Imperial College London

ProfessorPaulElliott

Faculty of MedicineSchool of Public Health

Chair in Epidemiology and Public Health Medicine
 
 
 
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Contact

 

+44 (0)20 7594 3328p.elliott Website

 
 
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Assistant

 

Miss Jennifer Wells +44 (0)20 7594 3328

 
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Location

 

154Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

616 results found

Toledano MB, Auvinen A, Tettamanti G, Cao Y, Feychting M, Ahlbom A, Fremling K, Heinävaara S, Kojo K, Knowles G, Smith RB, Schüz J, Johansen C, Poulsen AH, Deltour I, Vermeulen R, Kromhout H, Elliott P, Hillert Let al., 2017, An international prospective cohort study of mobile phone users and health (COSMOS): Factors affecting validity of self-reported mobile phone use., International Journal of Hygiene and Environmental Health, Vol: 221, Pages: 1-8, ISSN: 1438-4639

This study investigates validity of self-reported mobile phone use in a subset of 75 993 adults from the COSMOS cohort study. Agreement between self-reported and operator-derived mobile call frequency and duration for a 3-month period was assessed using Cohen's weighted Kappa (κ). Sensitivity and specificity of both self-reported high (≥10 calls/day or ≥4h/week) and low (≤6 calls/week or <30min/week) mobile phone use were calculated, as compared to operator data. For users of one mobile phone, agreement was fair for call frequency (κ=0.35, 95% CI: 0.35, 0.36) and moderate for call duration (κ=0.50, 95% CI: 0.49, 0.50). Self-reported low call frequency and duration demonstrated high sensitivity (87% and 76% respectively), but for high call frequency and duration sensitivity was lower (38% and 56% respectively), reflecting a tendency for greater underestimation than overestimation. Validity of self-reported mobile phone use was lower in women, younger age groups and those reporting symptoms during/shortly after using a mobile phone. This study highlights the ongoing value of using self-report data to measure mobile phone use. Furthermore, compared to continuous scale estimates used by previous studies, categorical response options used in COSMOS appear to improve validity considerably, most likely by preventing unrealistically high estimates from being reported.

Journal article

castagne R, Boulange CL, Karaman I, campanella, Santos Ferreira DL, Kaluarachchi MR, lehne, Moayyeri A, Lewis MR, Spagou K, DOna AC, Evangelos V, Tracy R, Greenland P, Lindon JC, ebbels TMD, elliott, tzoulaki, Chadeau Met al., 2017, Improving visualisation and interpretation of metabolome-wide association studies (MWAS): an application in a population-based cohort using untargeted 1H NMR metabolic profiling., Journal of Proteome Research, Vol: 16, Pages: 3623-3633, ISSN: 1535-3893

1H NMR spectroscopy of biofluids generates reproducible data allowing detection and quantification of small molecules in large population cohorts. Statistical models to analyze such data are now well-established, and the use of univariate metabolome wide association studies (MWAS) investigating the spectral features separately has emerged as a computationally efficient and interpretable alternative to multivariate models. The MWAS rely on the accurate estimation of a metabolome wide significance level (MWSL) to be applied to control the family wise error rate. Subsequent interpretation requires efficient visualization and formal feature annotation, which, in-turn, call for efficient prioritization of spectral variables of interest. Using human serum 1H NMR spectroscopic profiles from 3948 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), we have performed a series of MWAS for serum levels of glucose. We first propose an extension of the conventional MWSL that yields stable estimates of the MWSL across the different model parameterizations and distributional features of the outcome. We propose both efficient visualization methods and a strategy based on subsampling and internal validation to prioritize the associations. Our work proposes and illustrates practical and scalable solutions to facilitate the implementation of the MWAS approach and improve interpretation in large cohort studies.

Journal article

Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, Hagenaars SP, Ritchie SJ, Marioni RE, Fawns-Ritchie C, Liewald DCM, Okely JA, Ahola-Olli AV, Barnes CLK, Bertram L, Bis JC, Burdick KE, Christoforou A, DeRosse P, Djurovic S, Espeseth T, Giakoumaki S, Giddaluru S, Gustavson DE, Hayward C, Hofer E, Ikram MA, Karlsson R, Knowles E, Lahti J, Leber M, Li S, Mather KA, Melle I, Morris D, Oldmeadow C, Palviainen T, Payton A, Pazoki R, Petrovic K, Reynolds CA, Sargurupremraj M, Scholz M, Smith JA, Smith AV, Terzikhan N, Thalamuthu A, Trompet S, Lee SJVD, Ware EB, Windham BG, Wright MJ, Yang J, Yu J, Ames D, Amin N, Amouyel P, Andreassen OA, Armstrong NJ, Assareh AA, Attia JR, Attix D, Avramopoulos D, Bennett DA, Böhmer AC, Boyle PA, Brodaty H, Campbell H, Cannon TD, Cirulli ET, Congdon E, Conley ED, Corley J, Cox SR, Dale AM, Dehghan A, Dick D, Dickinson D, Eriksson JG, Evangelou E, Faul JD, Ford I, Freimer NA, Gao H, Giegling I, Gillespie NA, Gordon SD, Gottesman RF, Griswold ME, Gudnason V, Harris TB, Hartmann AM, Hatzimanolis A, Heiss G, Holliday EG, Joshi PK, Kähönen M, Kardia SLR, Karlsson I, Kleineidam L, Knopman DS, Kochan NA, Konte B, Kwok JB, Hellard SL, Lee T, Lehtimäki T, Li S-C, Liu T, Koini M, London E, Longstreth WT, Lopez OL, Loukola A, Luck T, Lundervold AJ, Lundquist A, Lyytikäinen L-P, Martin NG, Montgomery GW, Murray AD, Need AC, Noordam R, Nyberg L, Ollier W, Papenberg G, Pattie A, Polasek O, Poldrack RA, Psaty BM, Reppermund S, Riedel-Heller SG, Rose RJ, Rotter JI, Roussos P, Rovio SP, Saba Y, Sabb FW, Sachdev PS, Satizabal C, Schmid M, Scott RJ, Scult MA, Simino J, Slagboom PE, Smyrnis N, Soumaré A, Stefanis NC, Stott DJ, Straub RE, Sundet K, Taylor AM, Taylor KD, Tzoulaki I, Tzourio C, Uitterlinden A, Vitart V, Voineskos AN, Kaprio J, Wagner M, Wagner H, Weinhold L, Wen KH, Widen E, Yang Q, Zhao W, Adams HHH, Arking DE, Bilder RM, Bitsios P, Boerwinkle E, Chiba-Falek O, Corvin A, Jager PLD, Debette S, Donohoe G, Elliott P, Fitzpatrick AL Get al., 2017, Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360), Publisher: Cold Spring Harbor Laboratory

<jats:p>General cognitive function is a prominent human trait associated with many important life outcomes<jats:sup>1,2</jats:sup>, including longevity<jats:sup>3</jats:sup>. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants<jats:sup>4,5,6</jats:sup>. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (<jats:italic>P</jats:italic>&lt;5 x 10<jats:sup>−8</jats:sup>) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function were <jats:italic>SGCZ</jats:italic>, <jats:italic>ATXN1</jats:italic>, <jats:italic>MAPT</jats:italic>, <jats:italic>AUTS2</jats:italic>, and <jats:italic>P2RY6</jats:italic>. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.</jats:p>

Working paper

Mousas A, Ntritsos G, Chen M-H, Huffman JE, Tzoulaki I, Elliott P, Psaty BM, Auer PL, Johnson AD, Evangelou E, Lettre G, Reiner APet al., 2017, Rare coding variants pinpoint genes that control human hematological traits., Plos Genetics, Vol: 13, ISSN: 1553-7404

The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45–0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39–0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

Journal article

Suzuki H, Gao H, Bai W, Evangelou E, Glocker B, O'Regan DP, Elliott P, Matthews PMet al., 2017, Hypertension and white matter microstructures in healthy participants in UK Biobank, Publisher: OXFORD UNIV PRESS, Pages: 248-249, ISSN: 0195-668X

Conference paper

Poulter NR, et al, 2017, Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney, Hypertension, Vol: 70, Pages: e4-e19, ISSN: 0194-911X

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Journal article

Oude Griep LM, Elliott P, 2017, Cardiovascular Diseases: Sodium and Blood Pressure, Public Health Nutrition, Publisher: John Wiley & Sons, ISBN: 9781118660973

Public Health Nutrition Edited by Judith L Buttriss, Ailsa A Welch, John M Kearney and Susan A Lanham-New In this second edition of the bestselling title from the acclaimed Nutrition Society Textbook series, Public Health Nutrition has been ...

Book chapter

Cai Y, Hodgson S, Blangiardo M, Gulliver J, Morley D, Vienneau D, de Hoogh K, Key T, Hveem K, Elliott P, Hansell Aet al., 2017, Road traffic noise and incident cardiovascular disease: a joint analysis of HUNT, EPIC-Oxford and UK Biobank, ICBEN 2017 Proceedings

Aims: This study aimed to investigate the effects of long-term exposure to road traffic noise on incident CVD in three large cohorts: HUNT, EPIC-Oxford and UK Biobank. Methods: In a complete-case sample (N=361,699), 4,014 IHD and 2,109 cerebrovascular incident cases were ascertained between baseline (1993-2010) and end of follow-up (2008-2015) through medical record linkage. Annual mean road traffic noise exposure was modelled at baseline address. Individual-level covariate data were harmonised and data were pooled. Analyses used Cox proportional hazards model with adjustments for confounders, including air pollution. Results: For an interquartile range (IQR) (3.9 dBA) higher daytime noise, a non-significant association with incident IHD was seen (Hazard ratio (HR): 1.015, 95% Confidence Interval (CI): 0.989-1.042), fully adjusted. Statistically significant associations and interaction terms were seen in obese individuals (HR: 1.099, 95%CI: 1.029-1.174), and current-smokers (HR: 1.054, 95%CI: 1.007-1.103). No associations were found for ischemic or hemorrhagic stroke. Conclusions: Our study strengthens the evidence base for an effect of road traffic noise on incident IHD, whilst the association with incident stroke remains unclear.

Journal article

Kenge AP, Bentham J, Zhou B, Bixby H, Taddei C, Chan Q, Elliott P, Ezzati M, Mbanya JCNet al., 2017, Trends in obesity and diabetes across regions in Africa from 1980 to 2014: an analysis of pooled population-based studies., International Journal of Epidemiology, Vol: 46, Pages: 1421-1432, ISSN: 1464-3685

Background: The 2016 Dar Es Salaam Call to Action on Diabetes and other NCDs advocates national multi-sectoral NCD strategies and action plans based on available data and information from countries of sub-Saharan Africa and beyond. We estimated trends, from 1980 to 2014, in age-standardised mean body mass index (BMI) and diabetes prevalence in these countries in order to assess the co-progression and assist policy formulation.Methods: We pooled data from African and world-wide population-based studies which measured height, weight, and biomarkers to assess diabetes status in adults aged >18 years. A Bayesian hierarchical model was used to estimate trends, by sex, for 200 countries and territories including 53 countries across five African regions, (central, eastern, northern, southern and western) in mean BMI and diabetes prevalence (defined as either fasting plasma glucose of >7.0 mmol/L, history of diabetes diagnosis, or use of insulin or oral glucose control agents). ResultsAfrican data came from 245 population-based surveys (1.2 million participants) for BMI and 76 surveys (182 000 participants) for diabetes prevalence estimates. Countries with the highest number of data sources for BMI were South Africa (n=17), Nigeria (n=15) and Egypt (n=13); and for diabetes estimates, Tanzania (n=8), Tunisia (n=7), Cameroon, Egypt and South Africa (all n=6). The age-standardised mean BMI increased from 21.0 kg/m2 (95% credible interval: 20.3-21.7) to 23.0 kg/m2 (22.7-23.3) in men, and from 21.9 kg/m2 (21.3-22.5) to 24.9 kg/m2 (24.6-25.1) in women. The age-standardised prevalence of diabetes increased from 3.4% (1.5-6.3) to 8.5% (6.5-10.8) in men, and from 4.1% (2.0-7.5) to 8.9 % (6.9-11.2) in women. Estimates in northern and southern regions were mostly higher than the global average; those in central, eastern and western regions were lower than global averages. A positive association (correlation coefficient ≃0.9) was observed between mean BMI and diabetes prevalence

Journal article

Cai Y, Hansell A, Blangiardo M, Burton P, de Hoogh K, Doiron D, Fortier I, Gulliver J, Hveem K, Mbatchou S, Morley D, Stolk R, Zijlema W, Elliott P, Hodgson Set al., 2017, Long-term exposure to road traffic noise, ambient air pollution and cardiovascular risk factors in the HUNT and Lifelines cohorts, European Heart Journal, Vol: 38, Pages: 2290-2296, ISSN: 1522-9645

AimsBlood biochemistry may provide information on associations between road traffic noise, air pollution, and cardiovascular disease risk. We evaluated this in two large European cohorts (HUNT3, Lifelines).Methods and resultsRoad traffic noise exposure was modelled for 2009 using a simplified version of the Common Noise Assessment Methods in Europe (CNOSSOS-EU). Annual ambient air pollution (PM10, NO2) at residence was estimated for 2007 using a Land Use Regression model. The statistical platform DataSHIELD was used to pool data from 144 082 participants aged ≥20 years to enable individual-level analysis. Generalized linear models were fitted to assess cross-sectional associations between pollutants and high-sensitivity C-reactive protein (hsCRP), blood lipids and for (Lifelines only) fasting blood glucose, for samples taken during recruitment in 2006–2013. Pooling both cohorts, an inter-quartile range (IQR) higher day-time noise (5.1 dB(A)) was associated with 1.1% [95% confidence interval (95% CI: 0.02–2.2%)] higher hsCRP, 0.7% (95% CI: 0.3–1.1%) higher triglycerides, and 0.5% (95% CI: 0.3–0.7%) higher high-density lipoprotein (HDL); only the association with HDL was robust to adjustment for air pollution. An IQR higher PM10 (2.0 µg/m3) or NO2 (7.4 µg/m3) was associated with higher triglycerides (1.9%, 95% CI: 1.5–2.4% and 2.2%, 95% CI: 1.6–2.7%), independent of adjustment for noise. Additionally for NO2, a significant association with hsCRP (1.9%, 95% CI: 0.5–3.3%) was seen. In Lifelines, an IQR higher noise (4.2 dB(A)) and PM10 (2.4 µg/m3) was associated with 0.2% (95% CI: 0.1–0.3%) and 0.6% (95% CI: 0.4–0.7%) higher fasting glucose respectively, with both remaining robust to adjustment for air/noise pollution.ConclusionLong-term exposures to road traffic noise and ambient air pollution were associated with blood biochemistry, providing a possible link b

Journal article

Scheelbeek P, Chowdhury MAH, Haines A, Alam D, Hoque MA, Butler AP, Khan AE, Mojumder SK, Blangiardo MAG, Elliott P, Vineis Pet al., 2017, Drinking Water Salinity and Raised Blood Pressure: Evidence from a Cohort Study in Coastal Bangladesh., Environmental Health Perspectives, Vol: 125, ISSN: 0091-6765

BACKGROUND: Millions of coastal inhabitants in Southeast Asia have been experiencing increasing sodium concentrations in their drinking-water sources, likely partially due to climate change. High (dietary) sodium intake has convincingly been proven to increase risk of hypertension; it remains unknown, however, whether consumption of sodium in drinking water could have similar effects on health. OBJECTIVES: We present the results of a cohort study in which we assessed the effects of drinking-water sodium (DWS) on blood pressure (BP) in coastal populations in Bangladesh. METHODS: DWS, BP, and information on personal, lifestyle, and environmental factors were collected from 581 participants. We used generalized linear latent and mixed methods to model the effects of DWS on BP and assessed the associations between changes in DWS and BP when participants experienced changing sodium levels in water, switched from "conventional" ponds or tube wells to alternatives [managed aquifer recharge (MAR) and rainwater harvesting] that aimed to reduce sodium levels, or experienced a combination of these changes. RESULTS: DWS concentrations were highly associated with BP after adjustments for confounding factors. Furthermore, for each 100 mg/L reduction in sodium in drinking water, systolic/diastolic BP was lower on average by 0.95/0.57 mmHg, and odds of hypertension were lower by 14%. However, MAR did not consistently lower sodium levels. CONCLUSIONS: DWS is an important source of daily sodium intake in salinity-affected areas and is a risk factor for hypertension. Considering the likely increasing trend in coastal salinity, prompt action is required. Because MAR showed variable effects, alternative technologies for providing reliable, safe, low-sodium fresh water should be developed alongside improvements in MAR and evaluated in "real-life" salinity-affected settings. https://doi.org/10.1289/EHP659.

Journal article

Cai Y, Hodgson S, Blangiardo M, De Hoogh K, Morley D, Gulliver J, Hveem K, Elliott P, Hansell Aet al., 2017, Ambient Air Pollution, Traffic Noise And Adult-Onset Asthma: The Hunt Study, Norway, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X

Conference paper

Al-Dabhani K, Tsilidis K, Murphy N, Ward H, Elliot P, Riboli E, Gunter M, Tzoulaki Iet al., 2017, Prevalence of vitamin D deficiency and association with metabolic syndrome in a Qatari population, Nutrition and Diabetes, Vol: 7, ISSN: 2044-4052

Background/ObjectivesDespite long hours of sunlight in Qatar and other regions of the Middle East, vitamin D deficiency has been rising. In parallel, the prevalence metabolic syndrome has also been increasing in Qatar. Vitamin D levels have been associated with metabolic syndrome but data are inconsistent and no studies have addressed these inter-relationships in a Middle Eastern population where the prevalence of these conditions is high. The objective is to investigate the prevalence of vitamin D deficiency and its association with metabolic syndrome and its components in the Qatar Biobank population.Subjects/MethodsA cross-sectional study of 1 205 participants (702 women and 503 men) from the Qatar Biobank, comprising Qataris and non-Qataris between the ages of 18 to 80 years, was used to perform multivariate linear regression analyses to examine the association between metabolic syndrome and prevalence of vitamin D deficiency (defined as <20 ng/mL serum vitamin D levels) adjusting for age, sex, ethnicity, season of blood collection, physical activity, and education. Odds ratios and 95% confidence intervals were calculated for all analyses. ResultsApproximately 64% of participants were vitamin D deficient (<20 ng/mL) with more men being deficient (68.6%) than women (61.3%). Serum vitamin D was 8% lower in individuals with metabolic syndrome (RR: 0.92, 95%CI: 0.87 – 0.98, p-value: 0.01) compared to individuals without metabolic syndrome. Waist circumference and HDL as well as high triglyceride levels were also significantly positively associated with vitamin D deficiency. No association was found between the other components of metabolic syndrome or diabetes and the presence of vitamin D deficiency. ConclusionsVitamin D deficiency is prevalent in this Qatari population. Presence of metabolic syndrome was associated with presence of vitamin D deficiency. Future prospective studies need to be conducted to investigate the potential for causality.

Journal article

Gibson R, Eriksen R, Lamb K, Mcmeel Y, Vergnaud A, Spear J, Aresu M, Chan Q, Elliott P, Frost Get al., 2017, Dietary assessment of British police force employees: a description of diet record coding procedures and cross-sectional evaluation of dietary energy intake reporting (the airwave health monitoring study), BMJ Open, Vol: 7, ISSN: 2044-6055

Objectives: Dietary intake is a key aspect of occupational health. To capture the characteristics of dietary behaviour that is affected by occupational environment that may impact on disease risk, collection of prospective multi-day dietary records are required. The aims of this paper are to: i) the collection of multi day dietary data in the Airwaves health monitoring study, ii) describe the dietarycoding procedures applied and iii) investigate the plausibilityof dietary reporting in this occupational cohort. Design: A dietary coding protocol for this large-scale studywas developed to minimise coding error rate. Participants (n4,412) who completed 7-day food records were included for cross-sectional analyses. Energy intake misreporting wasestimated using the Goldberg method. Multivariate logistic regression models were applied to determine participant characteristics associated with energy intake misreporting. Setting: British police force employees enrolled (2007 to 2012) into the Airwave Health Monitoring Study. Results: The mean code error rate per food diary was3.7% (SD 3.2%). The strongest predictors of energy intake under-reporting were body mass index (BMI) and physical activity. Compared to participants withBMI <25kg/m2, thosewith BMI >30kg/m2 had increased odds of being classified as under-reporting energy intake (men OR 5.20 95%CI 3.92, 6.89; women OR 2.66 95%CI 1.85, 3.83). Men and women in the highest physical activity category compared to the lowest were also more likely to be classified as under-reporting (men OR 3.33 95%CI 2.46, 4.50; women OR 4.34 95%CI 2.91, 6.55). Conclusions: A reproducible dietary record coding procedure has been developed to minimise coding error in complex 7-day diet diaries. The prevalence of energy intake under-reporting is comparable to existingnational UK cohortsand, in agreement with p

Journal article

Manning A, Highland HM, Gasser J, Sim X, Tukiainen T, Fontanillas P, Grarup N, Rivas MA, Mahajan A, Locke AE, Cingolani P, Pers TH, Viñuela A, Brown AA, Wu Y, Flannick J, Fuchsberger C, Gamazon ER, Gaulton KJ, Im HK, Teslovich TM, Blackwell TW, Bork-Jensen J, Burtt NP, Chen Y, Green T, Hartl C, Kang HM, Kumar A, Ladenvall C, Ma C, Moutsianas L, Pearson RD, Perry JR, Rayner NW, Robertson NR, Scott LJ, van de Bunt M, Eriksson JG, Jula A, Koskinen S, Lehtimäki T, Palotie A, Raitakari OT, Jacobs SB, Wessel J, Chu AY, Scott RA, Goodarzi MO, Blancher C, Buck G, Buck D, Chines PS, Gabriel S, Gjesing AP, Groves CJ, Hollensted M, Huyghe JR, Jackson AU, Jun G, Justesen JM, Mangino M, Murphy J, Neville M, Onofrio R, Small KS, Stringham HM, Trakalo J, Banks E, Carey J, Carneiro MO, DePristo M, Farjoun Y, Fennell T, Goldstein JI, Grant G, Hrabé de Angelis M, Maguire J, Neale BM, Poplin R, Purcell S, Schwarzmayr T, Shakir K, Smith JD, Strom TM, Wieland T, Lindstrom J, Brandslund I, Christensen C, Surdulescu GL, Lakka TA, Doney AS, Nilsson P, Wareham NJ, Langenberg C, Varga TV, Franks PW, Rolandsson O, Rosengren AH, Farook VS, Thameem F, Puppala S, Kumar S, Lehman DM, Jenkinson CP, Curran JE, Hale DE, Fowler SP, Arya R, DeFronzo RA, Abboud HE, Syvänen AC, Hicks PJ, Palmer ND, Ng MC, Bowden DW, Freedman BI, Esko T, Mägi R, Milani L, Mihailov E, Metspalu A, Narisu N, Kinnunen L, Bonnycastle LL, Swift A, Pasko D, Wood AR, Fadista J, Pollin TI, Barzilai N, Atzmon G, Glaser B, Thorand B, Strauch K, Peters A, Roden M, Müller-Nurasyid M, Liang L, Kriebel J, Illig T, Grallert H, Gieger C, Meisinger C, Lannfelt L, Musani SK, Griswold M, Taylor HA, Wilson G, Correa A, Oksa H, Scott WR, Afzal U, Tan ST, Loh M, Chambers JC, Sehmi J, Kooner JS, Lehne B, Cho YS, Lee JY, Han BG, Käräjämäki A, Qi Q, Qi L, Huang J, Hu FB, Melander O, Orho-Melander M, Below JE, Aguilar D, Wong TY, Liu J, Khor CC, Chia KS, Lim WY, Cheng CY, Chan E, Tai ES, Aung T, Linneberg A, Isomaa B, Meitinger T, Tuomi T, Hakasteet al., 2017, A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk., Diabetes, Vol: 66, Pages: 2019-2032, ISSN: 0012-1797

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

Journal article

Neal B, Tian M, Li N, Elliott P, Yan LL, Labarthe DR, Huang L, Yin X, Hao Z, Stepien S, Shi J, Feng X, Zhang J, Zhang Y, Zhang R, Wu Yet al., 2017, Rationale, design, and baseline characteristics of the Salt Substitute and Stroke Study (SSaSS)-A large-scale cluster randomized controlled trial, American Heart Journal, Vol: 188, Pages: 109-117, ISSN: 0002-8703

Lowering sodium intake with a reduced-sodium, added potassium salt substitute has been proved to lower blood pressure levels. Whether the same strategy will also reduce the risks of vascular outcomes is uncertain and controversial. The SSaSS has been designed to test whether sodium reduction achieved with a salt substitute can reduce the risk of vascular disease. The study is a large-scale, open, cluster-randomized controlled trial done in 600 villages across 5 provinces in China. Participants have either a history of stroke or an elevated risk of stroke based on age and blood pressure level at entry. Villages were randomized in a 1:1 ratio to intervention or continued usual care. Salt substitute is provided free of charge to participants in villages assigned to the intervention group. Follow-up is scheduled every 6 months for 5 years, and all potential endpoints are reviewed by a masked adjudication committee. The primary end point is fatal and nonfatal stroke, and the 2 secondary endpoints are total major cardiovascular events and total mortality. The study has been designed to provide 90% statistical power (with 2-sided α = .05) to detect a 13% or greater relative risk reduction for stroke. The power estimate assumes a primary outcome event rate of 3.5% per year and a systolic blood pressure difference of 3.0 mm Hg between randomized groups. Recruitment is complete and there are 20,996 participants (about 35 per village) that have been enrolled. Mean age is 65 years and 49% are female. There were 73% enrolled on the basis of a history of stroke. The trial is well placed to describe the effects of salt substitution on the risks of vascular disease and death and will provide important policy-relevant data.

Journal article

Pertiwi K, Oude Griep LM, Stamler J, Chan Q, Geleijnse JM, Steffen LM, Rodriguez B, Daviglus ML, Van Horn L, Elliott Pet al., 2017, Relationship of potato consumption, total and by preparation method with blood pressure and body mass index: The International Population Study on Macronutrients and Blood Pressure (INTERMAP) US study, Scientific Sessions on Epidemiology and Prevention, Lifestyle and Cardiometabolic Health of the American Hearth Association, Publisher: American Heart Association, Pages: AP272-AP272, ISSN: 0009-7322

Background: Limited evidence from prospective US cohort studies suggests that higher potato intake is associated with a higher risk of hypertension and obesity. Different preparation methods affect the nutritional composition of potatoes and are related to different dietary choices that may influence associations with blood pressure and body mass index (BMI).Objective: To investigate potato consumption, total and by preparation method, in relation to blood pressure and BMI.Methods: We used cross-sectional data of 2,195 participants aged 40 to 59 in 1996-1997 from the United States samples of the population-based INTERMAP study. During four visits, four in-depth multipass 24-hour dietary recalls and eight blood pressure measurements were collected. Reported potato intakes were categorized as fried and non-fried potatoes, using the USDA food grouping system. Potato intakes (g/1000 kcal) were averaged over four days. Regression coefficients per 2SD higher intake were estimated using multivariate linear regression analyses with adjustments for age, sex, sample, lifestyle and disease factors, and other food groups. To assess influence on the association, diet quality (by Dietary Approaches to Stop Hypertension adherence score), BMI, urinary sodium and potassium were added separately to the previous model.Results: Median intake of total, non-fried, and fried potatoes were 40 g/d, 23 g/d and 8 g/d, respectively. Total and non-fried potato intakes were not associated with blood pressure. The association between fried potatoes and blood pressure varied by sex (P for interaction=0.03).In women, higher fried potato intake (2SD: 20 g/1000 kcal) was associated with a +3.00 mmHg (95%CI: 1.29, 4.71) higher systolic and +1.26 mmHg (95%CI: 0.15, 2.38) higher diastolic blood pressure, which prevailed after additional, but separate, adjustments for BMI, diet quality, urinary sodium and potassium. Potato chips contributed predominantly (79%) to fried potato intake and accounted for the

Conference paper

Asaria P, Elliott P, Douglass M, Obermeyer Z, Soljak M, Majeed A, Ezzati Met al., 2017, Acute myocardial infarction hospital admissions and deaths in England: a national follow-back and follow-forward record-linkage study, Lancet Public Health, Vol: 2, Pages: e191-e201, ISSN: 2468-2667

Background Little information is available on how primary and comorbid acute myocardial infarction contribute to the mortality burden of acute myocardial infarction, the share of these deaths that occur during or after a hospital admission, and the reasons for hospital admission of those who died from acute myocardial infarction. Our aim was to fill in these gaps in the knowledge about deaths and hospital admissions due to acute myocardial infarction. Methods We used individually linked national hospital admission and mortality data for England from 2006 to 2010 to identify all primary and comorbid diagnoses of acute myocardial infarction during hospital stay and their associated fatality rates (during or within 28 days of being in hospital). Data were obtained from the UK Small Area Health Statistics Unit and supplied by the Health and Social Care Information Centre (now NHS Digital) and the Office of National Statistics. We calculated event rates (reported as per 100 000 population for relevant age and sex groups) and case-fatality rate for primary acute myocardial infarction diagnosed during the first physician encounter or during subsequent encounters, and acute myocardial infarction diagnosed only as a comorbidity. We also calculated what proportion of deaths from acute myocardial infarction occurred in people who had been in hospital on or within the 28 days preceding death, and whether acute myocardial infarction was one of the recorded diagnoses in such admissions. Findings Acute myocardial infarction was diagnosed in the first physician encounter in 307 496 (69%) of 446 744 admissions with a diagnosis of acute myocardial infarction, in the second or later physician encounter in 52 374 (12%) admissions, and recorded only as a comorbidity in 86 874 (19%) admissions. Patients with comorbid diagnoses of acute myocardial infarction had two to three times the case-fatality rate of patients in whom acute myocardial infarction was a primary diagnosis. 135 950 death

Journal article

Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, Ntalla I, Surendran P, Liu C, Cook JP, Kraja AT, Drenos F, Loh M, Verweij N, Marten J, Karaman I, Lepe MPS, O'Reilly PF, Knight J, Snieder H, Kato N, He J, Tai ES, Said MA, Porteous D, Alver M, Poulter N, Farrall M, Gansevoort RT, Padmanabhan S, Magi R, Stanton A, Connell J, Bakker SJL, Metspalu A, Shields DC, Thom S, Brown M, Sever P, Esko T, Hayward C, van der Harst P, Saleheen D, Chowdhury R, Chambers JC, Chasman DI, Chakravarti A, Newton-Cheh C, Lindgren CM, Levy D, Kooner JS, Keavney B, Tomaszewski M, Samani NJ, Howson JMM, Tobin MD, Munroe PB, Ehret GB, Wain LV, Barnes MR, Tzoulaki J, Caulfield MJ, Elliott P, Wain LV, Vaez A, Jansen R, Joehanes R, van der Most PJ, Erzurumluoglu AM, O'Reilly P, Cabrera CP, Warren HR, Rose LM, Verwoert GC, Hottenga J-J, Strawbridge RJ, Esko T, Arking DE, Hwang S-J, Guo X, Kutalik Z, Trompet S, Shrine N, Teumer A, Ried JS, Bis JC, Smith AV, Amin N, Nolte IM, Lyytikainen L-P, Mahajan A, Wareham NJ, Hofer E, Joshi PK, Kristiansson K, Traglia M, Havulinna AS, Goel A, Nalls MA, Sober S, Vuckovic D, Luan J, Del Greco M F, Ayers KL, Marrugat J, Ruggiero D, Lopez LM, Niiranen T, Enroth S, Jackson AU, Nelson CP, Huffman JE, Zhang W, Marten J, Gandin I, Harris SE, Zemonik T, Lu Y, Evangelou E, Shah N, de Borst MH, Mangino M, Prins BP, Campbell A, Li-Gao R, Chauhan G, Oldmeadow C, Abecasis G, Abedi M, Barbieri CM, Barnes MR, Batini C, Blake T, Boehnke M, Bottinger EP, Braund PS, Brown M, Brumat M, Campbell H, Chambers JC, Cocca M, Collins F, Connell J, Cordell HJ, Damman JJ, Davies G, de Geus EJ, de Mutsert R, Deelen J, Demirkale Y, Doney ASF, Dorr M, Farrall M, Ferreira T, Franberg M, Gao H, Giedraitis V, Gieger C, Giulianini F, Gow AJ, Hamsten A, Harris TB, Hofman A, Holliday EG, Jarvelin M-R, Johansson A, Johnson AD, Jousilahti P, Jula A, Kahonen M, Kathiresan S, Khaw K-T, Kolcic I, Koskinen S, Langenberg C, Larson M, Launer LJ, Lehne B, Liewald DCM, Lin L, Lind L, Mach F, Mamaet al., 2017, Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk, NATURE GENETICS, Vol: 49, Pages: 403-415, ISSN: 1061-4036

Journal article

Chekmeneva E, Correia GDS, Chan Q, Wijeyesekera A, Tin A, Young JH, Elliott P, Nicholson JK, Holmes Eet al., 2017, Optimization and Application of Direct Infusion Nanoelectrospray HRMS Method for Large-Scale Urinary Metabolic Phenotyping in Molecular Epidemiology, JOURNAL OF PROTEOME RESEARCH, Vol: 16, Pages: 1646-1658, ISSN: 1535-3893

Large-scale metabolic profiling requires the development of novel economical high-throughput analytical methods to facilitate characterization of systemic metabolic variation in population phenotypes. We report a fit-for-purpose direct infusion nanoelectrospray high-resolution mass spectrometry (DI-nESI-HRMS) method with time-of-flight detection for rapid targeted parallel analysis of over 40 urinary metabolites. The newly developed 2 min infusion method requires <10 μL of urine sample and generates high-resolution MS profiles in both positive and negative polarities, enabling further data mining and relative quantification of hundreds of metabolites. Here we present optimization of the DI-nESI-HRMS method in a detailed step-by-step guide and provide a workflow with rigorous quality assessment for large-scale studies. We demonstrate for the first time the application of the method for urinary metabolic profiling in human epidemiological investigations. Implementation of the presented DI-nESI-HRMS method enabled cost-efficient analysis of >10 000 24 h urine samples from the INTERMAP study in 12 weeks and >2200 spot urine samples from the ARIC study in <3 weeks with the required sensitivity and accuracy. We illustrate the application of the technique by characterizing the differences in metabolic phenotypes of the USA and Japanese population from the INTERMAP study.

Journal article

Stringhini S, Carmeli C, Jokela M, Avendano M, Muennig P, Guida F, Ricceri F, d'Errico A, Barros H, Bochud M, Chadeau-Hyam M, Clavel-Chapelon F, Costa G, Delpierre C, Fraga S, Goldberg M, Giles GG, Krogh V, Kelly-Irving M, Layte R, Lasserre AM, Marmot MG, Preisig M, Shipley MJ, Vollenweider P, Zins M, Kawachi I, Steptoe A, Mackenbach JP, Vineis P, Kivimaki Met al., 2017, Socioeconomic status and the 25 x 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1.7 million men and women, LANCET, Vol: 389, Pages: 1229-1237, ISSN: 0140-6736

Background:In 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors.Methods:We did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 × 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 × 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors.Findings:During 26·6 million person-years at risk (mean follow-up 13·3 years [SD 6·4 years]), 310 277 participants died. HR for the 25 × 25 risk factors and mortality varied between 1·04 (95% CI 0·98–1·11) for obesity in men and 2 ·17 (2·06–2·29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1·42, 95% CI 1·38–1·45 for men; 1·34, 1·28–1·39 for women); this association remained significant in mutually adjusted models that included the 25 × 25 factors (HR 1·26, 1·21–1·32, men and women combined). The population attrib

Journal article

Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Elliott P, Chambers JC, Evangelou E, Kooner JS, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJF, Frayling TM, Hirschorn JS, Deloukas P, Lettre Get al., 2017, Rare and low-frequency coding variants alter human adult height, Nature, Vol: 542, Pages: 186-190, ISSN: 0028-0836

Heightis a highly heritable, classic polygenic traitwith~700common associated variants identified so far through genome-wide association studies. Here,we report 83 height-associated codingvariants with lowerminor allele frequencies(range of0.1-4.8%)and effects ofup to 2 16cm/allele(e.g.in IHH, STC2, ARand CRISPLD2), >10timesthe average effect of common variants.In functional follow-upstudies,rare height-increasing allelesof STC2(+1-2 cm/allele) compromisedproteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4in vitro, resulting in higher bioavailability of insulin-like growth factors.These 83height-associated variants overlapgenes mutated in monogenic growth disordersand highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis)involved in growth.Our results demonstratethatsufficiently large sample sizescan uncoverrare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes,andthat these variantsimplicate relevant genes and pathways.

