[Show abstract][Hide abstract] ABSTRACT: DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis of genome-wide DNA methylation data remains to be determined. We developed a comprehensive analysis pipeline for epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWAS using permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identification of methylation quantitative trait loci for hypothesis driven follow-up experiments.
[Show abstract][Hide abstract] ABSTRACT: Large-scale prospective cohort studies are invaluable in epidemiology, but they are increasingly difficult and costly to establish and follow-up. More efficient methods for recruitment, data collection and follow-up are essential if such studies are to remain feasible with limited public and research funds. Here, we discuss how these challenges were addressed in the UK COSMOS cohort study where fixed budget and limited time frame necessitated new approaches to consent and recruitment between 2009-2012. Web-based e-consent and data collection should be considered in large scale observational studies, as they offer a streamlined experience which benefits both participants and researchers and save costs. Commercial providers of register and marketing data, smartphones, apps, email, social media, and the internet offer innovative possibilities for identifying, recruiting and following up cohorts. Using examples from UK COSMOS, this article sets out the dos and don’ts for today's cohort studies and provides a guide on how best to take advantage of new technologies and innovative methods to simplify logistics and minimise costs. Thus a more streamlined experience to the benefit of both research participants and researchers becomes achievable.
PLoS ONE 07/2015; 10(7). DOI:10.1371/journal.pone.0131521 · 3.23 Impact Factor
[Show abstract][Hide abstract] 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.
European Journal of Nutrition 06/2015; DOI:10.1007/s00394-015-0969-z · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ischaemic heart disease, stroke, and other cardiovascular diseases (CVDs) lead to 17.5 million deaths worldwide per year. Taking into account population ageing, CVD death rates are decreasing steadily both in regions with reliable trend data and globally. The declines in high-income countries and some Latin American countries have been ongoing for decades without slowing. These positive trends have broadly coincided with, and benefited from, declines in smoking and physiological risk factors, such as blood pressure and serum cholesterol levels. These declines have also coincided with, and benefited from, improvements in medical care, including primary prevention, diagnosis, and treatment of acute CVDs, as well as post-hospital care, especially in the past 40 years. These variables, however, explain neither why the decline began when it did, nor the similarities and differences in the start time and rate of the decline between countries and sexes. In Russia and some other former Soviet countries, changes in volume and patterns of alcohol consumption have caused sharp rises in CVD mortality since the early 1990s. An important challenge in reaching firm conclusions about the drivers of these remarkable international trends is the paucity of time-trend data on CVD incidence, risk factors throughout the life-course, and clinical care.
[Show abstract][Hide abstract] ABSTRACT: This article summarizes current data and approaches to assess sodium intake in individuals and populations. A review of the literature on sodium excretion and intake estimation supports the continued use of 24-h urine collections for assessing population and individual sodium intake. Since 2000, 29 studies used urine biomarkers to estimate population sodium intake, primarily among adults. More than half used 24-h urine; the rest used a spot/casual, overnight, or 12-h specimen. Associations between individual sodium intake and health outcomes were investigated in 13 prospective cohort studies published since 2000. Only three included an indicator of long-term individual sodium intake, i.e., multiple 24-h urine specimens collected several days apart. Although not insurmountable, logistic challenges of 24-h urine collection remain a barrier for research on the relationship of sodium intake and chronic disease. Newer approaches, including modeling based on shorter collections, offer promise for estimating population sodium intake in some groups. Expected final online publication date for the Annual Review of Nutrition Volume 35 is July 17, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
[Show abstract][Hide abstract] ABSTRACT: Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
PLoS Medicine 03/2015; 12(3):e1001779. DOI:10.1371/journal.pmed.1001779 · 14.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adverse blood pressure (BP) is a major independent risk factor for epidemic cardiovascular diseases affecting almost one third of the US adult population. This review synthesizes results from studies published over the past few years on BP differences and prevalent hypertension between US blacks and whites and their different intakes of foods (e.g., fruits, vegetables, and dairy products) and micronutrients (e.g., vitamin D, calcium, potassium, and phosphorus). Studies have consistently reported higher prevalence of adverse BP levels and hypertension and less favorable dietary intakes in blacks than in whites, but the influence of specific dietary factors on high BP risk for blacks remains unclear.
Current Hypertension Reports 02/2015; 17(2):517. DOI:10.1007/s11906-014-0517-x · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background—Epidemiologic evidence is sparse on the effect of dietary behaviors and diet
quality on body mass index (BMI) that may be important drivers of the obesity epidemic.
Objective—This study investigated the relationships of frequency of eating and time of intake to
energy density, nutrient quality and BMI using data from the INTERnational study on MAcro/
micronutrients and blood Pressure (INTERMAP) including 2,696 men and women aged 40-59
from the United States and the United Kingdom.
Design—INTERMAP is a cross-sectional investigation with four 24-hour dietary recalls and
BMI measurements conducted between 1996 and 1999. Consumption of solid foods was
aggregated into eating occasion. Nutrient density is expressed using the Nutrient Rich Food (NRF
9.3) index. The ratio of evening/morning energy intake was calculated; mean values of four visits
Statistical analyses performed—Characteristics across eating occasion categories are
presented as adjusted mean with corresponding 95% confidence interval. Multiple linear
regression models were used to examine associations of eating occasions, ratio of evening/
morning energy intake, dietary energy density, and NRF 9.3 index with BMI.
Results—Compared to participants with < 4 eating occasions/24-hours, those with ≥ 6 eating
occasions/24-hours had lower mean: BMI: 27.3 vs. 29.0 kg/m2; total energy intake: 2,129 vs.
2,472 kcal/24-hours; dietary energy density: 1.5 vs. 2.1 kcal/g; and higher NRF 9.3 index: 34.3 vs.
28.1. In multiple regression analyses, higher evening intake relative to morning intake was directly
associated with BMI; however this did not influence the relationship between eating frequency
Conclusions—Our results suggest that a larger number of small meals may be associated with
improved diet quality and lower BMI. This may have implications for behavioral approaches to
controlling the obesity epidemic.
Journal of the American Academy of Nutrition and Dietetics 01/2015; 115(4). DOI:10.1016/j.jand.2014.11.017 · 2.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.
We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24±4 kg/m2). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87%±3%; R2 = 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160%±2%; R2 = 0.92).
Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.
PLoS Medicine 12/2014; 11(12):e1001765. DOI:10.1371/journal.pmed.1001765 · 14.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Observational studies have suggested that the risks of non-communicable diseases in voluntary migrants become similar to
those in the host population after one or more generations, supporting the hypothesis that these diseases have a predominantly
environmental (rather than inherited) origin. However, no study has been conducted thus far to identify alterations at the
molecular level that might mediate these changes in disease risk after migration.
Methods: Using genome-wide DNA methylation profiles from more than 1000 Italian participants, we conducted an epigenome-wide association
study (EWAS) to identify differences between south-to-north migrants and their origin (southern natives) and host (north-western
Results: We identified several differentially methylated CpG loci, in particular when comparing south-to-north migrants with north-western
natives. We hypothesise that these alterations may underlie an adaptive response to exposure differentials that exist between
origin and host populations.
Conclusions: Our study is the first large agnostic investigation of DNA methylation changes linked to migratory processes, and shows the
potential of EWAS to investigate their biological effects.
International Journal of Epidemiology 10/2014; DOI:10.1093/ije/dyu198 · 9.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The Airwave Health Monitoring Study was established to evaluate possible health risks associated with use of TETRA, a digital communication system used by police forces and other emergency services in Great Britain since 2001. The study has been broadened to investigate more generally the health of the work force.
From 2004, participants from each force who agreed to participate were enrolled either with an enrolment questionnaire or a comprehensive health screening performed locally. This includes questionnaire, 7-day food diaries, anthropometry, measurements of cardiovascular and cognitive function, blood chemistry, coagulation and haematology. Blood and urine samples are stored in vapour phase liquid nitrogen allowing long-term access for biochemical or genetic analysis. Access to the resource is via an access committee and a steering committee, including external scientific advisers as well as representatives of the police officers and staff.
By the end of 2012, the study had recruited 42,112 participants, of whom 35,199 (83.6%) had attended the health screening. Almost two thirds of participants were men and 71% of them were a TETRA user. Being in lower ranks (constable/sergeant and staff) was associated with a worse cardio-metabolic risk profile compared to higher ranks (inspector or chief inspector, superintendent and above).
The Airwave Health Monitoring Study is the only large-scale cohort study of police employees worldwide. The specificities of this sample, such as its well-defined job hierarchy, make it a particularly valuable occupational cohort. Participants have consented to the use of their data and samples for future, currently unspecified, research purposes.
Environmental Research 10/2014; 134:280–285. DOI:10.1016/j.envres.2014.07.025 · 3.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Dietary Approaches to Stop Hypertension-Sodium (DASH-Sodium) trial demonstrated beneficial effects on blood pressure (BP) of the DASH diet with lower sodium intake when compared with typical American diet. The subsequent Optimal Macronutrient Intake Trial for Heart Health (OMNIHEART) trial reported additional BP benefits from replacing carbohydrate in the DASH diet with either protein or monounsaturated fats. The primary aim of this study is to assess possible BP benefits of an OMNIHEART-like diet in free-living Americans using cross-sectional US population data of The International Study of Macronutrients, Micronutrients and Blood Pressure (INTERMAP) study. The INTERMAP data include four 24-hour dietary recalls, 2 timed 24-hour urine collections, 8 BP readings for 2195 individuals aged 40 to 59 years from 8 US INTERMAP population samples. Analyses are conducted using 2 approaches: (1) regression of BP on a linear OMNIHEART nutrient score calculated for each individual and (2) a Bayesian approach comparing estimated BP levels of an OMNIHEART-like nutrient profile with a typical American nutrient profile. After adjustment for potential confounders, an OMNIHEART score higher by 1 point was associated with systolic/diastolic BP differences of -1.0/-0.5 mm Hg (both P<0.001). Mean systolic/diastolic BPs were 111.3/68.4 and 115.2/70.6 mm Hg for Bayesian OMNIHEART and Control profiles, respectively, after controlling for possible confounders, with BP differences of -3.9/-2.2 mm Hg, P(difference ≤0)=0.98/0.96. Findings were comparable for men and women, for nonhypertensive participants, and with adjustment for antihypertensive treatment. Our findings from data on US population samples indicate broad generalizability of OMNIHEART results beyond the trial setting and support recommendations for an OMNIHEART-style diet for prevention/control of population-wide adverse BP levels.
[Show abstract][Hide abstract] ABSTRACT: Objective: Habitual high-salt intake raises blood pressure and risk of cardiovascular diseases. To prevent/control these risks, reduced salt diet (RSD) is recommended in many countries and some people report practicing it; however, little is known about actual achievement. This population-based study assessed level of 24-h dietary sodium intake of participants reporting RSD and others. Method: Participants were 4680 men and women ages 40-59 years randomly selected from 17 populations in People's Republic of China (PRC), Japan, UK and USA, for an observational study on diet and blood pressure (INTERMAP). Daily sodium intake was determined by two timed 24-h urine collections. Antihypertensive treatment status and RSD were ascertained by questionnaire. Results: Participants reporting RSD were few; 3.1% (Japan), 1.3% (PRC), 2.5% (UK), 7.2% (USA); 15.1, 7.9, 16.7 and 16.8% of people with treated hypertension. For those reporting RSD, 24-h urinary sodium excretion was significantly, but only modestly lower than for others, by 17.9 mmol/day (Japan), 56.7 (PRC) and 14.7 (USA), but higher by 10.5 in UK. Sodium intakes for participants reporting RSD remained higher than recommended; 181.0 mmol/day (Japan), 171.5 (PRC), 155.2 (UK) and 148.9 (USA). For these people, as for others, main sources of salt were processed foods in Japan, UK and USA; in PRC, salt added in preparation at home. Conclusion: Enhanced sustained efforts are needed to raise general awareness of the harmful effects of salt on health and the benefits of salt reduction. Population approaches are needed to reduce salt content of processed foods and restaurant meals.
Journal of Hypertension 09/2014; 32(12). DOI:10.1097/HJH.0000000000000341 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
PLoS ONE 08/2014; 9(8):e102645. DOI:10.1371/journal.pone.0102645 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Fetal and postnatal growth have been associated with adult blood pressure (BP), but findings about the relative importance of growth at different stages of life on BP are inconsistent.
Methods The study population comprised 5198 participants from the Northern Finland Birth Cohort 1966 with data on birth weight, height and weight measurements until adolescence, systolic and diastolic BP at 31 years and several covariates. Structural equation modelling was used in the analysis.
Results Negative direct effects of birth weight on adult systolic BP were observed (standardised regression coefficients: −0.08 (−0.14 to −0.03) in males and −0.04 (−0.09 to 0.01) in females, equalling −1.99 (−3.32 to −0.65) and −1.01 (−2.33 to 0.32) mm Hg/kg, respectively). Immediate postnatal growth was associated with adult BP only indirectly via growth later in life. In contrast, growth from adiposity rebound onwards had large direct, indirect and total effects on adult BP. Current body mass index was the strongest growth-related predictor of adult BP (0.36 (0.30 to 0.41) in males and 0.31 (0.24, 0.37) in females, equalling 1.29 (1.09 to 1.48) and 0.81 (0.63 to 0.99) mm Hg/(kg/m2), respectively).
Conclusions Our path analytical approach provides evidence for the importance of both fetal growth and postnatal growth, especially from adiposity rebound onwards, in determining adult BP, together with genetic predisposition and behavioural factors.
Journal of Epidemiology & Community Health 08/2014; 68(12). DOI:10.1136/jech-2013-203661 · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010.
We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates.
In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain.
The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases.