF=14.1%, OR=1.08, p=5.75 × 10−9), which also replicated in independent studies (p = 3.45 × 10−4). We …

Higher intake of fruit and vegetables, nuts, and whole grains has each been prospectively associated with lower morbidity and mortality of cardiometabolic diseases (CMDs) in adults (1–4). These consistent observations from high-quality and large prospective cohorts strongly implicate that substances rich in plant foods may confer important cardiometabolic benefits. Yet, it remains a matter of debate which specific micronutrients, minerals, phytochemicals, and/or bioactive components of these plant foods may be responsible for cardiometabolic protection (5). Polyphenols such as flavonoids have been shown to have antioxidant, anti-inflammatory, and antithrombotic properties and may improve vascular endothelial function, insulin secretion, and action, as well as lower blood pressure (6). To date, mechanistic studies have come from animal experiments and small, short-term clinical studies that have not evaluated …

Background Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer. Methods This study examined the association between prediagnosis cardiovascular health and total and cause‐specific mortality among 12,076 postmenopausal women who developed local‐ or regional‐stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity‐related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non‐Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival. Results After a median follow‐up of 10.0 years from the date of the …

BackgroundAssessing estimated sodium (Na) and potassium (K) intakes derived from 24-h urinary excretions compared with a spot urine sample, if comparable, could reduce participant burden in epidemiologic and clinical studies.ObjectivesIn a 2-week controlled-feeding study, Na and K excretions from a 24-h urine collection were compared with a first-void spot urine sample, applying established algorithms and enhanced models to estimate 24-h excretion. Actual and estimated 24-h excretions were evaluated relative to mean daily Na and K intakes in the feeding study.MethodsA total of 153 older postmenopausal women ages 75.4 ± 3.5 y participated in a 2-wk controlled-feeding study with a 4-d repeating menu cycle based on their usual intake (ClinicalTrials.gov Identifier: NCT00000611). Of the 150 participants who provided both a first-void spot urine sample and a 24-h urine collection on the penultimate study …

Cardiovascular disease (CVD) and environmental degradation are leading global health problems of our time. Recent studies have linked exposure to heavy metals to the risks of CVD and diabetes, particularly in populations from low- and middle-income countries, where concomitant rapid development occurs. In this review, we 1) assessed the totality, quantity, and consistency of the available epidemiological studies, linking heavy metal exposures to the risk of CVD (including stroke and coronary heart disease); 2) discussed the potential biological mechanisms underlying some tantalizing observations in humans; and 3) identified gaps in our knowledge base that must be investigated in future work. An accumulating body of evidence from both experimental and obser- vational studies implicates exposure to heavy metals, in a dose-response manner, in the increased risk of CVD. The limitations of most existing …

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 …

Background: Most studies that analyze the association between serum folate levels and cognitive function either restrict their assessments to specific clinical scenarios or do not include middle-aged individuals, to whom strategies for preventing cognitive impairment may be more feasible. Objective: To examine the association between serum folate levels and cognitive function in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment. Methods: Data from 4,571 ELSA-Brasil participants who live in the state of São Paulo, aged 35-74 years, were analyzed. The word list learning, delayed recall, word recognition, verbal fluency, and Trail Making Test Part B consisted in the cognitive tests. For each test, age, sex, and education-specific standardized scores and a global cognitive score were calculated. Crude and adjusted linear regression models were used to examine the associations of serum folate levels with cognitive test scores. Results: In multivariable-adjusted models, serum folate was not associated with global cognitive score (β=-0.043; 95% confidence interval [95%CI] -0.135 to 0.050 for lowest vs. highest quintile group), nor with any cognitive test performance. We did not find associations between serum folate and global cognitive scores in subgroups stratified by age, sex, or use of vitamin supplements either. Conclusions: We did not find significant associations between serum folate and cognitive performance in this large sample, which is characterized by a context of food fortification policies and a consequent low frequency of folate deficiency. Positive results from previous studies may not apply to the …

BackgroundFamilial dysalbuminemic hyperthyroxinemia (FDH) is a rare autosomal dominant disorder whose clinical characteristics remain incompletely understood, we investigated the role of albumin gene mutation in relation to miscarriage rate in a large pedigree of FDH followed up for 4 years.Patients and MethodsThe proband and extended family with unexplained miscarriage and hyperthyroxinemia were identified and genotypes in candidate genes and thyroid function tests (TFTs), including changes in TFTs during pregnancy were comprehensively assessed. We also evaluated the development and growth of children in this large FDH pedigree during four years follow-up.ResultThe R218S variant in the albumin gene was identified in the proband and her relatives with hyperthyroxinemia who were diagnosed as FDH. Among the family members who underwent TFTs, 11 of 17 (65%) had similar changes in …

Type 2 diabetes is increasing in all ancestry groups. Part of its genetic basis may reside among the rare (minor allele frequency <0.1%) variants that make up the vast majority of human genetic variation. We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h2=53% (P=4.2×10−5) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures to annotate and group rare variants with respect to gene expression, chromatin state and three-dimensional chromatin architecture, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h2=8%, P=2.4×10−3). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.

Background Most studies that analyze the association between serum folate levels and cognitive function either restrict their assessments to specific clinical scenarios or do not include middle-aged individuals, to whom strategies for preventing cognitive impairment may be more feasible. Objective To examine the association between serum folate levels and cognitive function in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline assessment. Methods Data from 4,571 ELSA-Brasil participants who live in the state of São Paulo, aged 35-74 years, were analyzed. The word list learning, delayed recall, word recognition, verbal fluency, and Trail Making Test Part B consisted in the cognitive tests. For each test, age, sex, and education-specific standardized scores and a global cognitive score were calculated. Crude and adjusted linear regression models were used to examine the associations of …

Background Although sub‐Saharan Africa has a high prevalence of cardiovascular diseases (CVDs), there remains a lack of systematic and comprehensive assessment of risk factors and early CVD outcomes in adults in sub‐Saharan Africa. Methods and Results Using a stratified multistage random sampling method, we recruited 1106 men and women, aged >18 years, from the general population in Ghana to participate in a national health survey from 2016 to 2017. In Ghanaian adults, the age‐standardized prevalence of known CVD risk factors was 15.1% (95% CI, 12.9%–17.3%) for obesity, 6.8% (95% CI, 5.1%–8.5%) for diabetes mellitus, 26.1% (95% CI, 22.9%–29.4%) for hypertension, and 9.3% (95% CI, 7.1%–11.5%) for hyperuricemia. In addition, 10.1% (95% CI, 7.0%–13.2%) of adults had peripheral artery disease, 8.3% (95% CI, 6.7%–10.0%) had carotid thickening, 4.1% (95% CI, 2.9%–5.2%) had left …

Background In the WHI-HT trials (Women’s Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not. Methods Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes. Metabolites with discordant effects by HT type were evaluated for association with incident CHD in 944 participants (472 CHD cases) in the WHI-OS (Women’s Health Initiative Observational Study), with replication in an independent cohort …

BackgroundCholine plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites.ObjectivesThis study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites.MethodsWe analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993–1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate …