Showing papers by "Paul Elliott published in 2016"
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Mariachiara Di Cesare1, Mariachiara Di Cesare2, James Bentham1, Gretchen A Stevens3 +738 more•Institutions (60)
TL;DR: The posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue, is calculated.
3,766 citations
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James Bentham1, Mariachiara Di Cesare2, Mariachiara Di Cesare1, Gretchen A Stevens3 +787 more•Institutions (246)
TL;DR: The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
Abstract: Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
1,348 citations
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Christian Fuchsberger1, Christian Fuchsberger2, Jason Flannick3, Jason Flannick4 +346 more•Institutions (77)
TL;DR: In this paper, the authors performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing for 12,940 individuals from five ancestry groups.
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
866 citations
01 Jan 2016
TL;DR: Large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes, but most fell within regions previously identified by genome-wide association studies.
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
698 citations
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TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
409 citations
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TL;DR: In this article, the authors identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals, and 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues.
Abstract: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
332 citations
01 Jan 2016
TL;DR: The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney, expanding current knowledge of blood pressure–related pathways and highlighting tissues beyond the classical renal system in blood pressure regulation.
272 citations
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TL;DR: Thirty new blood pressure– or hypertension-associated genetic regions in the general population are identified, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects than common variants.
Abstract: High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
250 citations
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TL;DR: It is shown that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain, suggesting that a liver–brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
Abstract: Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10−12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver–brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
205 citations
20 Oct 2016
159 citations
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TL;DR: In this paper, the authors provide an overview of the data and evidence on worldwide exposures to CVD risk factors and associated health effects, and identify directions for research and surveillance to better estimate the effects of cardiovascular disease risk factors, and policy options for reducing CVD burden by modifying preventable risk factors.
Abstract: Information on exposure to, and health effects of, cardiovascular disease (CVD) risk factors is needed to develop effective strategies to prevent CVD events and deaths. Here, we provide an overview of the data and evidence on worldwide exposures to CVD risk factors and the associated health effects. Global comparative risk assessment studies have estimated that hundreds of thousands or millions of CVD deaths are attributable to established CVD risk factors (high blood pressure and serum cholesterol, smoking, and high blood glucose), high body mass index, harmful alcohol use, some dietary and environmental exposures, and physical inactivity. The established risk factors plus body mass index are collectively responsible for ≈9.7 million annual CVD deaths, with high blood pressure accounting for more CVD deaths than any other risk factor. Age-standardized CVD death rates attributable to established risk factors plus high body mass index are lowest in high-income countries, followed by Latin America and the Caribbean; they are highest in the region of central and eastern Europe and central Asia. However, estimates of the health effects of CVD risk factors are highly uncertain because there are insufficient population-based data on exposure to most CVD risk factors and because the magnitudes of their effects on CVDs in observational studies are likely to be biased. We identify directions for research and surveillance to better estimate the effects of CVD risk factors and policy options for reducing CVD burden by modifying preventable risk factors.
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TL;DR: The results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects.
Abstract: To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liquid chromatography–mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. However, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein, we describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry (oaTOF-MS), exceptional measurement precision is exemp...
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TL;DR: This work introduces a new approach, based on multivariate simulation, which deals effectively with the highly correlated structure and high-dimensionality of metabolic phenotyping data, and investigates the complex relationship between sample size, power, and effect size for real multivariate data sets.
Abstract: Estimation of statistical power and sample size is a key aspect of experimental design. However, in metabolic phenotyping, there is currently no accepted approach for these tasks, in large part due to the unknown nature of the expected effect. In such hypothesis free science, neither the number or class of important analytes nor the effect size are known a priori. We introduce a new approach, based on multivariate simulation, which deals effectively with the highly correlated structure and high-dimensionality of metabolic phenotyping data. First, a large data set is simulated based on the characteristics of a pilot study investigating a given biomedical issue. An effect of a given size, corresponding either to a discrete (classification) or continuous (regression) outcome is then added. Different sample sizes are modeled by randomly selecting data sets of various sizes from the simulated data. We investigate different methods for effect detection, including univariate and multivariate techniques. Our fram...
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Université de Montréal1, GlaxoSmithKline2, Imperial College London3, University of Ioannina4, National Institutes of Health5, Washington University in St. Louis6, University of Greifswald7, Icahn School of Medicine at Mount Sinai8, Harvard University9, Broad Institute10, Kanazawa University11, Vanderbilt University12, University of Washington13, University of Minnesota14, Johns Hopkins University School of Medicine15, University of Virginia16, Erasmus University Rotterdam17, University of Tartu18, University of Edinburgh19, University of North Carolina at Chapel Hill20, Baylor College of Medicine21, University of Texas Health Science Center at Houston22, University of Copenhagen23, Brigham and Women's Hospital24, Lund University25, Greifswald University Hospital26, University of Iceland27, University of Alabama at Birmingham28, University of Tampere29, Stanford University30, Wake Forest University31, Group Health Cooperative32, University of Turku33, UCLA Medical Center34, Los Angeles Biomedical Research Institute35, University of Vermont36, Stony Brook University37, Uppsala University38, University of Auckland39, University of Mississippi Medical Center40, University of Michigan41, University of Wisconsin–Milwaukee42, Fred Hutchinson Cancer Research Center43
TL;DR: These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits, and suggest the involvement of new genes in human erythropoiesis.
Abstract: Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10−10 for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10−8 for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10−11) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10−9). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10−7). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
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TL;DR: Results from the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP), a cross-sectional epidemiological study of 4,680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom, and the United States, published over the past few years on cross cultural BP differences are synthesized.
Abstract: Adverse blood pressure (BP) is a major independent risk factor for epidemic cardiovascular diseases affecting almost one-quarter of the adult population worldwide. Dietary intake is a major determinant in the development and progression of high BP. Lifestyle modifications, including recommended dietary guidelines, are advocated by the American Society of Hypertension, the International Society of Hypertension, the Japanese Society of Hypertension, and many other organisations for treating all hypertensive people, prior to initiating drug therapy and as an adjunct to medication in persons already on drug therapy. Lifestyle modification can also reduce high BP and prevent development of hypertension. This review synthesizes results from the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP), a cross-sectional epidemiological study of 4,680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom, and the United States, published over the past few years on cross cultural BP differences. INTERMAP has previously reported that intakes of vegetable protein, glutamic acid, total and insoluble fibre, total polyunsaturated fatty acid and linoleic acid, total n-3 fatty acid and linolenic acid, phosphorus, calcium, magnesium, and non-heme iron were inversely related to BP. Direct associations of sugars (fructose, glucose, and sucrose) and sugar-sweetened beverages (especially combined with high sodium intake), cholesterol, glycine, alanine, and oleic acid from animal sources with BP were also reported by the INTERMAP Study.
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TL;DR: There were clear differences in population sodium and potassium intake between villages that were most likely a consequence of increased use of salt substitute.
Abstract: Background
Average sodium intake and stroke mortality in northern China are both among the highest in the world. An effective, low-cost strategy to reduce sodium intake in this population is urgently needed.
Objective
We sought to determine the effects of a community-based sodium reduction program on salt consumption in rural northern China.
Design
This study was a cluster-randomized trial done over 18 months in 120 townships (one village from each township) from five provinces. Sixty control villages were compared to 60 intervention villages that were given access to a reduced-sodium, added-potassium salt substitute in conjunction with a community-based health education program focusing on sodium reduction. The primary outcome was the difference in 24-hour urinary sodium excretion between randomized groups.
Results
Among 1,903 people with valid 24-hour urine collections, mean urinary sodium excretion in intervention compared with control villages was reduced by 5.5% (-14mmol/day, 95% confidence interval -26 to -1; p = 0.03), potassium excretion was increased by 16% (+7mmol/day, +4 to +10; p<0.001), and sodium to potassium ratio declined by 15% (-0.9, -1.2 to -0.5; p<0.001). Mean blood pressure differences were -1.1 mm Hg systolic (-3.3 to +1.1; p = 0.33) and -0.7 mm Hg diastolic (-2.2 to +0.8, p = 0.35) and the difference in the proportion with hypertension was -1.3% (-5.1 to 2.5, p = 0.56).
Conclusion
There were clear differences in population sodium and potassium intake between villages that were most likely a consequence of increased use of salt substitute. The absence of effects on blood pressure reflects the moderate changes in sodium and potassium intake achieved.
Trial Registration
Clinicaltrials.gov identifier: NCT01259700.
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National Institutes of Health1, Icahn School of Medicine at Mount Sinai2, Université de Montréal3, Vanderbilt University4, University of Washington5, University of Edinburgh6, University of Greifswald7, Stanford University8, University of Virginia9, University of Tartu10, Brigham and Women's Hospital11, University of Minnesota12, Erasmus University Medical Center13, University of Texas Health Science Center at Houston14, University of Iceland15, Stony Brook University16, GlaxoSmithKline17, University of Ioannina18, Imperial College London19, Johns Hopkins University School of Medicine20, Greifswald University Hospital21, University of North Carolina at Chapel Hill22, Wake Forest University23, University of Tampere24, Uppsala University25, Harvard University26, Broad Institute27, Erasmus University Rotterdam28, Baylor College of Medicine29, Morehouse School of Medicine30, University of California, Los Angeles31, Group Health Cooperative32, University of Auckland33, University of Michigan34, University of Mississippi Medical Center35, University of Vermont36, Fred Hutchinson Cancer Research Center37, University of Wisconsin–Milwaukee38
TL;DR: An exome array-based meta-analysis of total WBC and subtype counts in a multi-ancestry discovery and replication sample of ∼157,622 individuals suggests a prominent shared genetic architecture with inflammatory and autoimmune diseases.
Abstract: White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3′ UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
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TL;DR: The effect of drinking water sodium on blood pressure of pregnant women in coastal Bangladesh is examined: increases in blood pressure in this group could severely affect maternal and fetal health.
Abstract: Coastal areas in Southeast Asia are experiencing high sodium concentrations in drinking water sources that are commonly consumed by local populations. Salinity problems caused by episodic cyclones and subsequent seawater inundations are likely (partly) related to climate change and further exacerbated by changes in upstream river flow and local land-use activities. Dietary (food) sodium plays an important role in the global burden of hypertensive disease. It remains unknown, however, if sodium in drinking water-rather than food-has similar effects on blood pressure and disease risk. In this study, we examined the effect of drinking water sodium on blood pressure of pregnant women: increases in blood pressure in this group could severely affect maternal and fetal health. Data on blood pressure, drinking water source, and personal, lifestyle, and environmental confounders was obtained from 701 normotensive pregnant women residing in coastal Bangladesh. Generalized linear mixed regression models were used to investigate association of systolic and diastolic blood pressure of these-otherwise healthy-women with their water source. After adjustment for confounders, drinkers of tube well and pond water (high saline sources) were found to have significantly higher average systolic (+4.85 and +3.62 mm Hg) and diastolic (+2.30 and +1.72 mm Hg) blood pressures than rainwater drinkers. Drinking water salinity problems are expected to exacerbate in the future, putting millions of coastal people-including pregnant women-at increased risk of hypertension and associated diseases. There is an urgent need to further explore the health risks associated to this understudied environmental health problem and feasibility of possible adaptation strategies.
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TL;DR: With appropriate bias correction, casual urine Na/K ratio may be a useful, low-burden alternative method to 24-h urine for estimation of population urinary sodium-to-potassium ratio.
Abstract: Background Association between casual and 24-h urinary sodium-to-potassium (Na/K) ratio is well recognized, although it has not been validated in diverse demographic groups. Our aim was to assess utility across and within populations of casual urine to estimate 24-h urinary Na/K ratio using data from the INTERSALT Study. Methods The INTERSALT Study collected cross-sectional standardized data on casual urinary sodium and potassium and also on timed 24-h urinary sodium and potassium for 10 065 individuals from 52 population samples in 32 countries (1985-87). Pearson correlation coefficients and agreement were computed for Na/K ratio of casual urine against 24-h urinary Na/K ratio both at population and individual levels. Results Pearson correlation coefficients relating means of 24-h urine and casual urine Na/K ratio were r = 0.96 and r = 0.69 in analyses across populations and individuals, respectively. Correlations of casual urine Na/creatinine and K/creatinine ratios with 24-h urinary Na and K excretion, respectively, were lower than correlation of casual and 24-h urinary Na/K ratio in analyses across populations and individuals. The bias estimate with the Bland-Altman method, defined as the difference between Na/K ratio of 24-h urine and casual urine, was approximately 0.4 across both populations and individuals. Spread around, the mean bias was higher for individuals than populations. Conclusion With appropriate bias correction, casual urine Na/K ratio may be a useful, low-burden alternative method to 24-h urine for estimation of population urinary Na/K ratio. It may also be applicable for assessment of the urinary Na/K ratio of individuals, with use of repeated measurements to reduce measurement error and increase precision.
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Erasmus University Rotterdam1, Baylor College of Medicine2, University of Washington3, National Institutes of Health4, University of Virginia5, University of Iceland6, Washington University in St. Louis7, Boston University8, University of Edinburgh9, University of North Carolina at Chapel Hill10, Leiden University11, University of Helsinki12, University of Groningen13, Ealing Hospital14, VU University Amsterdam15, University of Ioannina16, University of Tampere17, Loyola University Chicago18, Utrecht University19, Johns Hopkins University20, University of Texas Health Science Center at Houston21, University of Aberdeen22, University of Glasgow23, Harvard University24, University of Split25, National Institute for Health and Welfare26, Imperial College London27, University of Turku28, University of the West Indies29, Wellcome Trust Sanger Institute30, University of Mississippi31, Group Health Cooperative32, University of California, Los Angeles33
TL;DR: This study illustrates that GWAS with high-scale imputation may still help to unravel the biological mechanism behind circulating lipid levels and identifies five new associations at four loci within genes that can be linked biologically to lipid metabolism.
Abstract: BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
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TL;DR: This paper presents the COMBI-BIO NMR analysis pipeline and demonstrates its fitness for purpose using representative quality control (QC) samples, successfully addressing the methodological challenges of this large multifaceted study.
Abstract: Large-scale metabolomics studies involving thousands of samples present multiple challenges in data analysis, particularly when an untargeted platform is used. Studies with multiple cohorts and analysis platforms exacerbate existing problems such as peak alignment and normalization. Therefore, there is a need for robust processing pipelines that can ensure reliable data for statistical analysis. The COMBI-BIO project incorporates serum from ∼8000 individuals, in three cohorts, profiled by six assays in two phases using both 1H NMR and UPLC–MS. Here we present the COMBI-BIO NMR analysis pipeline and demonstrate its fitness for purpose using representative quality control (QC) samples. NMR spectra were first aligned and normalized. After eliminating interfering signals, outliers identified using Hotelling’s T2 were removed and a cohort/phase adjustment was applied, resulting in two NMR data sets (CPMG and NOESY). Alignment of the NMR data was shown to increase the correlation-based alignment quality measure...
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Pompeu Fabra University1, University of Barcelona2, Imperial College London3, University of Basel4, McGill University5, Swiss Tropical and Public Health Institute6, McGill University Health Centre7, Cancer Epidemiology Unit8, Norwegian University of Science and Technology9, National Institutes of Health10, University of Bristol11, Imperial College Healthcare12, University Medical Center Groningen13
TL;DR: The study suggests that road traffic noise may be related to increased heart rate, and no consistent evidence for a relation between noise and blood pressure was found.
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TL;DR: The introduction of smoke-free legislation in England had an immediate estimated beneficial impact on birth outcomes overall, although it did not observe improvements across all age, ethnic, or deprivation groups.
Abstract: Background:Environmental tobacco smoke has an adverse association with preterm birth and birth weight. England introduced a new law to make virtually all enclosed public places and workplaces smoke free on July 1, 2007. We investigated the effect of smoke-free legislation on birth outcomes in Englan
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TL;DR: ONS and NN4B offer the most complete and accurate record of births in England, but where more detailed clinical information is required, HES deliveries offers a high quality data set that captures the majority of English births.
Abstract: Background In England there are four national routinely collected data sets on births: Office for National Statistics (ONS) births based on birth registrations; Hospital Episode Statistics (HES) deliveries (mothers’ information); HES births (babies’ information); and NHS Numbers for Babies (NN4B) based on ONS births plus gestational age and ethnicity information. This study describes and compares these data, with the aim of recommending the most appropriate data set(s) for use in epidemiological research and surveillance. Methods We assessed the completeness and quality of the data sets in relation to use in epidemiological research and surveillance and produced detailed descriptive statistics on common reproductive outcomes for each data set including temporal and spatial trends. Results ONS births is a high quality complete data set but lacks interpretive and clinical information. HES deliveries showed good agreement with ONS births but HES births showed larger amounts of missing or unavailable data. Both HES data sets had improved quality from 2003 onwards, but showed some local spatial variability. NN4B showed excellent agreement with ONS and HES deliveries for the years available (2006–2010). Annual number of births increased by 17.6% comparing 2002 with 2010 (ONS births). Approximately 6% of births were of low birth weight (2.6% term low birth weight) and 0.5% were stillbirths. Conclusions Routinely collected data on births provide a valuable resource for researchers. ONS and NN4B offer the most complete and accurate record of births. Where more detailed clinical information is required, HES deliveries offers a high quality data set that captures the majority of English births.
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TL;DR: Recommendations to limit meat intake (processed and unprocessed) to maintain and improve cardiovascular health are consistent with recommendations to limit blood pressure.
Abstract: Background: Epidemiologic evidence suggests that relationships of red meat consumption with risk of cardiovascular diseases depends on whether or not the meat is processed, including addition of preservatives, but evidence is limited for blood pressure (BP). Objective: To examine cross-sectional associations with BP of unprocessed and processed red meat and poultry consumption, total and by type, using data from the INTERnational study on MAcro/micronutrients and blood Pressure. Design: INTERnational study on MAcro/micronutrients and blood Pressure included 4680 men and women ages 40–59 years from 17 population samples in Japan, China, the United Kingdom, and the United States. During four visits, eight BP measurements, four multipass 24-h dietary recalls, and two timed 24-h urine samples were collected. Results: Average daily total unprocessed/processed meat consumption (g/1000 kcal) was 20/5 in East Asian and 38/21 in Western participants. Unprocessed meat intakes comprised red meat for 75% in East Asian and 50% in Western participants. In Westerners, multiple linear regression analyses showed SBP/DBP differences for total unprocessed red meat consumption higher by 25 g/1000 kcal +0.74/+0.57 mmHg (P = 0.03/0.01) and for unprocessed poultry of +0.79/+0.16 mmHg (P = 0.02/0.50). Unprocessed red meat was not related to BP in East Asian participants. In Westerners, SBP/DBP differences for processed red meat higher by 12.5 g/1000 kcal were +1.20/+0.24 mmHg (P < 0.01/0.24), due to consumption of cold cuts and sausages (+1.59/+0.32 mmHg, P < 0.001/0.27). Conclusion: These findings are consistent with recommendations to limit meat intake (processed and unprocessed) to maintain and improve cardiovascular health.
01 Jan 2016
TL;DR: In this paper, the authors performed the largest genome-wide association metaanalysis and replication study to date (>105,000 individuals) and identified a genetic basis for alcohol consumption during nonaddictive drinking and found that a locus in the gene encoding β-Klotho is associated with alcohol consumption.
Abstract: Significance Alcohol is a widely consumed drug in western societies that can lead to addiction. A small shift in consumption can have dramatic consequences on public health. We performed the largest genome-wide association metaanalysis and replication study to date (>105,000 individuals) and identified a genetic basis for alcohol consumption during nonaddictive drinking. We found that a locus in the gene encoding β-Klotho is associated with alcohol consumption. β-Klotho is an essential receptor component for the endocrine FGFs, FGF19 and FGF21. Using mouse models and pharmacologic administration of FGF21, we show that β-Klotho in the brain controls alcohol drinking. These findings reveal a mechanism regulating alcohol consumption in humans that may be pharmacologically tractable for reducing alcohol intake. Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10−12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver–brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
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Shiga University of Medical Science1, Ryukoku University2, University of Human Arts and Sciences3, Osaka City University4, Kanazawa Medical University5, Iwate Medical University6, RMIT University7, Keio University8, National Heart Foundation of Australia9, University of Hawaii at Manoa10, Imperial College London11, Northwestern University12
TL;DR: All three LCD scores were significantly positively related to HDLc and the plant-based LCD score was significantly inversely related to CRP, indicating Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors.
Abstract: Low-carbohydrate diets (LCD) are a popular dietary strategy for weight reduction. The effects of LCD on long-term outcome vary depending on type of LCD, possibly due to the fact that effects on cardiometabolic risk factors may vary with different types of LCD. Accordingly, we studied these relations. We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), high-sensitivity C-reactive protein (CRP), total cholesterol, glycated hemoglobin, and uric acid, and nutrient intakes by standardized methods in men and women ages 40–59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) + polyunsaturated fatty acids (PUFA). In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, and years of education, all three LCD scores were significantly positively related to HDLc (all P < 0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log CRP (coefficient = −0.010, P = 0.018). All three LCD scores were significantly positively related to HDLc. The plant-based LCD score was significantly inversely related to CRP. Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors.
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TL;DR: The findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.
Abstract: NHMRC: 1020285, 1037916
National Institute for Health Research, UK
British Heart Foundation
Medical Research Council
Wellcome Trust
NIH
University of Oklahoma Health Sciences Center
Mauritius Ministry of Health and Quality of Life
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TL;DR: Observed effects of exposure to TETRA signals on the electroencephalogram and electrocardiogram are consistent with vagal nerve stimulation in the chest by TETra, however given the small effect on heart rate variability and the lack of consistency it seems unlikely that this will have a significant impact on health.
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TL;DR: This study aims to identify a reliable method for estimating mean population salt intake from spot urine samples by comparing the performance of existing equations against one other and against estimates derived from 24-hour urine samples and to develop a novel equation that performs better than existing equations to estimate mean population Salt intake.
Abstract: Background: Methods based on spot urine samples (a single sample at one time-point) have been identified as a possible alternative approach to 24-hour urine samples for determining mean population salt intake. Objective: The aim of this study is to identify a reliable method for estimating mean population salt intake from spot urine samples. This will be done by comparing the performance of existing equations against one other and against estimates derived from 24-hour urine samples. The effects of factors such as ethnicity, sex, age, body mass index, antihypertensive drug use, health status, and timing of spot urine collection will be explored. The capacity of spot urine samples to measure change in salt intake over time will also be determined. Finally, we aim to develop a novel equation (or equations) that performs better than existing equations to estimate mean population salt intake. Methods: A systematic review and meta-analysis of individual participant data will be conducted. A search has been conducted to identify human studies that report salt (or sodium) excretion based upon 24-hour urine samples and spot urine samples. There were no restrictions on language, study sample size, or characteristics of the study population. MEDLINE via OvidSP (1946-present), Premedline via OvidSP, EMBASE, Global Health via OvidSP (1910-present), and the Cochrane Library were searched, and two reviewers identified eligible studies. The authors of these studies will be invited to contribute data according to a standard format. Individual participant records will be compiled and a series of analyses will be completed to: (1) compare existing equations for estimating 24-hour salt intake from spot urine samples with 24-hour urine samples, and assess the degree of bias according to key demographic and clinical characteristics; (2) assess the reliability of using spot urine samples to measure population changes in salt intake overtime; and (3) develop a novel equation that performs better than existing equations to estimate mean population salt intake. Results: The search strategy identified 538 records; 100 records were obtained for review in full text and 73 have been confirmed as eligible. In addition, 68 abstracts were identified, some of which may contain data eligible for inclusion. Individual participant data will be requested from the authors of eligible studies. Conclusions: Many equations for estimating salt intake from spot urine samples have been developed and validated, although most have been studied in very specific settings. This meta-analysis of individual participant data will enable a much broader understanding of the capacity for spot urine samples to estimate population salt intake. [JMIR Res Protoc 2016;5(3):e190]