Journal article

Garcia Perez I, Posma JM, Gibson R, Chambers ES, Hansen TH, Vestergaard H, Hansen T, Beckmann M, Pedersen O, Elliott P, Stamler J, Nicholson JK, Draper J, Mathers JC, Holmes E, Frost Get al., 2017, Objective assessment of dietary patterns using metabolic phenotyping: a randomized, controlled, crossover trial, The Lancet Diabetes & Endocrinology, Vol: 5, Pages: 184-195, ISSN: 2213-8587

Background: The burden of non-communicable diseases, such as obesity, diabetes, coronary heart disease and cancer, can be reduced by the consumption of healthy diets. Accurate monitoring of changes in dietary patterns in response to food policy implementation is challenging. Metabolic profiling allows simultaneous measurement of hundreds of metabolites in urine, many of them influenced by food intake. We aim to classify people according to dietary behaviour and enhance dietary reporting using metabolic profiling of urine.Methods: To develop metabolite models from 19 healthy volunteers who attended a clinical research unit for four day periods on four occasions. We used the World Health Organisation’s healthy eating guidelines (increase fruits, vegetables, wholegrains, dietary fibre and decrease fats, sugars, and salt) to develop four dietary interventions lasting for four days each that ranged from a diet associated with a low to high risk of developing non-communicable disease. Urine samples were measured by 1H-NMR spectroscopy. This study is registered as an International Standard Randomized Controlled Trial, number ISRCTN 43087333. INTERMAP U.K. (n=225) and a healthy-eating Danish cohort (n=66) were used as free-living validation datasets.Findings: There was clear separation between the urinary metabolite profiles of the four diets. We also demonstrated significant stepwise differences in metabolite levels between the lowest and highest metabolic risk diets and developed metabolite models for each diet. Application of the derived metabolite models to independent cohorts confirmed the association between urinary metabolic and dietary profiles in INTERMAP (P<0•001) and the Danish cohort (P<0•001).Interpretation: Urinary metabolite models, developed in a highly controlled environment, can classify groups of free-living people into consumers of dietary profiles associated with lower or higher non-communicable disease risk based on multivariate m

Journal article

Zijlema W, Cai Y, Doiron D, Mbatchou S, Fortier I, Gulliver J, de Hoogh K, Morley D, Hodgson S, Elliott P, Key T, Kongsgard H, Hveem K, Gaye A, Burton P, Hansell A, Stolk R, Rosmalen Jet al., 2017, Corrigendum to "Road traffic noise, blood pressure and heart rate: Pooled analyses of harmonized data from 88,336 participants" [Envrion. Res. 151 (2016) 804-813], Environmental Research, Vol: 152, Pages: 520-520, ISSN: 0013-9351

Journal article

Douglas P, Freni-Sterrantino A, Leal Sanchez M, Ashworth DC, Ghosh RE, Fecht D, Font A, Blangiardo M, Gulliver J, Toledano MB, Elliott P, De Hoogh K, Fuller GW, Hansell ALet al., 2017, Estimating Particulate Exposure from Modern Municipal Waste Incinerators in Great Britain, Environmental science & technology, Vol: 51, Pages: 7511-7519, ISSN: 0013-936X

Municipal Waste Incineration (MWI) is regulated through the European Union Directive on Industrial Emissions (IED), but there is ongoing public concern regarding potential hazards to health. Using dispersion modeling, we estimated spatial variability in PM10 concentrations arising from MWIs at postcodes (average 12 households) within 10 km of MWIs in Great Britain (GB) in 2003-2010. We also investigated change points in PM10 emissions in relation to introduction of EU Waste Incineration Directive (EU-WID) (subsequently transposed into IED) and correlations of PM10 with SO2, NOx, heavy metals, polychlorinated dibenzo-p-dioxins/furan (PCDD/F), polycyclic aromatic hydrocarbon (PAH) and polychlorinated biphenyl (PCB) emissions. Yearly average modeled PM10 concentrations were 1.00 × 10-5 to 5.53 × 10-2 μg m-3, a small contribution to ambient background levels which were typically 6.59-2.68 × 101 μg m-3, 3-5 orders of magnitude higher. While low, concentration surfaces are likely to represent a spatial proxy of other relevant pollutants. There were statistically significant correlations between PM10 and heavy metal compounds (other heavy metals (r = 0.43, p = <0.001)), PAHs (r = 0.20, p = 0.050), and PCBs (r = 0.19, p = 0.022). No clear change points were detected following EU-WID implementation, possibly as incinerators were operating to EU-WID standards before the implementation date. Results will be used in an epidemiological analysis examining potential associations between MWIs and health outcomes.

Journal article

Iwahori T, Miura K, Ueshima H, Chan Q, Dyer AR, Elliott P, Stamler Jet al., 2016, Estimating 24-hour urinary sodium/potassium ratio from casual (“spot”) urinary sodium/potassium ratio: The INTERSALT Study, International Journal of Epidemiology, Vol: 46, Pages: 1564-1572, ISSN: 1464-3685

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.

Journal article

Chan Q, Loo RL, Ebbels TMD, Van Horn L, Daviglus ML, Stamler J, Nicholson JK, Holmes E, Elliott Pet al., 2016, Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: An overview, Hypertension Research, Vol: 40, Pages: 336-345, ISSN: 1348-4214

The aetiopathogenesis of cardiovascular diseases (CVD) is multifactorial. Adverse bloodpressure (BP) is a major independent risk factor for epidemic CVD affecting about 40% of theadult population worldwide and resulting in significant morbidity and mortality. Metabolicphenotyping of biological fluids has proven its application in characterising low moleculeweight metabolites providing novel insights into gene-environmental-gut microbiomeinteraction in relations to a disease state. In this review, we synthesise key results from theInternational Study of Macro/Micronutrients and Blood Pressure (INTERMAP) Study, a cross-sectional epidemiological study of 4,680 men and women aged 40-59 years from Japan, thePeople’s Republic of China, the United Kingdom, and the United States. We describe theadvancements we have made on: 1) analytical techniques for high throughput metabolicphenotyping; 2) statistical analyses for biomarker identification; 3) discovery of unique food-specific biomarkers; and 4) application of metabolome-wide association (MWA) studies togain a better understanding into the molecular mechanisms of cross cultural and regional BPdifferences.

