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The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. 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 associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Animal studies have revealed gut microbial and metabolic pathways of blood pressure (BP) regulation, yet few epidemiological studies have collected microbiota and metabolomics data in the same individuals. In a population-based, Chinese cohort who did not report antihypertension medication use (30–69 years, 54% women), thus minimizing BP treatment effects, we examined multivariable-adjusted (eg, diet, physical activity, smoking, kidney function), cross-sectional associations between measures of gut microbiota (16S rRNA [ribosomal ribonucleic acid], N=1003), and plasma metabolome (liquid chromatography-mass spectrometry, N=434) with systolic (SBP, mean [SD]=126.0 [17.4] mm Hg) and diastolic BP (DBP [80.7 (10.7) mm Hg]). We found that the overall microbial community assessed by principal coordinate analysis varied by SBP and DBP (permutational multivariate ANOVA P P P

Background: There is increasing evidence that sodium consumption alters the gut microbiota and host metabolome in murine models and small studies in humans. However, there is a lack of population-based studies that capture large variations in sodium consumption as well as potassium consumption. Objective: We examined the associations of energy-adjusted dietary sodium (milligrams/kilocalorie), potassium, and sodium-to-potassium (Na/K) ratio with the microbiota and plasma metabolome in a well-characterized Chinese cohort with habitual excessive sodium and deficient potassium consumption. Methods: We estimated dietary intakes from 3 consecutive validated 24-h recalls and household inventories. In 2833 adults (18-80 y old, 51.2% females), we analyzed microbial (genus-level 16S ribosomal RNA) between-person diversity, using distance-based redundancy analysis (dbRDA), and within-person diversity and taxa abundance using linear regression, accounting for geographic variation in both. In a subsample (n = 392), we analyzed the overall metabolome (dbRDA) and individual metabolites (linear regression). P values for specific taxa and metabolites were false discovery rate adjusted (q-value). Results: Sodium, potassium, and Na/K ratio were associated with microbial between-person diversity (dbRDA P < 0.01) and several specific taxa with large geographic variation, including pathogenic Staphylococcus and Moraxellaceae, and SCFA-producing Phascolarctobacterium and Lachnospiraceae (q-value < 0.05). For example, sodium and Na/K ratio were positively associated with Staphylococcus and Moraxellaceae in Liaoning, whereas potassium was positively associated with 2 genera from Lachnospiraceae in Shanghai. Additionally, sodium, potassium, and Na/K ratio were associated with the overall metabolome (dbRDA P ≤ 0.01) and several individual metabolites, including butyrate/isobutyrate and gut-derived phenolics such as 1,2,3-benzenetriol sulfate, which was negatively associated with sodium in Guizhou (q-value < 0.05). Conclusions: Our findings suggest that sodium and potassium consumption is associated with taxa and metabolites that have been implicated in cardiometabolic health, providing insights into the potential roles of gut microbiota and host metabolites in the pathogenesis of sodium- and potassium-associated diseases. More studies are needed to confirm our results.

Mitigating age-related disease and disability presents challenges. Physical activity (PA) may be influential for prolonging health and functioning, warranting characterization of its patterns over the life course in population-based data. With the availability of up to three self-reported assessments of past year leisure-time PA (LTPA) over multiple decades in 15,036 participants (26% African American; 55% women; mean baseline age=54; median follow-up=23 years) from the Atherosclerosis Risk in Communities (ARIC) Study sampled from four U.S. communities, race-sex-stratified trajectories of average weekly intensity (metabolic equivalent of task (MET)), duration (hours), and energy expenditure or volume (MET-h) of LTPA were developed from age 45 to 90 using joint models to accommodate expected non-ignorable attrition. Declines in weekly LTPA intensity, duration, and volume from age 70 to 90 were observed in white women (2.9 to 1.2 MET; 2.5 to 0.6 h; 11.1 to 2.6 MET-h), white men (2.5 to 1.0 MET; 3.5 to 1.8 h; 15.5 to 6.4 MET-h), African American women (2.5 to 2.4 MET; 0.8 to 0.1 h; 6.7 to 6.0 MET-h), and African American men (2.3 to 1.4 MET; 1.5 to 0.6 h; 8.0 to 2.3 MET-h). These data reveal population-wide shifts towards less active lifestyles in older adulthood.

Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. Conclusion This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.

Background Research examining the role of obesity in cardiovascular disease (CVD) often fails to adequately consider heterogeneity in obesity severity, distribution, and duration. Methods and Results We here use multivariate latent class mixed models in the biracial Atherosclerosis Risk in Communities study (N=14 514; mean age=54 years; 55% female) to associate obesity subclasses (derived from body mass index, waist circumference, self‐reported weight at age 25, tricep skinfold, and calf circumference across up to four triennial visits) with total mortality, incident CVD, and CVD risk factors. We identified four obesity subclasses, summarized by their body mass index and waist circumference slope as decline (4.1%), stable/slow decline (67.8%), moderate increase (24.6%), and rapid increase (3.6%) subclasses. Compared with participants in the stable/slow decline subclass, the decline subclass was associated with elevated mortality (hazard ratio [HR] 1.45, 95% CI 1.31, 1.60, P P P =0.0002), and coronary heart disease (HR 1.36, 95% CI 1.14, 1.63, P =0.0008), adjusting for baseline body mass index and CVD risk factor profile. The moderate increase latent class was not associated with any significant differences in CVD risk as compared to the stable/slow decline latent class and was associated with a lower overall risk of mortality (HR 0.85, 95% CI 0.80, 0.90, P P =0.004). Conclusions Consideration of heterogeneity and longitudinal changes in obesity measures is needed in clinical care for a more precision‐oriented view of CVD risk.

Objective This study aimed to understand how an increase in abdominal adiposity relative to overall adiposity is associated with blood pressure (BP) change. Methods A sex-stratified mixed linear model was used to examine the association (95% CI) between annual changes in waist circumference (WC) and systolic blood pressure and diastolic blood pressure, estimated from two to eight repeated measures across the 1993-2015 China Health and Nutrition Survey, among 5,742 men and 5,972 women (18-66 years) with no history of antihypertension medication use. Results The association between annual WC change and BP change remained statistically significant but was attenuated after controlling for annual BMI change, regardless of baseline abdominal obesity or overweight status. Each 10-cm annual WC gain in men and women was associated with a 0.98-mm Hg (95% CI: 0.61-1.35) and a 0.97-mm Hg (95% CI: 0.62-1.32) annual increase in systolic blood pressure and a 1.13-mm Hg (95% CI: 0.87-1.38) and a 0.74-mm Hg (95% CI: 0.51-0.97) annual increase in diastolic blood pressure, respectively, independent of annual BMI change. Conclusions WC gain may elevate BP even in the absence of BMI gain. BP management that addresses only BMI gain could overlook individuals at risk of elevated BP who have increased WC but not BMI.

BACKGROUND Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal ( RESULTS The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

US Latinos, a growing, aging population, are disproportionately burdened by cognitive decline and dementia. Identification of modifiable risk factors is needed for interventions aimed at reducing risk. Broad sociocultural context may illuminate complex etiology among culturally diverse Latinos. Among 1,418 older (≥60 years), low–socioeconomic position (SEP) Latinos (predominantly of Mexican descent) in Sacramento, California, we examined whether US acculturation was associated with cognitive performance, cognitive decline, and dementia/ cognitive impairment without dementia over a 10-year period and whether education modified the associations (Sacramento Area Latino Study on Aging, 1998–2008). Analyses used linear mixed models, competing-risk regression, and inverse probability of censoring weights for attrition. Participants with high US acculturation had better cognitive performance (0.21 fewer cognitive errors at grand-mean-centered age 70 years) than those with low acculturation after adjustment for sociodemographic factors, practice effects, and survey language. Results may have been driven by cultural language use rather than identity factors (e.g., ethnic identity, interactions). Rate of cognitive decline and risk of dementia/cognitive impairment without dementia did not differ by acculturation, regardless of education (β = 0.00 (standard error, 0.00) and hazard ratio = 0.81 (95% confidence interval: 0.49, 1.35), respectively). High US acculturation was associated with better cognitive performance among these older, low-SEP Latinos. Acculturation may benefit cognition when SEP is low. Future studies should incorporate extended longitudinal assessments among more diverse groups.

Epidemiological studies suggest a positive association between obesity and fecal short-chain fatty acids (SCFAs) produced by microbial fermentation of dietary carbohydrates, while animal models suggest increased energy harvest through colonic SCFA production in obesity. However, there is a lack of human population-based studies with dietary intake data, plasma SCFAs, gut microbial, and anthropometric data. In 490 Chinese adults aged 30&ndash, 68 years, we examined the associations between key plasma SCFAs (butyrate/isobutyrate, isovalerate, and valerate measured by non-targeted plasma metabolomics) with body mass index (BMI) using multivariable-adjusted linear regression. We then assessed whether overweight (BMI &ge, 24 kg/m2) modified the association between dietary-precursors of SCFAs (insoluble fiber, total carbohydrates, and high-fiber foods) with plasma SCFAs. In a sub-sample (n = 209) with gut metagenome data, we examined the association between gut microbial SCFA-producers with BMI. We found positive associations between butyrate/isobutyrate and BMI (p-value &lt, 0.05). The associations between insoluble fiber and butyrate/isobutyrate differed by overweight (p-value &lt, 0.10). There was no statistical evidence for an association between microbial SCFA-producers and BMI. In sum, plasma SCFAs were positively associated with BMI and that the colonic fermentation of fiber may differ for adults with versus without overweight.

Background Excess adiposity, which affects 69% of US adults, increases coronary heart disease ( CHD ) risk in an association that manifests below conventional obesity cut points. The population‐level impact on CHD risk that is attainable through modest adiposity reductions in populations is not well characterized. We estimated the effect of hypothetical reductions in both body mass index ( BMI ) and waist circumference ( WC ) on CHD incidence. Methods and Results The study population included 13 610 ARIC (Atherosclerosis Risk in Communities) participants. Our hypothetical reduction in BMI or WC was applied relative to the temporal trend, with no hypothetical reduction among those with BMI >24 or WC >88 cm, respectively. This threshold for hypothetical reduction is near the clinical guidelines for excess adiposity. CHD risk differences compared the hypothetical reduction with no reduction. Sensitivity analysis was conducted to estimate the effect of applying the hypothetical BMI reduction at the established overweight cut point of 25. Cumulative 12‐year CHD incidence with no intervention was 6.3% (95% CI, 5.9–6.8%). Risk differences following the hypothetical BMI and WC reductions were −0.6% (95% CI, −1.0% to −0.1%) and −1.0% (95% CI, −1.4% to −0.5%), respectively. These results were robust for the sensitivity analyses. Consequently, we estimated that this hypothetical reduction of 5% in BMI and WC, respectively, could have prevented 9% and 16%, respectively, of the CHD events occurring in this study population over 12 years, after adjustment for established CHD risk factors. Conclusions Meaningful CHD risk reductions could derive from modest reductions in adiposity attainable through lifestyle modification.

Background Experimental and observational research has suggested the potential for increased type 2 diabetes (T2D) risk among populations taking statins for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, few studies have directly compared statin-associated benefits and harms or examined heterogeneity by population subgroups or assumed treatment effect. Thus, we compared ASCVD risk reduction and T2D incidence increases across 3 statin treatment guidelines or recommendations among adults without a history of ASCVD or T2D who were eligible for statin treatment initiation. Methods and findings Simulations were conducted using Markov models that integrated data from contemporary population-based studies of non-Hispanic African American and white adults aged 40–75 years with published meta-analyses. Statin treatment eligibility was determined by predicted 10-year ASCVD risk (5%, 7.5%, or 10%). We calculated the number needed to treat (NNT) to prevent one ASCVD event and the number needed to harm (NNH) to incur one incident case of T2D. The likelihood to be helped or harmed (LHH) was calculated as ratio of NNH to NNT. Heterogeneity in statin-associated benefit was examined by sex, age, and statin-associated T2D relative risk (RR) (range: 1.11–1.55). A total of 61,125,042 U.S. adults (58.5% female; 89.4% white; mean age = 54.7 years) composed our primary prevention population, among whom 13–28 million adults were eligible for statin initiation. Overall, the number of ASCVD events prevented was at least twice as large as the number of incident cases of T2D incurred (LHH range: 2.26–2.90). However, the number of T2D cases incurred surpassed the number of ASCVD events prevented when higher statin-associated T2D RRs were assumed (LHH range: 0.72–0.94). In addition, females (LHH range: 1.74–2.40) and adults aged 40–50 years (LHH range: 1.00–1.14) received lower absolute benefits of statin treatment compared with males (LHH range: 2.55–3.00) and adults aged 70–75 years (LHH range: 3.95–3.96). Projected differences in LHH by age and sex became more pronounced as statin-associated T2D RR increased, with a majority of scenarios projecting LHHs < 1 for females and adults aged 40–50 years. This study’s primary limitation was uncertainty in estimates of statin-associated T2D risk, highlighting areas in which additional clinical and public health research is needed. Conclusions Our projections suggest that females and younger adult populations shoulder the highest relative burden of statin-associated T2D risk., Joseph Engada and colleagues model the reduction in cardiovascular disease risk across three statin treatment guidelines., Author summary Why was this study done? Statins are a widely prescribed medication used to prevent atherosclerotic cardiovascular disease (ASCVD). Past research has suggested the potential for increased type 2 diabetes (T2D) risk among populations taking statins. Few studies have compared statin-associated benefits (ASCVD prevention) and statin-associated harms (increased T2D incidence) using different statin treatment guidelines and recommendations in contemporary U.S. populations or by population subgroups defined by age and sex. What did the researchers do and find? We developed a simulation model to compare statin treatment guidelines and recommendations in a U.S. population without T2D or a previous ASCVD event by synthesizing data from contemporary population-based studies with published meta-analyses. Using the model, our projections suggested that the number of ASCVD events prevented was at least twice as large as the number of incident cases of T2D incurred. However, the number of T2D cases incurred surpassed the number of ASCVD events prevented when higher statin-associated T2D relative risks (RRs) were assumed. Our models also suggest that females and the youngest adults received lower absolute benefits of statin treatment compared with males and the oldest adults. Projected differences by age and sex also were more pronounced as the effect of statins on T2D was increased. For females and younger populations, a majority of these scenarios suggested that the number of new T2D cases was greater than the number of ASCVD events prevented. What do these findings mean? Our projections suggested that females and younger adult populations shoulder the highest relative burden of statin-associated T2D risk. Clinical and public health research to more precisely quantify statin’s effects on T2D is needed given the sensitivity of projections to this simulation parameter.

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10−8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10−8) and multi-trait analysis (P = 2.9 × 10−9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Background Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment—lymph node evaluation and radiologic imaging—EMT marker measurements might improve the ability of clinicians to assess the patient’s risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. Methods We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. Results All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. Conclusions The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions. Electronic supplementary material The online version of this article (10.1186/s12885-017-3964-3) contains supplementary material, which is available to authorized users.

ObjectivePR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies.MethodsStudy-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results.ResultsWe identified a novel genome-wide association (P−8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (PConclusionsOur results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations.

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, 3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.

Background Evidence shows that dietary factors play an important role in blood pressure. However, there is no clear understanding of whether hypertension diagnosis is associated with dietary modifications. The aim of this study is to estimate the longitudinal association between hypertension diagnosis and subsequent changes (within 2–4 years) in dietary sodium, potassium, and sodium‐potassium (Na/K) ratio. Methods and Results We included adults (18–75 years, n=16 264) from up to 9 waves (1991–2015) of the China Health and Nutrition Survey. Diet data were collected using three 24‐hour dietary recalls and a household food inventory. We used fixed‐effects models to estimate the association between newly self‐reported diagnosed hypertension and subsequent within‐individual changes in sodium, potassium, and Na/K ratio. We also examined changes among couples and at the household level. Results suggest that on average, men who were diagnosed with hypertension decreased their sodium intake by 251 mg/d and their Na/K ratio by 0.19 within 2 to 4 years after diagnosis ( P P Conclusions Our findings suggest that hypertension diagnosis for a man may result in modest dietary improvements for him, his wife, and other household members. Yet, diagnosis for a woman does not seem to result in dietary changes for her or her household members.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11–34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations., Author summary Admixed African and Hispanic/Latino populations remain understudied in genetic studies of complex diseases. These populations have more complex linkage disequilibrium (LD) structure that can impair mapping of variants. Genotype imputation represents an approach to improve genome coverage, especially for rare or ancestry-specific variation; however, these understudied populations also have smaller relevant imputation reference panels. In this study, we leveraged >100,000 phased sequences generated from the multi-ethnic NHLBI TOPMed project for imputation in ~21,600 individuals of African ancestry (AAs) and ~21,700 Hispanics/Latinos. We demonstrated substantially higher imputation quality for low frequency and rare variants in comparison to the 1000 Genomes Project and Haplotype Reference Consortium reference panels. Analysis of quantitative hematological traits led to the discovery of associations with two rare variants in the HBB gene; one of these variants was replicated in an independent sample, and the other is known to cause anemia in the homozygous state. By comparison, the same HBB variants would not have been genome-wide significant using current reference panels due to lower imputation quality. Our findings demonstrate the power of TOPMed whole genome sequencing data for imputation and subsequent association analysis in admixed African and Hispanic/Latino populations.

Acculturation may shape the disproportionate burden of poor sleep among Latinos in the United States. Existing studies are limited by unidimensional acculturation proxies that are incapable of capturing cultural complexities across generations. Understanding how acculturation relates to sleep may lead to the identification of modifiable intervention targets. We used multivariable regression and latent class methods to examine cross-sectional associations between a validated multidimensional scale of US acculturation and self-reported poor sleep measures. We analyzed an intergenerational cohort: first-generation (GEN1) older Latinos (Sacramento Area Latino Study on Aging; N = 1,716; median age: 69.5) and second-generation (GEN2) middle-aged offspring and relatives of GEN1 (Niños Lifestyle and Diabetes Study; N = 670; median age: 54.0) in Sacramento, California. GEN1 with high US acculturation, compared with high acculturation towards another origin/ancestral country, had less restless sleep (prevalence ratio [PR] [95% confidence interval (CI)]: 0.67 [0.54, 0.84]) and a higher likelihood of being in the best sleep class than the worst (OR [95% CI]: 1.62 [1.09, 2.40]), but among nonmanual occupations, high intergenerational US acculturation was associated with more general fatigue (PR [95% CI: 1.86 [1.11, 3.10]). GEN2 with high intergenerational US acculturation reported shorter sleep (PR [95% CI]: 2.86 [1.02, 7.99]). High US acculturation shaped sleep differentially by generation, socioeconomic context, and intergenerational acculturative status. High US acculturation was associated with better sleep among older, lower socioeconomic Latinos, but with shorter sleep duration among middle-aged, higher socioeconomic Latinos; results also differed by parental acculturation status. Upon replication, future studies should incorporate prospective and intergenerational designs to uncover sociobehavioral pathways by which acculturation may shape sleep to ultimately inform intervention efforts.

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio- metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p

Key Points Question Did US mortality trends during 1999-2011 and 2011-2018 differ for obesity-associated cancers and cancers not associated with obesity? Findings Using 20 years of cross-sectional mortality data, this study found that after 2011, mortality improvements accelerated for cancers not associated with obesity. In contrast, mortality improvements decelerated for obesity-associated cancers, paralleling recent trends for heart disease mortality. Meaning The study results are consistent with the hypothesis that the obesity epidemic may have been associated with slowed improvement in obesity-associated cancer mortality., Importance Heart disease and cancer are the 2 major diseases associated with mortality risk in the United States. Four decades of improvements in heart disease mortality slowed after 2011; this slowing has been associated with the obesity epidemic. The same pattern has not been observed for total cancer mortality. However, trends in total cancer mortality may obscure patterns specific to obesity-associated cancers. Objective To investigate whether trends in obesity-associated cancer mortality mirror the slowed mortality improvements observed for heart disease associated with the obesity epidemic. Design, Setting, and Participants This cross-sectional study compared US mortality trends for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision–defined cancer (total cancer, obesity-associated cancer, and cancer not associated with obesity) and heart disease deaths from January 1, 1999, to December 31, 2018. Data were included on decedents with complete information on the underlying cause of death, age, sex, race, and ethnicity. Exposures Changes in age-adjusted cause-specific mortality rates between 1999-2011 and 2011-2018 were compared. Main Outcomes and Measures Annual relative rates of change in age-adjusted mortality rates (AAMRs) in the overall population and stratified by sex, race, and ethnicity were estimated using Poisson regression. Differences in AAMR annual relative rates of change before and after 2011 were evaluated using Wald tests. Results A total of 50 163 483 decedents met the inclusion criteria (50.1% female decedents, 79.9% non-Hispanic White decedents, and 11.7% non-Hispanic Black decedents; mean [SD] age, 72.8 [18.5] years). In contrast with heart disease mortality, for which improvements slowed between 1999-2011 and 2011-2018, decreases in total cancer AAMR relative change accelerated between 1999-2011 (−1.48 [95% CI, −1.43 to −1.52]) and 2011-2018 (−1.77 [95% CI, −1.67 to −1.86]) (P, This cross-sectional study investigates whether trends in obesity-associated cancer mortality mirror the slowed mortality improvements observed for heart disease associated with the obesity epidemic.

AIMS To conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations. METHODS Studies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model. RESULTS We identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran =

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

While much of the chronic kidney disease (CKD) literature focuses on the role of blood pressure reduction in delaying CKD progression, little is known about the benefits of modest population-wide decrements in blood pressure on incident CKD. The authors used multivariable linear regression to characterize the impact on incident CKD of two approaches for blood pressure management: (1) a 1-mm Hg reduction in systolic BP across the entire study population; and (2) a 10% reduction in participants with unaware, untreated, and uncontrolled BP above goal as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) thresholds. Over a mean of 20 years of follow-up (ARIC [Atherosclerosis Risk in Communities] study, n = 15 390), 3852 incident CKD events were ascertained. After adjustment, a 1-mm Hg decrement in systolic BP across the population was associated with an estimated 11.7 (95% confidence interval [CI], 6.2-17.3) and 13.4 (95% CI, 10.3-16.6) fewer CKD events per 100 000 person-years in blacks and whites, respectively. Among participants with BP above JNC 7 goal, a 10% decrease in unaware, untreated, or uncontrolled BP was associated with 3.2 (95% CI, 2.0-4.9), 2.8 (95% CI, 1.8-4.3), and 5.8 (95% CI, 3.6-8.8) fewer CKD events per 100 000 person-years in blacks and 3.1 (95% CI, 2.3-4.1), 0.7 (95% CI, 0.5-0.9), and 1.0 (95% CI, 1.3-2.4) fewer CKD events per 100 000 person-years in whites. Modest population-wide reductions in systolic BP hold potential for the primary prevention of CKD.

To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (≥20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007–2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008–2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C.

Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Background and Purpose— Alcohol consumption is common in the United States and may confer beneficial cardiovascular effects at light-to-moderate doses. The alcohol–stroke relationship remains debated. We estimated the relationship between midlife, self-reported alcohol consumption and ischemic stroke and intracerebral hemorrhage (ICH) in a biracial cohort. Methods— We examined 12 433 never and current drinkers in the Atherosclerosis Risk in Communities study, aged 45 to 64 years at baseline. Participants self-reported usual drinks per week of beer, wine, and liquor at baseline. We used multivariate Cox proportional hazards regression to assess the association of current alcohol consumption relative to lifetime abstention with incident ischemic stroke and ICH and modification by sex–race group. We modeled alcohol intake with quadratic splines to further assess dose–response relationships. Results— One third of participants self-reported abstention, 39% and 24%, respectively, consumed ≤3 and 4 to 17 drinks/wk, and only 5% reported heavier drinking. There were 773 ischemic strokes and 81 ICH over follow-up (median ≈22.6 years). For ischemic stroke, light and moderate alcohol consumption were not associated with incidence (hazard ratios, 0.98; 95% CI, 0.79–1.21; 1.06, 0.84–1.34), whereas heavier drinking was associated with a 31% increased rate relative to abstention (hazard ratios, 1.31; 95% CI, 0.92–1.86). For ICH, moderate-to-heavy (hazard ratios, 1.99; 95% CI, 1.07–3.70), but not light, consumption increased incidence. Conclusions— Self-reported light-to-moderate alcohol consumption at midlife was not associated with reduced stroke risk compared with abstention over 20 years of follow-up in the Atherosclerosis Risk in Communities study. Heavier consumption increased the risk for both outcomes as did moderate intake for ICH.

Anemia is associated with poor prognosis in patients hospitalized with acute decompensated heart failure (ADHF). Whether the impact of anemia differs by heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) is uncertain. We examined hospital surveillance data captured by the Atherosclerosis Risk in Communities Study from January 1, 2005, to December 31, 2010. Diagnoses of ADHF were validated by standardized physician review of the medical record. Anemia was classified using the World Health Organization criteria (12 g/dl for women and13 g/dl for men), and HF type was determined by the ejection fraction (40% for HFrEF and ≥40% for HFpEF). Hospital length of stay and 1-year mortality outcomes were analyzed by multivariable regression, weighted to account for the sampling design, and adjusted for demographics and clinical covariates. Over 6 years, 15,461 (weighted) hospitalized events for ADHF (59% HFrEF) occurred in the catchment of the Atherosclerosis Risk in Communities, based on 3,309 sampled events. Anemia was associated with a mortality hazard ratio of 2.1 (95% confidence interval [CI] 1.6 to 2.7) in patients classified with HFpEF and 1.4 (95% CI 1.1 to 1.7) in those with HFrEF; p for interaction = 0.05. The mean increase in length of hospital stay associated with anemia was 3.5 days (95% CI 3.4 to 3.6) for patients with HFpEF, compared with 1.8 days (95% CI 1.7 to 1.9) for those with HFrEF; p for interaction0.0001. In conclusion, the incremental risks of death and lengthened hospital stay associated with anemia are more pronounced in ADHF patients classified with HFpEF than HFrEF.

Background: It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%–7.5%) 10-year predicted risk of ASCVD. Methods and Results: We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms. Conclusions: Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1–3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4–10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States—where minority populations have a disproportionately higher burden of chronic conditions13—the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

OBJECTIVE: PR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure, and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed, and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14,756 participants of Hispanic/Latino ancestry from three studies. METHODS: Study-specific summary results of the association between 1000 Genomes Phase 1 imputed SNPs and PR assumed an additive genetic model and were adjusted for global ancestry, study center/region, and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African, and European descent. ENCODE and RoadMap data were used to annotate results. RESULTS: We identified a novel genome-wide association (P

Background Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. Methods and results We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, p interaction =3.9e −9 ) and rs9830388 in UBE2E2 (β=25.2, p interaction =1.7e −8 ). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, p interaction =2.55e −8 ). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (p interaction >0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. Conclusions Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

Importance Many studies have assessed racial/ethnic and sex disparities in the prevalence of elevated blood pressure (BP) from childhood to adulthood, yet few have examined differences in age-specific transitions between categories of BP over the life course in contemporary, multiracial/multiethnic populations. Objective To estimate age, racial/ethnic, and sex–specific annual net transition probabilities between categories of BP using Markov modeling of cross-sectional data from the National Health and Nutrition Examination Survey. Design, Setting, and Participants National probability sample (National Health and Nutrition Examination Survey in 2007-2008, 2009-2010, and 2011-2012) of 17 747 African American, white American, and Mexican American participants aged 8 to 80 years. The data were analyzed from September 2014 to November 2015. Main Outcomes and Measures Age-specific American Heart Association–defined BP categories. Results Three National Health and Nutrition Examination Survey cross-sectional samples were used to characterize the ages at which self-reported African American (n = 4973), white American (n = 8886), and Mexican American (n = 3888) populations transitioned between ideal BP, prehypertension, and hypertension across the life course. At age 8 years, disparities in the prevalence of ideal BP were observed, with the prevalence being lower among boys (86.6%-88.8%) compared with girls (93.0%-96.3%). From ages 8 to 30 years, annual net transition probabilities from ideal to prehypertension among male individuals were more than 2 times the net transition probabilities of their female counterparts. The largest net transition probabilities for ages 8 to 30 years occurred in African American young men, among whom a net 2.9% (95% CI, 2.3%-3.4%) of those with ideal BP transitioned to prehypertension 1 year later. Mexican American young women aged 8 to 30 years experienced the lowest ideal to prehypertension net transition probabilities (0.6%; 95% CI, 0.3%-0.8%). After age 40 years, ideal to prehypertension net transition probabilities stabilized or decreased (range, 3.0%-4.5%) for men, whereas net transition probabilities for women increased rapidly (range, 2.6%-13.0%). Mexican American women exhibited the largest ideal to prehypertension net transition probabilities after age 60 years. The largest prehypertension to hypertension net transition probabilities occurred at young ages in boys of white race/ethnicity and African Americans, approximately age 8 years and age 25 years, respectively, while net transition probabilities for white women and Mexican Americans increased over the life course. Conclusions and Relevance Heterogeneity in net transition probabilities from ideal BP emerge during childhood, with associated rapid declines in ideal BP observed in boys and African Americans, thus introducing disparities. Primordial prevention beginning in childhood and into early adulthood is necessary to preempt the development of prehypertension and hypertension, as well as associated racial/ethnic and sex disparities.

Systemic arterial compliance, the systolic to diastolic change in volume divided by the change in pressure, is a measure of vascular function that may be used to predict cardiovascular outcomes. The gold standard method of measurement, quantifying stroke volume and aortic pulse pressure (PP) invasively by thermodilution and catheter manometers, is a validated index of total arterial compliance.1,2 However, noninvasive estimates of systemic arterial compliance can be derived by the ratio of echocardiographic stroke volume and brachial arterial PP (SV/PP).2 Although noninvasive estimates of arterial compliance are well suited for prospective screenings and longitudinal epidemiologic studies, most observations relating arterial compliance and cardiovascular disease (CVD) have been drawn from cross-sectional analyses. Age,3,4 hypertension,5 concentric left ventricular hypertrophy,6 diastolic left ventricular dysfunction,7–9 hypercholesterolemia,10 fasting insulin,7,11 and Framingham risk score12 have all been associated with echocardiographic arterial compliance. Prospective analyses of echocardiographic arterial compliance have primarily been limited to Europeans but have predicted mortality in patients with diabetes13 and fatal and nonfatal cardiovascular events in hypertensives14,15 and in the general population.8 To date, few studies have assessed echocardiographic systemic arterial compliance in blacks, and none have analyzed cardiovascular events as explicit, rather than composite, outcomes. We analyzed associations between echocardiographic arterial compliance and incident stroke, heart failure, and coronary events in a cohort of blacks free of prevalent CVD and followed prospectively by the Atherosclerosis Risk in Communities (ARIC) study. We also compared the risks of cardiovascular outcomes associated with arterial compliance with those associated with PP and examined model performances to compare the predictive validity of echocardiographic arterial compliance and PP models.

Although ambient concentrations of particulate matter ≤10 μm (PM10) are often used as proxies for total personal exposure, correlation (r) between ambient and personal PM10 concentrations varies. Factors underlying this variation and its effect on health outcome-PM exposure relationships remain poorly understood.We conducted a random-effects meta-analysis to estimate effects of study, participant, and environmental factors on r; used the estimates to impute personal exposure from ambient PM10 concentrations among 4,012 nonsmoking, participants with diabetes in the Women's Health Initiative clinical trial; and then estimated the associations of ambient and imputed personal PM10 concentrations with electrocardiographic measures, such as heart rate variability.We identified 15 studies (in years 1990-2009) of 342 participants in five countries. The median r was 0.46 (range = 0.13 to 0.72). There was little evidence of funnel plot asymmetry but substantial heterogeneity of r, which increased 0.05 (95% confidence interval = 0.01 to 0.09) per 10 µg/m increase in mean ambient PM10 concentration. Substituting imputed personal exposure for ambient PM10 concentrations shifted mean percent changes in electrocardiographic measures per 10 µg/m increase in exposure away from the null and decreased their precision, for example, -2.0% (-4.6% to 0.7%) versus -7.9% (-15.9% to 0.9%), for the standard deviation of normal-to-normal RR interval duration.Analogous distributions and heterogeneity of r in extant meta-analyses of ambient and personal PM2.5 concentrations suggest that observed shifts in mean percent change and decreases in precision may be generalizable across particle size.

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with pCONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

Understanding demographic differences in transitions across physical activity (PA) levels is important for informing PA-promoting interventions, yet few studies have examined these transitions in contemporary multi-ethnic adult populations. We estimated age-, race/ethnicity-, and sex-specific 1-year net transition probabilities (NTPs) for National Health and Nutrition Examination Survey (2007–2012, n=11,556) and Hispanic Community Health Study/Study of Latinos (2008–2011, n=15,585) adult participants using novel Markov-type state transition models developed for cross-sectional data. Among populations with ideal PA (≥150 minutes/week; ranging from 56% (non-Hispanic black females) to 88% (non-Hispanic white males) at age 20), NTPs to intermediate PA (>0–

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

Background Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. Objective To identify novel genetic variants associated with resting heart rate in African Americans. Methods Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci ( P ≤2.5×10 −8 ). Results Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10 −15 ). This SNP was approximately 350 kb downstream of GJA1 , a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6 , which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. Conclusions An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

Background— Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. Methods and Results— First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval ( P =0.94). Genome-wide significant associations ( P –8 ) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P =2×10 –15 ) and ATP1B1 (rs1320976, P =2×10 –10 ). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values ( P –5 ) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1 , KCNH2 , LITAF , and PLN . Conclusions— We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

Background Studies examining the health effects of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) commonly use ambient PM2.5 concentrations measured at distal monitoring sites as proxies for personal exposure and assume spatial homogeneity of ambient PM2.5. An alternative proxy—the residential outdoor PM2.5 concentration measured adjacent to participant homes—has few advantages under this assumption. Objectives We systematically reviewed the correlation between residential outdoor PM2.5 and personal PM2.5 (r̄j) as a means of comparing the magnitude and sources of measurement error associated with their use as exposure surrogates. Methods We searched seven electronic reference databases for studies of the within-participant residential outdoor-personal PM2.5 correlation. Results The search identified 567 candidate studies, nine of which were abstracted in duplicate, that were published between 1996 and 2008. They represented 329 nonsmoking participants 6–93 years of age in eight U.S. cities, among whom r̄j was estimated (median, 0.53; range, 0.25–0.79) based on a median of seven residential outdoor-personal PM2.5 pairs per participant. We found modest evidence of publication bias (symmetric funnel plot; pBegg = 0.4; pEgger = 0.2); however, we identified evidence of heterogeneity (Cochran’s Q-test p = 0.05). Of the 20 characteristics examined, earlier study midpoints, eastern longitudes, older mean age, higher outdoor temperatures, and lower personal-residential outdoor PM2.5 differences were associated with increased within-participant residential outdoor-personal PM2.5 correlations. Conclusions These findings were similar to those from a contemporaneous meta-analysis that examined ambient-personal PM2.5 correlations (r̄j = median, 0.54; range, 0.09–0.83). Collectively, the meta-analyses suggest that residential outdoor-personal and ambient-personal PM2.5 correlations merit greater consideration when evaluating the potential for bias in studies of PM2.5-mediated health effects.

Aims Although studies of the accuracy of heart failure (HF) classification scoring systems are available, few have examined their performance when restricted to self-reported items. Methods and results We evaluated the association between a simplified version of the Gothenburg score, a validated HF score comprised of cardiac and pulmonary signs and symptoms and medication use, and incident HF hospitalizations in 15 430 Atherosclerosis Risk in Communities (ARIC) Study participants. Gothenburg scores (range: 0–3) were constructed using self-reported items obtained at study baseline (1987–89). Incident HF hospitalization over 14.7 years of follow-up was defined as the first identified hospitalization with an ICD-9 discharge code of 428 (n = 1668). Self-reported Gothenburg scores demonstrated very high agreement with the original metric comprised of self-reported and clinical measures and were directly associated with incident HF hospitalizations: [score = 1: hazard rate ratio (HRR) = 1.23 (1.07–1.42); score = 2: HRR = 2.17 (1.92–2.43); score = 3: HRR = 3.98 (3.37–4.70)]. Conclusion In a population-based cohort, self-reported Gothenburg criteria items were associated with hospitalized HF over a prolonged follow-up time. The association was also consistent across groups defined by sex and race, suggesting that this simple score deserves further study as a screening tool for the identification of individuals at high risk of HF in resource-limited settings.

Elevated blood pressure in midlife contributes significantly to the risk of cardiovascular disease. However, patterns of blood pressure increase may differ among individuals and may result in differential risk. Our goal was to examine the contribution of longitudinal patterns of blood pressure change to incidence of heart failure, coronary heart disease, stroke, and cardiovascular disease mortality. Latent class growth models were used to identify patterns of change in blood pressure across 4 clinical examinations (1987–1998) among 9845 Atherosclerosis Risk in Communities (ARIC) cohort participants (mean age, 53.7 [SD 5.7] years). Patterns of change in systolic blood pressure included slowly and steeply increasing, a decreasing and a sustained elevated blood pressure. Changes in diastolic and mid–blood pressure (½ systolic+½ diastolic) were less pronounced. The association of blood pressure pattern group membership with incidence of clinical outcomes was examined in follow-up from the fourth clinical examination (1996–1998) to December 31, 2011, using Poisson regression models adjusted for demographic and metabolic characteristics, and hypertension medication use. A gradient of rates of all events was observed across the identified patterns. Associations were attenuated after adjustment for covariates. Cumulative systolic blood pressure load, rather than the temporal pattern of change in systolic blood pressure itself, plays a role in determining the risk of cardiovascular disease, in particular, of heart failure and cardiovascular disease mortality, independent of blood pressure level measured at one point in time.

Background US blood pressure reduction policies are largely restricted to hypertensive populations and associated benefits are often estimated based on unrealistic interventions. Methods and Results We used multivariable linear regression to estimate incidence rate differences contrasting the impact of 2 pragmatic hypothetical interventions to reduce coronary heart disease, stroke, and heart failure ( HF ) incidence: (1) a population‐wide intervention that reduced systolic blood pressure by 1 mm Hg and (2) targeted interventions that reduced the prevalence of unaware, untreated, or uncontrolled blood pressure above goal (per Eighth Joint National Committee treatment thresholds) by 10%. In the Atherosclerosis Risk in Communities Study (n=15 744; 45 to 64 years at baseline, 1987–1989), incident coronary heart disease and stroke were adjudicated by physician panels. Incident HF was defined as the first hospitalization with discharge diagnosis code of “428.” A 10% proportional reduction in unaware, untreated, or uncontrolled blood pressure above goal resulted in ≈4.61, 3.55, and 11.01 fewer HF events per 100 000 person‐years in African Americans, and 3.77, 1.63, and 4.44 fewer HF events per 100 000 person‐years, respectively, in whites. In contrast, a 1 mm Hg population‐wide systolic blood pressure reduction was associated with 20.3 and 13.3 fewer HF events per 100 000 person‐years in African Americans and whites, respectively. Estimated event reductions for coronary heart disease and stroke were smaller than for HF , but followed a similar pattern for both population‐wide and targeted interventions. Conclusions Modest population‐wide shifts in systolic blood pressure could have a substantial impact on cardiovascular disease incidence and should be developed in parallel with interventions targeting populations with blood pressure above goal.

Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3–62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point.