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Covid-19 led to a dramatic change in the academic library work environment, with many workers shifting to a hybrid work schedule once they returned to in person work. The authors describe the impact of this schedule shift through the novel use of the socio-ecological model. The socio-ecological model looks at the impact of choices through varying circles or levels. The authors discuss the individual, interpersonal, community, and societal levels of impact that the switch to hybrid work had within their context and discuss their role as unit leaders and the decisions made to address these varying impacts.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

BACKGROUND: Long-term data on cardiovascular disease (CVD) and mortality in female carriers of the transthyretin (TTR) V122I (pV142I) variant, one of the most common variants of hereditary transthyretin cardiac amyloidosis, are sparse and the effects of blood pressure, heart rate, body mass index, and physical activity on CVD outcomes remain largely unknown. OBJECTIVES: The aim was to first examine the relationship of TTR V122I (pV142I) carrier status with CVD and mortality and second to investigate the effects of blood pressure, heart rate, body mass index, and physical activity in a large cohort of postmenopausal women. METHODS: The study population consisted of 9,862 non-Hispanic Black/African American women, 9,529 noncarriers and 333 TTR V122I carriers, enrolled in the Womens Health Initiative at 40 centers in the United States. Women were generally healthy and postmenopausal at the time of enrollment (1993-1998). CVD was defined as a composite endpoint consisting of coronary heart disease, stroke, acute heart failure or CVD death, and all-cause mortality. CVD cases were based on self-reported annual mailed health updates. All information was centrally adjudicated by trained physicians. HRs and 95% CIs were obtained from adjusted Cox proportional hazards models. RESULTS: Among 9,862 Black female participants (mean age: 62 years [IQR: 56-67 years]), the population frequency of the TTR V122I variant was 3.4% (333 variant carriers and 9,529 noncarriers). During a mean follow-up of 16.1 years (IQR: 9.7-22.2 years), incident CVD occurred in 2,229 noncarriers and 96 carriers, whereas 2,689 noncarriers and 108 carriers died. In adjusted models including demographic, lifestyle, and medical history covariates, TTR V122I carriers were at higher risk of the composite endpoint CVD (HR: 1.52; 95% CI: 1.22-1.88), acute heart failure (HR: 2.21; 95% CI: 1.53-3.18), coronary heart disease (HR: 1.80; 95% CI: 1.30-2.47), CVD death (HR: 1.70; 95% CI: 1.26-2.30), and all-cause mortality (HR: 1.28; 95% CI: 1.04-1.56). The authors found a significant interaction by age but not by blood pressure, heart rate, body mass index, or physical activity. CONCLUSIONS: Black female TTR V122I (pV142I) carriers have a higher CVD and all-cause mortality risk compared to noncarriers. In case of clinical suspicion of amyloidosis, they should be screened for TTR V122I (pV142I) carrier status to ensure early treatment onset.

PurposeAccurate and understandable information after genetic testing is critical for patients, family members, and professionals alike.MethodsAs part of a cross-site study from the Clinical Sequencing Evidence-Generating Research consortium, we investigated the information-seeking practices among patients and family members at 5 to 7 months after genetic testing results disclosure, assessing the perceived utility of a variety of information sources, such as family and friends, health care providers, support groups, and the internet.ResultsWe found that individuals placed a high value on information obtained from genetics professionals and health care workers, independent of genetic testing result case classifications as positive, inconclusive, or negative. The internet was also highly utilized and ranked. Study participants rated some information sources as more useful for positive results compared with inconclusive or negative outcomes, emphasizing that it may be difficult to identify helpful information for individuals receiving an uncertain or negative result. There were few data from non-English speakers, highlighting the need to develop strategies to reach this population.ConclusionOur study emphasizes the need for clinicians to provide accurate and comprehensible information to individuals from diverse populations after genetic testing.

While biomarkers have been proposed to identify individuals at risk for radiation-induced cardiovascular disease (RICVD), little is known about long-term associations with cardiac events. We examined associations of biomarkers of oxidative stress (myeloperoxidase, growth differentiation factor-15, 8-hydroxy-2-deoxyguanosine [8-OH-dG], placental growth factor), cardiac injury (troponin I, cystatin-C), inflammation (interleukin-6, C-reactive protein), and myocardial fibrosis (transforming growth factor-ß) with long-term RICVD in breast cancer (BC) survivors. We conducted a nested case-control study within the Womens Health Initiative of postmenopausal women with incident BC stages I-III, who received radiation and had pre- and post-BC diagnosis serum samples. Cases (n = 55) were defined as developing incident, physician-adjudicated myocardial infarction, coronary heart disease death, other CVD death, heart failure, or stroke after BC. Cases were matched to three controls (n = 158). After adjustment, a higher 8-OH-dG ratio was significantly associated with an elevated long-term risk of RICVD, suggesting oxidative DNA damage may be a putative pathway for RICVD.

BACKGROUND: The absence of consensus for outcomes in pediatric antibiotic trials is a major barrier to research harmonization and clinical translation. We sought to develop expert consensus on study outcomes for clinical trials of children with mild community-acquired pneumonia (CAP). METHODS: Applying the Delphi method, a multispecialty expert panel ranked the importance of various components of clinical response and treatment failure outcomes in children with mild CAP for use in research. During Round 1, panelists suggested additional outcomes in open-ended responses that were added to subsequent rounds of consensus building. For Rounds 2 and 3, panelists were provided their own prior responses and summary statistics for each item in the previous round. The consensus was defined by >70% agreement. RESULTS: The expert panel determined that response to and failure of treatment should be addressed at a median of 3 days after initiation. Complete or substantial improvement in fever, work of breathing, dyspnea, tachypnea when afebrile, oral intake, and activity should be included as components of adequate clinical response outcomes. Clinical signs and symptoms including persistent or worsening fever, work of breathing, and reduced oral intake should be included in treatment failure outcomes. Interventions including receipt of parenteral fluids, supplemental oxygen, need for high-flow nasal cannula oxygen therapy, and change in prescription of antibiotics should also be considered in treatment failure outcomes. CONCLUSIONS: Clinical response and treatment failure outcomes determined by the consensus of this multidisciplinary expert panel can be used for pediatric CAP studies to provide objective data translatable to clinical practice.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

BackgroundWhile large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries.ResultsAssociations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7).ConclusionsLow frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

PURPOSE: Studies examining biomarkers associated with fatigue in breast cancer survivors treated with radiation are limited. Therefore, we examined the longitudinal association between serum biomarkers and post-breast cancer fatigue in survivors treated with radiation: [oxidative stress] 8-hydroxyguanosine, myeloperoxidase; [inflammation] interleukin-6 (IL-6), c-reactive protein, growth differentiation factor-15 (GDF-15), placental growth factor, transforming growth factor-beta, [cardiac damage] cystatin-C, troponin-I. METHODS: In a secondary analysis, we included participants from the Womens Health Initiative if they had: a previous breast cancer diagnosis (stages I-III), no prior cardiovascular diseases, pre-and post-breast cancer serum samples drawn approximately 3 years apart, and fatigue measured using the Short-Form 36 vitality subscale at both serum collections. Biomarkers were measured using ELISA or RT-qPCR and modeled as the log2 post-to pre-breast cancer ratio. RESULTS: Overall, 180 women with a mean (SD) age of 67.0 (5.5) years were included. The mean (SD) vitality scores were 66.2 (17.2) and 59.7 (19.7) pre- and post-breast cancer, respectively. Using multivariable weighted linear regression, higher biomarker ratios of cystatin-C, IL-6, and GDF-15 were associated with a lower vitality score (i.e., higher fatigue). For example, for each 2-fold difference in cystatin-C biomarker ratio, the vitality score was lower by 7.31 points (95% CI: -14.2, -0.45). CONCLUSION: Inflammatory and cardiac damage biomarkers are associated with fatigue in breast cancer survivors treated with radiation; however, these findings should be replicated in a larger sample. Biomarkers could be measured in clinical practice or assessed in risk prediction models to help identify patients at high risk for fatigue.

BackgroundThe availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.MethodsWe conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.ResultsTwo blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P

BackgroundTo investigate the association between walking pace and the risk of heart failure (HF) and HF sub-types.MethodsWe 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 3 mph) with incident HF. We also examined the joint association of walking pace and duration with incident HF.ResultsThere 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.ConclusionWalking 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.

As affordability continues to be a growing concern in higher education, more institutions are building programs to not only bring down course materials costs for undergraduate students, but to align affordability with student success and retention. In this presentation, two institutions will share their program development around open and affordable course materials. One institution is just at the beginning of developing their program and has created a robust program for gathering data on student and course instructor needs and desires on their campus. The other institution has a much more well-established initiative with a focus on both OER and open educational practices, leveraging the impact of the program to advance the goals of access, equity, and student success. In both cases, campus partnerships ranging from undergraduate students to high-level administrators are a critical component to success. We will reflect on lessons learned for beginning and expanding programs, and the variety of pathways that can be pursued in expanding the reach of OER.Link to YouTube recording  https://youtu.be/fcCmeepklSA and conference page https://www.cni.org/topics/economic-models/open-educational-resource-program-development-a-view-from-two-institutions

BackgroundThis study evaluated the association between changes in physical performance and blood pressure (BP) (e.g., systolic [SBP], diastolic [DBP], pulse pressure) in older women.Methods5627 women (mean age 69.8 ± 3.7 y) with grip strength, chair stand, gait speed performance and clinic-measured BP at baseline and at least one follow-up (years 1, 3 or 6) were included. Generalized estimating equation analysis of multivariable models with standardized point estimates described the longitudinal association between physical performance and BP changes in the overall cohort, and in models stratified by baseline cardiovascular disease (CVD), time-varying antihypertensive medication use (none, ≥1) and enrollment age (65-69 y; 70-79 y).ResultsOverall, each z-score unit increment in grip strength was associated with 0.59 mmHg (95% CI 0.10, 1.08) higher SBP, and 0.39 mmHg (95% CI 0.11, 0.67) higher DBP. In stratified models, a standardized increment in grip strength was associated with higher SBP in women without CVD (0.81; 95% CI 0.23-1.39), among antihypertensive medication users (0.93; 95% CI 0.44, 1.41) and non-users (0.37; 95% CI 0.03, 0.71), and in those aged 65-69 y (0.64; 95% CI 0.04, 1.24). Similarly, a standardized increment in any of the three performance measures was associated with modestly higher DBP in antihypertensive medication users, and those aged 70-79 y. Associations between any performance measure and pulse pressure change were not significant.ConclusionThese results suggest a positive, and statistically significant relationship between physical performance and BP that appears to be influenced by CVD history, antihypertensive medication use, and age.

BackgroundCardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age.Methods and resultsWe performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint

BackgroundChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia.MethodsData from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.ResultsIn a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; P

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p

BackgroundAfrican American and Hispanic postmenopausal women have the highest risk for heart failure compared with other races, but heart failure prevalence is lower than expected in some national cohorts. It is unknown whether psychosocial factors are associated with lower risk of incident heart failure hospitalization among high-risk postmenopausal minority women.Methods and resultsUsing the Women's Health Initiative Study, African American and US Hispanic women were classified as high-risk for incident heart failure hospitalization with 1 or more traditional heart failure risk factors and the highest tertile heart failure genetic risk scores. Positive psychosocial factors (optimism, social support, religion) and negative psychosocial factors (living alone, social strain, depressive symptoms) were measured using validated survey instruments at baseline. Adjusted subdistribution hazard ratios of developing heart failure hospitalization were determined with death as a competing risk. Positive deviance indicated not developing incident heart failure hospitalization with 1 or more risk factors and the highest tertile for genetic risk. Among 7986 African American women (mean follow-up of 16 years), 27.0% demonstrated positive deviance. Among high-risk African American women, optimism was associated with modestly reduced risk of heart failure hospitalization (subdistribution hazard ratio 0.94, 95% confidence interval 0.91-0.99), and social strain was associated with modestly increased risk of heart failure hospitalization (subdistribution hazard ratio 1.07, 95% confidence interval 1.02-1.12) in the initial models; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses. Among 3341 Hispanic women, 25.1% demonstrated positive deviance. Among high-risk Hispanic women, living alone was associated with increased risk of heart failure hospitalization (subdistribution hazard ratio 1.97, 95% confidence interval 1.06-3.63) in unadjusted analyses; however, no psychosocial factors were associated with heart failure hospitalization in fully adjusted analyses.ConclusionsAmong postmenopausal African American and Hispanic women, a significant proportion remained free from heart failure hospitalization despite having the highest genetic risk profile and 1 or more traditional risk factors. No observed psychosocial factors were associated with incident heart failure hospitalization in high-risk African Americans and Hispanics. Additional investigation is needed to understand protective factors among high-risk African American and Hispanic women.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value

BackgroundThe prevalence of metabolic syndrome is higher among minority populations, including individuals of Mexican ethnic descent. Whether alignment to healthy dietary patterns is associated with lower risk of metabolic syndrome in this population is largely unknown.ObjectiveTo prospectively evaluate the associations between a priori diet quality scores and risk of metabolic syndrome and its components among postmenopausal women of Mexican ethnic descent.MethodsA total of 334 women of Mexican ethnic descent who participated in the Women's Health Initiative (WHI) observational study without metabolic syndrome or diabetes at baseline (1993-1998) were included. Baseline diets were scored with the Alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), the Healthy Eating Index (HEI-2010), the Mediterranean Diet Score (MDS), and the traditional Mexican Diet (MexD) score. Multivariable linear and logistic regression models were used to test the associations between baseline diet quality and risk of metabolic syndrome and its individual components at follow-up (2012-2013).ResultsApproximately 16% of women met the criteria for metabolic syndrome at follow-up. None of the diet quality indices were associated with risk of metabolic syndrome. However, higher vs lower DASH scores were associated with lower waist circumference (85.2 vs 88.0 cm) and glucose concentrations (90.0 vs 95.1 mg/dL), and higher HDL cholesterol (62.6 vs 59.0 mg/dL), while higher vs lower HEI-2010 scores were associated with lower waist circumference (83.9 vs 88.1 cm), triglycerides (103 vs 117 mg/dL) and glucose concentrations (89.5 vs 94.4 mg/dL), and higher HDL cholesterol levels (63.9 vs 58.5 mg/dL).ConclusionsDiet quality was not associated with risk of metabolic syndrome in this population. However, the results suggest that alignment to DASH and HEI-2010 recommendations may be beneficial for reducing some individual components of metabolic syndrome among postmenopausal women of Mexican descent.

Few studies have evaluated hypertension incidence in relation to walking, which is a common physical activity among adults. We examined the association between walking and hypertension incidence in 83 435 postmenopausal women who at baseline were aged 50 to 79 years, without known hypertension, heart failure, coronary heart disease, or stroke, and reported the ability to walk at least one block without assistance. Walking volume (metabolic equivalent hours per week) and speed (miles per hour) were assessed by questionnaire. Incident physician-diagnosed hypertension treated with medication was ascertained through annual questionnaires. During a mean 11-year follow-up, 38 230 hypertension cases were identified. After adjustment for covariates including nonwalking activities, a significant inverse association with hypertension was observed across categories of baseline walking volume (0 [referent], >0-3.5, 3.6-7.5, and >7.5 metabolic equivalent hours per week), hazard ratio: 1.00 (referent), 0.98, 0.95, 0.89; trend P4 miles per hour) also were associated with lower hypertension risk, hazard ratio: 1.00 (referent), 1.07, 0.95, 0.86, 0.79; trend P7.5 metabolic equivalent hours per week) and at faster speeds (≥2 miles per hour) is associated with lower hypertension risk in postmenopausal women. Walking should be encouraged as part of hypertension prevention in older adults.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.

BackgroundAlcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.MethodsIn the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.ResultsWe discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5.ConclusionsIn conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

Background: Postmenopausal women represent the highest population-based burden of cardiovascular disease, including sudden cardiac death (SCD). Our understanding of the etiology and risk factors contributing to fatal coronary heart disease (CHD) and SCD, particularly among women, is limited. This study examines the association between dietary magnesium intake and fatal CHD and SCD. Materials and Methods: We examined 153,569 postmenopausal women who participated in the Women's Health Initiative recruited between 1993 and 1998. Magnesium intake at baseline was assessed using a validated food frequency questionnaire, adjusting for energy via the residual method. Fatal CHD and SCD were identified over an average follow-up of 10.5 years. Results: For every standard deviation increase in magnesium intake, there was statistically significant risk reduction, after adjustment for confounders, of 7% for fatal CHD (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.89-0.97), and 18% risk reduction for SCD (HR 0.82, 95% CI 0.58-1.15) the latter of which did not reach statistical significance. In age-adjusted quartile analysis, women with the lowest magnesium intake (189 mg/day) had the greatest risk for fatal CHD (HR 1.54, 95% CI 1.40-1.69) and SCD (HR 1.70, 95% CI 0.94-3.07). This association was attenuated in the fully adjusted model, with HRs of 1.19 (95% CI 1.06-1.34) for CHD and 1.24 (95% CI 0.58-2.65) for SCD for the lowest quartile of magnesium intake. Conclusions: This study provides evidence of a potential inverse association between dietary magnesium and fatal CHD and a trend of magnesium with SCD in postmenopausal women. Future studies should confirm this association and consider clinical trials to test whether magnesium supplementation could reduce fatal CHD in high-risk individuals.

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies.

BackgroundGroup 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined.MethodsTo identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing.ResultsTissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.ConclusionsWe report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

Background Dietary patterns are associated with cardiovascular disease (CVD) risk in the general population, but diet-CVD association in populations with diabetes mellitus is limited. Our objective was to examine the association between diet quality and CVD risk in a population with type 2 diabetes mellitus. Methods and Results We analyzed prospective data from 5809 women with prevalent type 2 diabetes mellitus at baseline from the Women's Health Initiative. Diet quality was defined using alternate Mediterranean, Dietary Approach to Stop Hypertension, Paleolithic, and American Diabetes Association dietary pattern scores calculated from a validated food frequency questionnaire. Multivariable Cox's proportional hazard regression was used to analyze the risk of incident CVD. During mean 12.4 years of follow-up, 1454 (25%) incident CVD cases were documented. Women with higher alternate Mediterranean, Dietary Approach to Stop Hypertension, and American Diabetes Association dietary pattern scores had a lower risk of CVD compared with women with lower scores (Q5 v Q1) (hazard ratio [HR]aMed 0.77, 95% CI 0.65-0.93; HRDASH 0.69, 95% CI 0.58-0.83; HRADA 0.71, 95% CI 0.59-0.86). No association was observed between the Paleolithic score and CVD risk. Conclusions Dietary patterns that emphasize higher intake of fruits, vegetables, whole grains, nuts/seeds, legumes, a high unsaturated:saturated fat ratio, and lower intake of red and processed meats, added sugars, and sodium are associated with lower CVD risk in postmenopausal women with type 2 diabetes mellitus.

Background and aimsThe association of fatty acids with coronary heart disease (CHD) has been examined, mainly through dietary measurements, and has generated inconsistent results due to measurement error. Large observational studies and randomized controlled trials have shown that plasma phospholipid fatty acids (PL-FA), especially those less likely to be endogenously synthesized, are good biomarkers of dietary fatty acids. Thus, PL-FA profiles may better predict CHD risk with less measurement error.MethodsWe performed a matched case-control study of 2428 postmenopausal women nested in the Women's Health Initiative Observational Study. Plasma PL-FA were measured using gas chromatography and expressed as molar percentage (moL %). Multivariable conditional logistic regression was used to calculate odds ratios (95% CIs) for CHD associated with 1 moL % change in PL-FA.ResultsHigher plasma PL long-chain saturated fatty acids (SFA) were associated with increased CHD risk, while higher n-3 polyunsaturated fatty acids (PUFA) were associated with decreased risk. No significant associations were observed for very-long-chain SFA, monounsaturated fatty acids (MUFA), PUFA n-6 or trans fatty acids (TFA). Substituting 1 moL % PUFA n-6 or TFA with an equivalent proportion of PUFA n-3 were associated with lower CHD risk.ConclusionsHigher plasma PL long-chain SFA and lower PUFA n-3 were associated with increased CHD risk. A change in diet by limiting foods that are associated with plasma PL long-chain SFA and TFA while enhancing foods high in PUFA n-3 may be beneficial in CHD among postmenopausal women.

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Background Recent evidence suggests that racial/ethnic differences in circulating levels of free or bioavailable 25-hydroxy vitamin D (25[ OH ]D) rather than total 25( OH )D may explain apparent racial disparities in cardiovascular disease ( CVD ). We prospectively examined black-white differences in the associations of total, free, and bioavailable 25( OH )D, vitamin D-binding protein, and parathyroid hormone levels at baseline with incident CVD (including nonfatal myocardial infarction, nonfatal stroke, and CVD death) in postmenopausal women. Methods and Results We conducted a case-cohort study among 79 705 postmenopausal women, aged 50 to 79 years, who were free of CVD at baseline in the WHI-OS (Women's Health Initiative Observational Study). A subcohort of 1300 black and 1500 white participants were randomly chosen as controls; a total of 550 black and 1500 white women who developed incident CVD during a mean follow-up of 11 years were chosen as cases. We directly measured total 25( OH )D, vitamin D-binding protein, albumin, parathyroid hormone, and calculated free and bioavailable 25( OH )D. Weighted Cox proportional hazards models were used to examine their associations with CVD risk. Although vitamin D-binding protein and total, free, and bioavailable 25( OH )D were not significantly associated with CVD risk in black or white women, a significant positive association between parathyroid hormone and CVD risk persisted in white women (hazard ratio comparing the highest quartile with the lowest, 1.37; 95% CI , 1.06-1.77) but not in black women (hazard ratio comparing the highest quartile with the lowest, 1.12; 95% CI, 0.79-1.58), independent of total, free, and bioavailable 25( OH )D or vitamin D-binding protein. Conclusions Circulating levels of vitamin D biomarkers are not related to CVD risk in either white or black women. Higher parathyroid hormone levels may be an independent risk factor for CVD in white women.

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p

BackgroundThe higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups.Methods and resultsIn the WHI (Women's Health Initiative; 1993-2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased (P

Early life nutritional imbalances are risk factors for metabolic dysfunctions in adulthood, but the long term effects of perinatal exposure to high versus low protein diets are not completely understood. We exposed C57BL/6J offspring to a high protein/low carbohydrate (HP/LC) or low protein/high carbohydrate (LP/HC) diet during gestation and lactation, and measured metabolic phenotypes between birth and 10 months of age in male offspring. Perinatal HP/LC and LP/HC exposures resulted in a decreased ability to clear glucose in the offspring, with reduced baseline insulin and glucose concentrations in the LP/HC group and a reduced insulin response post-glucose challenge in the HP/LC group. The LP/HC diet group also showed reduced birth and weanling weights, whereas the HP/LC offspring displayed increased weanling weight with increased adiposity beyond 5 months of age. Gene expression profiling of hypothalamus and liver revealed alterations in diverse molecular pathways by both diets. Specifically, hypothalamic transcriptome and pathway analyses demonstrated perturbations of MAPK and hedgehog signaling, processes associated with neural restructuring and transmission, and phosphate metabolism by perinatal protein imbalances. Liver transcriptomics revealed changes in purine and phosphate metabolism, hedgehog signaling, and circadian rhythm pathways. Our results indicate maternal protein imbalances perturbing molecular pathways in central and peripheral metabolic tissues, thereby predisposing the male offspring to metabolic dysfunctions.

Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium.

ImportanceHealth outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.ObjectiveTo examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials.Design, setting, and participantsObservational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.InterventionsConjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).Main outcomes and measuresAll-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.ResultsAmong 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.Conclusions and relevanceAmong postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.Trial registrationclinicaltrials.gov Identifier: NCT00000611.

Fatty acids (FAs) are essential components of cell membranes and play an integral role in membrane fluidity. The lipophilic index [LI, defined as the sum of the products between FA levels and melting points (°C), divided by the total amount of FA: [Formula: see text]] is thought to reflect membrane and lipoprotein fluidity and may be associated with the risk of coronary heart disease (CHD). Therefore, we examined the associations of dietary and plasma phospholipid (PL) LI with CHD risk among postmenopausal women. We determined dietary LI for the cohort with completed baseline food frequency questionnaires and free of prevalent cardiovascular diseases in the Women's Health Initiative (WHI) observational study (N = 85,563). We additionally determined plasma PL LI in a matched case-control study (N = 2428) nested within the WHI observational cohort study. Cox proportional hazard regression and multivariable conditional logistic regression were used to calculate HRs/ORs for CHD risk between quartiles of LI after adjusting for potential sources of confounding and selection bias. Higher dietary LI in the cohort study and plasma PL LI in the case-control study were significantly associated with increased risk of CHD: HR = 1.18 (95% CI 1.07-1.31, P for trend

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Few studies have reported associations between periodontitis and cardiovascular disease (CVD) risk in older women, which is the objective of the present investigation. Participants were 57 001 postmenopausal women ages 55 to 89 years (mean 68 years; >85% 60 and older) who were enrolled (1993-1998) in the Women's Health Initiative Observational Study, and were without known CVD when history of periodontitis and edentulism was assessed by questionnaire at study Year-5 (1998-2003). There were 3589 incident CVD events and 3816 total deaths during a mean follow-up of 6.7 years. In multivariable analysis, periodontitis was not associated with CVD events, but was associated with higher total mortality (hazard ratio (HR)=1.12, 95% CI: 1.05-1.21). Edentulism was associated with higher age- and smoking-adjusted risks of CVD (HR=1.42, 95% CI: 1.27-1.59) and mortality (HR=1.47, 95% CI: 1.32-1.63). Further adjustment eliminated the association with CVD, but mortality remained significantly increased (HR=1.17, 95% CI: 1.02-1.33). Stratification on age, race-ethnicity, smoking, and diabetes mellitus yielded comparable results; however, edentulism was more strongly associated with CVD in women reporting ≥1 dental visit (HR=1.57) compared with

ObjectiveVasomotor symptoms (VMS) may be a marker of cardiovascular risk. We aimed to evaluate the cross-sectional association of VMS presence and severity with hemostatic parameter levels measured at baseline among Women's Health Initiative (WHI) Hormone Therapy trial postmenopausal participants.MethodsThis cross-sectional analysis included 2,148 postmenopausal women with measures of VMS presence and severity reported in the 4 weeks before WHI baseline, who were not using warfarin or hormone therapy and for whom the following baseline hemostatic parameters were measured within the WHI Cardiovascular Disease Biomarker Case-Control Study: antithrombin, plasminogen activator inhibitor-1, protein C antigen, total and free protein S antigen, total and free tissue factor pathway inhibitor, D-dimer, normalized activated protein C sensitivity ratio, and thrombin generation. Using multiple linear regression, we estimated the adjusted average difference in each hemostatic parameter associated with VMS presence and severity. A multiple comparisons-corrected P value was computed using the P-min procedure to determine statistical significance of our smallest observed P value.ResultsWomen were 67 years of age on average and 33% reported VMS presence at baseline. There was some suggestion that VMS presence may be associated with a -0.34 adjusted difference in normalized activated protein C sensitivity ratio compared with no VMS (95% CI, -0.60 to -0.087; P = 0.009), but this association was not significant after correction for multiple comparisons (P = 0.073). VMS presence or severity was not significantly associated with the other hemostatic parameters.ConclusionsWe found no convincing evidence that VMS presence or severity was associated with levels of hemostatic parameters among postmenopausal women.

BackgroundMuch controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE).MethodsWe performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis.ResultsThe studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively.ConclusionsExcept for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE.

INTRODUCTION:The perioperative pain experience shows great interindividual variability and is difficult to predict. The mu-1 opioid receptor gene (OPRM1) is known to play an important role in opioid-pain pathways. Since deoxyribonucleic acid (DNA) methylation is a potent repressor of gene expression, DNA methylation was evaluated at the OPRM1 promoter, as a predictor of preoperative, acute, and chronic postsurgical pain (CPSP). METHODS:A prospective observational cohort study was conducted in 133 adolescents with idiopathic scoliosis undergoing spine fusion under standard protocols. Data regarding pain, opioid consumption, anxiety, and catastrophizing (using validated questionnaires) were collected before and 2-3 months postsurgery. Outcomes evaluated were preoperative pain, acute postoperative pain (area under curve [AUC] for pain scores over 48 hours), and CPSP (numerical rating scale >3/10 at 2-3 months postsurgery). Blood samples collected preoperatively were analyzed for DNA methylation by pyrosequencing of 22 CpG sites at the OPRM1 gene promoter. The association of each pain outcome with the methylation percentage of each CpG site was assessed using multivariable regression, adjusting for significant (P

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.