Journal article

Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, Tsai P-C, Ried JS, Zhang W, Yang Y, Tan S, Fiorito G, Franke L, Guarrera S, Kasela S, Kriebel J, Richmond RC, Adamo M, Afzal U, Ala-Korpela M, Albetti B, Ammerpohl O, Apperley JF, Beekman M, Bertazzi PA, Black SL, Blancher C, Bonder M-J, Brosch M, Carstensen-Kirberg M, de Craen AJM, de Lusignan S, Dehghan A, Elkalaawy M, Fischer K, Franco OH, Gaunt TR, Hampe J, Hashemi M, Isaacs A, Jenkinson A, Jha S, Kato N, Krogh V, Laffan M, Meisinger C, Meitinger T, Mok ZY, Motta V, Ng HK, Nikolakopoulou Z, Nteliopoulos G, Panico S, Pervjakova N, Prokisch H, Rathmann W, Roden M, Rota F, Rozario MA, Sandling JK, Schafmayer C, Schramm K, Siebert R, Slagboom PE, Soininen P, Stolk L, Strauch K, Tai E-S, Tarantini L, Thorand B, Tigchelaar EF, Tumino R, Uitterlinden AG, van Duijn C, van Meurs JBJ, Vineis P, Wickremasinghe AR, Wijmenga C, Yang T-P, Yuan W, Zhernakova A, Batterham RL, Smith GD, Deloukas P, Heijmans BT, Herder C, Hofman A, Lindgren CM, Milani L, van der Harst P, Peters A, Illig T, Relton CL, Waldenberger M, Jaervelin M-R, Bollati V, Soong R, Spector TD, Scott J, McCarthy MI, Elliott P, Bell JT, Matullo G, Gieger C, Kooner JS, Grallert H, Chambers JCet al., 2016, Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity, Nature, Vol: 541, Pages: 81-+, ISSN: 0028-0836

Approximately 1.5 billion people worldwide are overweight oraffected by obesity, and are at risk of developing type 2 diabetes,cardiovascular disease and related metabolic and inflammatorydisturbances1,2. Although the mechanisms linking adiposity toassociated clinical conditions are poorly understood, recent studiessuggest that adiposity may influence DNA methylation3–6, a keyregulator of gene expression and molecular phenotype7. Here weuse epigenome-wide association to show that body mass index(BMI; a key measure of adiposity) is associated with widespreadchanges in DNA methylation (187 genetic loci with P<1×10−7,range P=9.2×10−8 to 6.0×10−46; n=10,261 samples). Geneticassociation analyses demonstrate that the alterations in DNAmethylation are predominantly the consequence of adiposity,rather than the cause. We find that methylation loci are enrichedfor functional genomic features in multiple tissues (P<0.05), andshow that sentinel methylation markers identify gene expressionsignatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to6.1×10−35, n=1,785 samples). The methylation loci identify genesinvolved in lipid and lipoprotein metabolism, substrate transportand inflammatory pathways. Finally, we show that the disturbancesin DNA methylation predict future development of type 2 diabetes(relative risk per 1 standard deviation increase in methylation riskscore: 2.3 (2.07–2.56); P=1.1×10−54). Our results provide newinsights into the biologic pathways influenced by adiposity, and mayenable development of new strategies for prediction and preventionof type 2 diabetes and other adverse clinical consequences of obesity

Journal article

Li N, Yan LL, Niu W, Yao C, Feng X, Zhang J, Shi J, Zhang Y, Zhang R, Hao Z, Chu H, Zhang J, Li X, Pan J, Li Z, Sun J, Zhou B, Zhao Y, Yu Y, Engelgau M, Labarthe D, Ma J, MacMahon S, Elliott P, Wu Y, Neal Bet al., 2016, The effects of a community-based sodium reduction program in rural china - a cluster-randomized trial, PLOS One, Vol: 11, ISSN: 1932-6203

BackgroundAverage 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.ObjectiveWe sought to determine the effects of a community-based sodium reduction program on salt consumption in rural northern China.DesignThis 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.ResultsAmong 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).ConclusionThere 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 RegistrationClinicaltrials.gov identifier: NCT01259700.

Journal article

Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Segura Lepe M, Akira S, Barbieri C, Baumeister S, Cauchi S, Clarke TK, Enroth S, Fischer K, Hällfors J, Harris SE, Hieber S, Hofer E, Hottenga JJ, Johansson Å, Joshi PK, Kaartinen N, Laitinen J, Lemaitre R, Loukola A, Luan J, Lyytikäinen LP, Mangino M, Manichaikul A, Mbarek H, Milaneschi Y, Moayyeri A, Mukamal K, Nelson C, Nettleton J, Partinen E, Rawal R, Robino A, Rose L, Sala C, Satoh T, Schmidt R, Schraut K, Scott R, Smith AV, Starr JM, Teumer A, Trompet S, Uitterlinden AG, Venturini C, Vergnaud AC, Verweij N, Vitart V, Vuckovic D, Wedenoja J, Yengo L, Yu B, Zhang W, Zhao JH, Boomsma DI, Chambers J, Chasman DI, Daniela T, de Geus E, Deary I, Eriksson JG, Esko T, Eulenburg V, Franco OH, Froguel P, Gieger C, Grabe HJ, Gudnason V, Gyllensten U, Harris TB, Hartikainen AL, Heath AC, Hocking L, Hofman A, Huth C, Jarvelin MR, Jukema JW, Kaprio J, Kooner JS, Kutalik Z, Lahti J, Langenberg C, Lehtimäki T, Liu Y, Madden PA, Martin N, Morrison A, Penninx B, Pirastu N, Psaty B, Raitakari O, Ridker P, Rose R, Rotter JI, Samani NJ, Schmidt H, Spector TD, Stott D, Strachan D, Tzoulaki I, van der Harst P, van Duijn CM, Marques-Vidal P, Vollenweider P, Wareham NJ, Whitfield JB, Wilson J, Wolffenbuttel B, Bakalkin G, Evangelou E, Liu Y, Rice KM, Desrivières S, Kliewer SA, Mangelsdorf DJ, Müller CP, Levy D, Elliott Pet al., 2016, KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 14372-14377, ISSN: 1091-6490

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.

Journal article

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