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

592 results found

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

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

Oude Griep LM, Chekmeneva E, Stamler J, Van Horn L, Chan Q, Ebbels TMD, Holmes E, Frost GS, Elliott Pet al., 2016, Urinary hippurate and proline betaine relative to fruit intake, blood pressure, and body mass index, Summer meeting 2016: New technology in nutrition research and practice, Publisher: Cambridge University Press (CUP), Pages: E178-E178, ISSN: 0029-6651

Conference paper

Evangelou E, Warren H, Cabrera C, Gao H, Tzoulaki I, Barnes M, Caulfield M, Elliott Pet al., 2016, UK Biobank GWAS Identifies over 100 Novel Variants Associated with Blood Pressure, Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: WILEY-BLACKWELL, Pages: 613-613, ISSN: 0741-0395

Conference paper

Cai Y, Zijlema WL, Doiron D, Blangiardo M, Burton PR, Fortier I, Gaye A, Gulliver J, de Hoogh K, Hveem K, Mbatchou S, Morley DW, Stolk RP, Elliott P, Hansell AL, Hodgson Set al., 2016, Ambient air pollution, traffic noise and adult asthma prevalence: a BioSHaRE approach, European Respiratory Journal, Vol: 49, ISSN: 0903-1936

We investigated the effects of both ambient air pollution and traffic noise on adult asthma prevalence, using harmonised data from three European cohort studies established in 2006–2013 (HUNT3, Lifelines and UK Biobank).Residential exposures to ambient air pollution (particulate matter with aerodynamic diameter <=10 µm (PM10) and nitrogen dioxide (NO2)) were estimated by a pan-European Land Use Regression model for 2007. Traffic noise for 2009 was modelled at home addresses by adapting a standardised noise assessment framework (CNOSSOS-EU). A cross-sectional analysis of 646 731 participants aged >=20 years was undertaken using DataSHIELD to pool data for individual-level analysis via a “compute to the data” approach. Multivariate logistic regression models were fitted to assess the effects of each exposure on lifetime and current asthma prevalence.PM10 or NO2 higher by 10 µg·m-3 was associated with 12.8% (95% CI 9.5–16.3%) and 1.9% (95% CI 1.1–2.8%) higher lifetime asthma prevalence, respectively, independent of confounders. Effects were larger in those aged >=50 years, ever-smokers and less educated. Noise exposure was not significantly associated with asthma prevalence.This study suggests that long-term ambient PM10 exposure is associated with asthma prevalence in western European adults. Traffic noise is not associated with asthma prevalence, but its potential to impact on asthma exacerbations needs further investigation.Long-term ambient PM10 exposure is associated with asthma prevalence in three European adult cohorts http://ow.ly/En4b3049S7X

Journal article

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

Introduction Exposure to road traffic noise may increase blood pressure and heart rate. It is unclear to what extent exposure to air pollution may influence this relationship. We investigated associations between noise, blood pressure and heart rate, with harmonized data from three European cohorts, while taking into account exposure to air pollution. Methods Road traffic noise exposure was assessed using a European noise model based on the Common Noise Assessment Methods in Europe framework (CNOSSOS-EU). Exposure to air pollution was estimated using a European-wide land use regression model. Blood pressure and heart rate were obtained by trained clinical professionals. Pooled cross-sectional analyses of harmonized data were conducted at the individual level and with random-effects meta-analyses. Results We analyzed data from 88,336 participants, across the three participating cohorts (mean age 47.0 (±13.9) years). Each 10 dB(A) increase in noise was associated with a 0.93 (95% CI 0.76;1.11) bpm increase in heart rate, but with a decrease in blood pressure of 0.01 (95% CI −0.24;0.23) mmHg for systolic and 0.38 (95% CI −0.53; −0.24) mmHg for diastolic blood pressure. Adjustments for PM10 or NO2 attenuated the associations, but remained significant for DBP and HR. Results for BP differed by cohort, with negative associations with noise in LifeLines, no significant associations in EPIC-Oxford, and positive associations with noise &gt;60 dB(A) in HUNT3. Conclusions Our study suggests that road traffic noise may be related to increased heart rate. No consistent evidence for a relation between noise and blood pressure was found.

Journal article

Huang L, Crino M, Wu JH, Woodward M, Land MA, McLean R, Webster J, Enkhtungalag B, Nowson CA, Elliott P, Cogswell M, Toft U, Mill JG, Furlanetto TW, Ilich JZ, Hong YH, Cohall D, Luzardo L, Noboa O, Holm E, Gerbes AL, Senousy B, Pinar Kara S, Brewster LM, Ueshima H, Subramanian S, Teo BW, Allen N, Choudhury SR, Polonia J, Yasuda Y, Campbell NR, Neal B, Petersen KSet al., 2016, Reliable quantification of the potential for equations based on spot urine samples to estimate population salt intake: protocol for a systematic review and meta-analysis., JMIR Research Protocols, Vol: 5, ISSN: 1929-0748

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

Journal article

Karaman I, Ferreira DL, Boulange CL, Kaluarachchi MR, Herrington D, Dona AC, Castagné R, Moayyeri A, Lehne B, Loh M, de Vries PS, Dehghan A, Franco O, Hofman A, Evangelou E, Tzoulaki I, Elliott P, Lindon JC, Ebbels TMet al., 2016, A workflow for integrated processing of multi-cohort untargeted 1H NMR metabolomics data in large scale metabolic epidemiology, Journal of Proteome Research, Vol: 15, Pages: 4188-4194, ISSN: 1535-3907

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 which can ensure reliable data for statistical analysis. The COMBI-BIO project incorporates serum from approximately 8000 individuals, in 3 cohorts, profiled by 6 assays in 2 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 datasets (CPMG and NOESY). Alignment of the NMR data was shown to increase the correlation-based alignment quality measure from 0.319 to 0.391 for CPMG and from 0.536 to 0.586 for NOESY, showing that the improvement was present across both large and small peaks. End-to-end quality assessment of the pipeline was achieved using Hotelling’s T2 distributions. For CPMG spectra, the interquartile range decreased from 1.425 in raw QC data to 0.679 in processed spectra, while the corresponding change for NOESY spectra was from 0.795 to 0.636 indicating an improvement in precision following processing. PCA indicated that gross phase and cohort differences were no longer present. These results illustrate that the pipeline produces robust and reproducible data, successfully addressing the methodological challenges of this large multi-faceted study.

Journal article

Surendran P, Drenos F, Young R, Warren H, Cook JP, Manning AK, Grarup N, Sim X, Barnes DR, Witkowska K, Staley JR, Tragante V, Tukiainen T, Yaghootkar H, Masca N, Freitag DF, Ferreira T, Giannakopoulou O, Tinker A, Harakalova M, Mihailov E, Liu C, Kraja AT, Nielsen SF, Rasheed A, Samuel M, Zhao W, Bonnycastle LL, Jackson AU, Narisu N, Swift AJ, Southam L, Marten J, Huyghe JR, Stančáková A, Fava C, Ohlsson T, Matchan A, