Showing papers by "Gerardo Heiss published in 2013"
Fred Hutchinson Cancer Research Center1, Rutgers University2, University of North Carolina at Chapel Hill3, University of Southern California4, Seattle Children's Research Institute5, Pennsylvania State University6, Translational Genomics Research Institute7, Heidelberg University (Ohio)8, Vanderbilt University9, Brown University10, University of Tennessee11, University of Hawaii12, National Institutes of Health13
TL;DR: A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.
Abstract: The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
233 citations
University of North Carolina at Chapel Hill1, University of Mississippi2, Heilongjiang University3, Case Western Reserve University4, Vanderbilt University5, National Institutes of Health6, Washington University in St. Louis7, Loyola University Chicago8, Emory University9, Icahn School of Medicine at Mount Sinai10, Johns Hopkins University11, University of Washington12, University of Virginia13, Stanford University14, University of Texas Health Science Center at Houston15, Wake Forest University16, University of Michigan17, Scripps Research Institute18, Tulane University19, University of Lausanne20, Medical College of Wisconsin21, Fred Hutchinson Cancer Research Center22, Harvard University23, University of Geneva24, Cedars-Sinai Medical Center25, Temple University26, Université de Montréal27, George Washington University28, Dartmouth College29, University of Ibadan30, Columbia University31, Tufts University32, Boston University33, University of Vermont34, Brown University35, AstraZeneca36, Broad Institute37, University of Alabama at Birmingham38, University of Western Ontario39, Northwestern University40, Hennepin County Medical Center41, Group Health Cooperative42, University of Utah43, University of California, San Francisco44, University of Pennsylvania45
TL;DR: It is suggested that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
Abstract: High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10−8) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
180 citations
Pennsylvania State University1, Vanderbilt University2, University of Southern California3, University of North Carolina at Chapel Hill4, Rutgers University5, University of Washington6, Fred Hutchinson Cancer Research Center7, National Institutes of Health8, Ohio State University9, University of Hawaii10, University of Pittsburgh11, University of Iowa12
TL;DR: Using a phenome-wide association study (PheWAS) approach, genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network are tested to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships.
Abstract: Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.
160 citations
TL;DR: From this analysis, it is estimated that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL- C levels.
Abstract: Eric Boerwinkle and colleagues report whole-genome sequencing of a population-based sample of 962 individuals from three Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. They analyze the genetic architecture of high-density lipoprotein cholesterol (HDL-C) levels and estimate that common variation contributes more to HDL-C heritability than rare variation.
130 citations
Houston Methodist Hospital1, Baylor College of Medicine2, Veterans Health Administration3, University of North Carolina at Chapel Hill4, University of Texas Southwestern Medical Center5, Johns Hopkins University6, University of Texas Health Science Center at Houston7, University of Wisconsin-Madison8, National Institutes of Health9, University of Mississippi10, University of Minnesota11
TL;DR: A simple sex-specific model that includes age, race, cTnT, and NT-proBNP provides a good model, whereas adding cTtnT andNT- ProBNP to clinical characteristics results in an excellent HF prediction model.
Abstract: BACKGROUND: Among the various cardiovascular diseases, heart failure (HF) is projected to have the largest increases in incidence over the coming decades; therefore, improving HF prediction is of significant value. We evaluated whether cardiac troponin T (cTnT) measured with a high-sensitivity assay and N-terminal pro–B-type natriuretic peptide (NT-proBNP), biomarkers strongly associated with incident HF, improve HF risk prediction in the Atherosclerosis Risk in Communities (ARIC) study.
METHODS: Using sex-specific models, we added cTnT and NT-proBNP to age and race (“laboratory report” model) and to the ARIC HF model (includes age, race, systolic blood pressure, antihypertensive medication use, current/former smoking, diabetes, body mass index, prevalent coronary heart disease, and heart rate) in 9868 participants without prevalent HF; area under the receiver operating characteristic curve (AUC), integrated discrimination improvement, net reclassification improvement (NRI), and model fit were described.
RESULTS: Over a mean follow-up of 10.4 years, 970 participants developed incident HF. Adding cTnT and NT-proBNP to the ARIC HF model significantly improved all statistical parameters (AUCs increased by 0.040 and 0.057; the continuous NRIs were 50.7% and 54.7% in women and men, respectively). Interestingly, the simpler laboratory report model was statistically no different than the ARIC HF model.
CONCLUSIONS: cTnT and NT-proBNP have significant value in HF risk prediction. A simple sex-specific model that includes age, race, cTnT, and NT-proBNP (which can be incorporated in a laboratory report) provides a good model, whereas adding cTnT and NT-proBNP to clinical characteristics results in an excellent HF prediction model.
84 citations
TL;DR: In these middle-aged adults, six-year cognitive decline was modestly associated with less frequent toothbrushing, plaque deposit, and greater odds of edentulism, but not with other oral behaviors or diseases.
Abstract: Even before dementia becomes apparent, cognitive decline may contribute to deterioration in oral health. This cohort study of middle-aged adults evaluated associations of six-year change in cognitive function with oral health behaviors and conditions in the Atherosclerosis Risk in Communities (ARIC) study. Cognitive function was measured at study visits in 1990-1992 and 1996-1998 with three tests: (a) Delayed Word Recall (DWR), (b) Digit Symbol Substitution (DSS), and (c) Word Fluency (WF). Cognitive decline scores were computed as ‘studentized’ residuals of 1996-1998 scores regressed against 1990-1992 scores. In 1996-1998, 10,050 participants answered dental screening questions, and 5,878 of 8,782 dentate participants received a comprehensive oral examination. Multiple regression models used cognitive change to predict oral health behaviors and conditions with adjustment for covariates. In the fully adjusted models, greater decline in all three measures of cognitive function was associated with increased odds of complete tooth loss. Greater decline in DSS and WF scores was associated with infrequent toothbrushing. Decline in WF scores was also associated with higher plaque levels. In these middle-aged adults, six-year cognitive decline was modestly associated with less frequent toothbrushing, plaque deposit, and greater odds of edentulism, but not with other oral behaviors or diseases.
82 citations
TL;DR: In this article, the authors explored the metabolomic antecedents of developing incident hypertension in a sample of blacks, a population with a high prevalence of hypertension and its comorbidities.
Abstract: Development of hypertension is influenced by genes, environmental effects, and their interactions, and the human metabolome is a measurable manifestation of gene-environment interaction. We explored the metabolomic antecedents of developing incident hypertension in a sample of blacks, a population with a high prevalence of hypertension and its comorbidities. We examined 896 black normotensives (565 women; aged, 45-64 years) from the Atherosclerosis Risk in Communities study, whose metabolome was measured in serum collected at the baseline examination and analyzed by high-throughput methods. The analyses presented here focus on 204 stably measured metabolites during a period of 4 to 6 weeks. Weibull parametric models considering interval censored data were used to assess the hazard ratio for incident hypertension. We used a modified Bonferroni correction accounting for the correlations among metabolites to define a threshold for statistical significance (P<3.9 × 10(-4)). During 10 years of follow-up, 38% of baseline normotensives developed hypertension (n=344). With adjustment for traditional risk factors and estimated glomerular filtration rate, each +1SD difference in baseline 4-hydroxyhippurate, a product of gut microbial fermentation, was associated with 17% higher risk of hypertension (P=2.5 × 10(-4)), which remained significant after adjusting for both baseline systolic and diastolic blood pressure (P=3.8 × 10(-4)). After principal component analyses, a sex steroids pattern was significantly associated with risk of incident hypertension (highest versus lowest quintile hazard ratio, 1.72; 95% confidence interval, 1.05-2.82; P for trend, 0.03), and stratified analyses suggested that this association was consistent in both sexes. Metabolomic analyses identify novel pathways in the pathogenesis of hypertension.
78 citations
TL;DR: A metabolomic analysis of stable serum metabolites among African Americans revealed novel biomarkers associated with incident heart failure independent of traditional risk factors.
Abstract: Heart failure is more prevalent among African Americans than in the general population. Metabolomic studies among African Americans may efficiently identify novel biomarkers of heart failure. We used untargeted methods to measure 204 stable serum metabolites and evaluated their associations with incident heart failure hospitalization (n = 276) after a median follow-up of 20 years (1987-2008) by using Cox regression in data from 1,744 African Americans aged 45-64 years without heart failure at baseline from the Jackson, Mississippi, field center of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for established risk factors, we found that 16 metabolites (6 named with known structural identities and 10 unnamed with unknown structural identities, the latter denoted by using the format X-12345) were associated with incident heart failure (P < 0.0004 based on a modified Bonferroni procedure). Of the 6 named metabolites, 4 are involved in amino acid metabolism, 1 (prolylhydroxyproline) is a dipeptide, and 1 (erythritol) is a sugar alcohol. After additional adjustment for kidney function, 2 metabolites remained associated with incident heart failure (for metabolite X-11308, hazard ratio = 0.75, 95% confidence interval: 0.65, 0.86; for metabolite X-11787, hazard ratio = 1.23, 95% confidence interval: 1.10, 1.37). Further structural analysis revealed X-11308 to be a dihydroxy docosatrienoic acid and X-11787 to be an isoform of either hydroxyleucine or hydroxyisoleucine. Our metabolomic analysis revealed novel biomarkers associated with incident heart failure independent of traditional risk factors.
73 citations
Johns Hopkins University1, Vanderbilt University2, Texas Biomedical Research Institute3, University of Washington4, University of Texas Health Science Center at Houston5, University of Southern California6, University of North Carolina at Chapel Hill7, University of Alabama at Birmingham8, University of Vermont9, University of Freiburg10, Northwestern University11, Rutgers University12, Memorial Hospital of South Bend13
TL;DR: In this paper, a loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations.
Abstract: A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008–2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10−67, P = 3.98 × 10−5, P = 6.97 × 10−9, and P = 5.33 × 10−4 in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10−10, P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10−80) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10−12). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
70 citations
TL;DR: The data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake and suggest that the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake are generalizability across populations.
Abstract: The prevalence of obesity has been increasing globally, resulting in increased rates of type 2 diabetes, cardiovascular disease, and certain cancers (1). Risk factors for obesity include a sedentary lifestyle, overconsumption of energy, and genetic susceptibility (2, 3). Recent genome-wide association studies have identified several common genetic variants associated with body mass index (BMI; weight (kg)/height (m)2), a measure of adiposity (4, 5). However, the mechanisms underlying these associations have yet to be characterized. Given that macronutrient consumption plays a key role in obesity (6), understanding the biological links between inherited genetic variation and components of energy intake may suggest strategies for reducing the increasing prevalence of obesity (7).
To date, at least 32 independent loci have been found to be associated with BMI (8). Many of the genes involved, such as the brain-derived neurotrophic factor gene (BDNF), the melanocortin 4 receptor gene (MC4R), and the fat mass and obesity-associated gene (FTO), are expressed in the central nervous system (9–11), suggesting that they may act through the neurological control of various aspects of energy balance. Indeed, studies have found that obesity risk variants in intron 1 of the FTO gene are associated with greater energy consumption (12–17) or frequency of energy consumption (18) and a reduction in satiety (19–21) and intake control (12, 22, 23). In a recent study of approximately 2,100 adults of mostly European descent (77%), McCaffery et al. (18) found that FTO rs1421085 was associated with percentage of calories derived from fat. Additionally, this and another study found that obesity risk variants in the potassium channel tetramerization domain-containing 15 gene (KCTD15) and BDNF were associated with macronutrient intake (24) or increased meat and dairy intake (18). However, many of these previous studies were conducted in populations of primarily European descent.
To further understand the relationship between obesity single-nucleotide polymorphisms (SNPs) and energy consumption, we investigated, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study (25), the relationship between 6 obesity risk variants and intake of macronutrients (carbohydrate, protein, ethanol, and fat and its subtypes) among type 2 diabetes-free adults from 5 racial/ethnic groups.
62 citations
University of Minnesota1, Boston University2, University of North Carolina at Chapel Hill3, University of Southern California4, Fred Hutchinson Cancer Research Center5, Roswell Park Cancer Institute6, University of Washington7, Rutgers University8, Tulane University9, City of Hope National Medical Center10, National Institutes of Health11, University of Pennsylvania12, University of Arizona13, Vanderbilt University14, Cambridge University Hospitals NHS Foundation Trust15, Harvard University16, University of Miami17, Stanford University18, Cancer Prevention Institute of California19, University of Hawaii at Manoa20, University of Mississippi21, Case Western Reserve University22, Scripps Health23, University of Alabama at Birmingham24, University of California, San Diego25, McGill University26, University of Pittsburgh27
TL;DR: The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links toMenarche timing in AA women.
Abstract: African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
TL;DR: In the largest genome-wide association study of cardiac structure and function to date in African Americans, it is suggested that 4 genetic loci related to left ventricular mass, interventricular septal wall thickness,left ventricular internal diastolic diameter, and ejection fraction may be unique to individuals of African ancestry.
Abstract: Background —Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results —Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 x10-07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43x10-07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 x10-07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 x10-08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 x10-07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
Conclusions —In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
TL;DR: Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical cardiovascular disease.
Abstract: Background—The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping may be informa...
University of North Carolina at Chapel Hill1, Fred Hutchinson Cancer Research Center2, University of Michigan3, Rutgers University4, University of Washington5, University of Pittsburgh6, University of Iowa7, George Washington University8, University of Southern California9, University of Hawaii10, National Institutes of Health11, Vanderbilt University12, Stanford University13, Ohio State University14, University of Mississippi15
TL;DR: Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples, and haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2's two-panel combination are recommended.
Abstract: Summary: Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples. Imputation in African Americans using 3384 haplotypes from the Exome Sequencing Project, compared with 2184 haplotypes from 1000 Genomes Project, increased effective sample size by 8.3–11.4% for coding variants with minor allele frequency 51%. No loss of imputation quality was observed using a panel built from phenotypic extremes. We recommend using haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2’s twopanel combination.
TL;DR: Evidence is not found to suggest that SCH is associated with increased MI risk among a population of predominantly older postmenopausal women with no prior history of MI.
Abstract: Context: Subclinical hypothyroidism (SCH) has been associated with an increased risk for cardiovascular disease. However, few studies have specifically examined the association between SCH and myocardial infarction (MI), and the relationship is poorly understood. Objectives: The purpose of this study was to evaluate incident MI risk in relation to SCH and severities of SCH among postmenopausal women. Methods: We used a population-based nested case-cohort design within the Women's Health Initiative observational study to examine the association between SCH and incident first-time MI risk among postmenopausal women in the United States. SCH was assessed using blood specimens collected at baseline. Participants presenting with normal free T4 levels and with thyrotropin levels of greater than 4.68–6.99 mU/L or 7.00 mU/L or greater were defined as having mild SCH or moderate/severe SCH, respectively. MI cases were centrally adjudicated by trained Women's Health Initiative staff. The primary analysis included 7...
TL;DR: OH is associated with higher AF incidence and a non-linear relationship between orthostatic change in SBP and incident AF was present after multivariable adjustment.
Abstract: Background
Autonomic fluctuations are associated with the initiation and possibly maintenance of atrial fibrillation (AF). However, little is known about the relationship between orthostatic blood pressure change, a common manifestation of autonomic dysfunction, and incident AF.
Methods
We examined whether supine-to-standing changes in systolic blood pressure (SBP) are associated with incident AF in 12,071 African American and white men and women aged 45–64 years, enrolled in the Atherosclerosis Risks in Communities (ARIC) study. Orthostatic hypotension (OH) was defined as a supine-standing drop in SBP by ≥20 mmHg or diastolic blood pressure by ≥10 mmHg. AF cases were identified based on study scheduled 12-lead ECG, hospital discharge ICD codes, and death certificates through 2009.
Results
OH was seen in 603 (5%) at baseline. During an average follow-up of 18.1 years, 1438 (11.9%) study participants developed AF. Incident AF occurred more commonly among those with OH than those without, a rate of 9.3 vs. 6.3 per 1000 person years, (p<0.001). The age, gender, and race adjusted hazard ratio (95%CI) of AF among those with OH compared to those without was 1.62 (1.34, 2.14). This association was attenuated after adjustment for common AF risk factors to HR 1.40 (1.15, 1.71), a strength similar to that of diabetes or hypertension with AF in the same model. A non-linear relationship between orthostatic change in SBP and incident AF was present after multivariable adjustment.
Conclusions
OH is associated with higher AF incidence. Whether interventions that decrease OH can reduce AF risk remains unknown.
University of Pennsylvania1, National Institutes of Health2, University of North Carolina at Chapel Hill3, Massachusetts Institute of Technology4, Lund University5, California Pacific Medical Center6, Temple University7, Jackson State University8, University of Washington9, University of California, San Diego10, University of Mississippi11, University of Minnesota12, Johns Hopkins University13, Tulane University14, Harvard University15, University of California, San Francisco16, University of Florida17, Wake Forest University18, Boston University19, Case Western Reserve University20, University of California, Los Angeles21, Scripps Research Institute22, University of Pittsburgh23, Group Health Cooperative24, University of Iowa25, Cedars-Sinai Medical Center26, City University of New York27
TL;DR: An intergenic region downstream of GJA1 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.
Johns Hopkins University1, Jacobi Medical Center2, University of Washington3, Cornell University4, University of North Carolina at Chapel Hill5, Vanderbilt University6, Texas Biomedical Research Institute7, University of Southern California8, University of Vermont9, Rutgers University10, Pennsylvania State University11
TL;DR: There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
TL;DR: Differences in short- and long-term case fatality by neighborhood socioeconomic factors have not been systematically studied in the United States and surveillance efforts can be expanded to incorporate measures of the neighborhood context to examine these associations over time.
TL;DR: In this article, the authors investigated whether tooth loss and periodontitis are associated with lower cognitive function in late middle-aged adults and found that having fewer teeth and gingival bleeding were associated with a lower DSS and word fluency test score, although periodontal pocket depth was not.
Abstract: Background It has not been established to what extent oral health is associated with cognitive function in late middle–aged adults. In this study, which is part of the national Atherosclerosis Risk in Communities (ARIC) study, the authors investigated whether tooth loss and periodontitis are associated with lower cognitive function. Methods The authors analyzed ARIC data measuring cognitive function in 11,097 participants from 1996 through 1998 according to tests of delayed word recall, digit-symbol substitution (DSS) and word fluency; 9,874 participants answered dental screening questions. Of the 8,554 dentate participants, 5,942 received oral examinations. The authors used measures of dental status, number of teeth and periodontitis (classified according to the Biofilm-Gingival Interface Index) in multiple linear regression models to estimate these factors' cross-sectional association with cognitive scores, adjusting for sociodemographic factors, cigarette smoking, alcohol use and diabetes. Results Approximately 13 percent of participants were edentulous. Of the dentate participants, 27.3 percent had fewer than 20 teeth and 12.4 percent had pocket depth of 4 millimeters or more with severe bleeding. Compared with dentate participants, edentulous participants had lower scores for all cognitive tests. Among the dentate participants, having fewer teeth and gingival bleeding were associated with lower DSS and word fluency test scores, although periodontal pocket depth was not. Conclusions In this cohort, edentulism was correlated with lower cognitive status. Tooth loss and gingival bleeding were markers of poorer executive function among dentate people. Practical Implications The association of lower cognitive scores with edentulism suggests that past oral diseases may be a risk indicator for cognitive decline, whereas the association with gingival inflammation indicates a possible effect of cognitive decline on oral health. Practitioners should be aware that both current and historical markers of oral disease might be associated with decline in cognitive function, even in adults of late middle age.
TL;DR: Findings suggest that RBP4 levels may be directly involved in the pathogenesis of type 2 diabetes in women, as well as in the population-based Atherosclerosis Risk in Communities Study.
Abstract: Introducao: A proteina carreadora de retinol 4 (RBP4) tem sido descrita como elo entre uma menor captura de glicose pelos adipocitos e sensibilidade sistemica a insulina. Objetivo: Determinar se os niveis de RBP4 em jejum predizem diabetes tipo 2. Metodo: Em um delineamento de caso-coorte, foram acompanhados 543 individuos de meia-idade que desenvolveram diabetes e 537 que nao desenvolveram diabetes ao longo de 9 anos no estudo Atherosclerosis Risk in Communities Study (ARIC). Foi realizada analise ponderada de riscos proporcionais de Cox para inferencia estatistica da associacao entre os niveis de RBP4 e diabetes incidente na coorte. Resultados: Mulheres com niveis de RBP4 no terceiro tercil apresentaram maior risco de desenvolver diabetes (HR = 1,74; 95% CI 1,03 – 2,94) em analises ajustadas para idade, etnia, centro, historia familiar de diabetes, hipertensao, taxa de filtracao glomerular, indice de massa corporal, razao cintura-quadril, niveis de acidos graxos nao esterificados, adiponectina, leptina, triglicerideos e HDL-C. Quando adicionalmente ajustado para os niveis de insulina de jejum, a significância dessa associacao se tornou limitrofe (HR = 1,68; 95% CI 1,00 – 2,82). Nenhuma associacao foi observada entre RBP4 e diabetes incidente em homens. Conclusao: Esses achados sugerem que os niveis de RBP4 possam estar diretamente envolvidos na patogenese do diabetes tipo 2 em mulheres.
TL;DR: Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared with a standardized physician reviewer panel.
Abstract: Background—An algorithm to classify heart failure (HF) end points inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records. Methods and Results—During 2005–2007, all hospitalizations were identified from 4 US communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by International Classification of Diseases discharge codes and demographics from men and women aged ≥55 years. The HF classification algorithm was automated and applied to 2729 (n=13 854 weighted hospitalizations) hospitalizations in which either brain natriuretic peptide measures or ejection fraction were documented (mean age, 75 years). There were 1403 (54%; n=7534 weighted) event...
TL;DR: Different methods to handle measurement error/misclassification in the Cox proportional hazards regression model—naive methods, regression calibration, pooled estimation, multiple imputation, corrected score estimation, and MC-SIMEX—by simulation are reviewed and compared.
Abstract: Measurement error/misclassification is commonplace in research when variable(s) cannot be measured accurately. A number of statistical methods have been developed to tackle this problem in a variety of settings and contexts. However, relatively few methods are available to handle misclassified categorical exposure variable(s) in the Cox proportional hazards regression model. In this article, we aim to review and compare different methods to handle this problem—naive methods, regression calibration, pooled estimation, multiple imputation, corrected score estimation, and MC-SIMEX—by simulation. These methods are also applied to a life course study with recalled data and historical records. In practice, the issue of measurement error/misclassification should be accounted for in design and analysis, whenever possible. Also, in the analysis, it could be more ideal to implement more than one correction method for estimation and inference, with proper understanding of underlying assumptions.
Journal Article•
TL;DR: A well-studied measure of central arterial stiffness is associated with cardiovascular disease and mortality and Brachial-ankle PWV (baPWV) is commonly used in clinical practice.
Abstract: Background: Carotid-femoral PWV (cfPWV), a well-studied measure of central arterial stiffness is associated with cardiovascular disease and mortality. Brachial-ankle PWV (baPWV) is commonly used in...
Journal Article•
TL;DR: This work has shown that microvascular abnormalities seen in the retina and assessed in the kidneys as micro-albuminuria may be associated with microVascular abnormalities in coronary beds and their relationship with coronary beds is unclear.
Abstract: Background: Microvascular abnormalities seen in the retina and assessed in the kidneys as micro-albuminuria may be associated with microvascular abnormalities in coronary beds Their relationship w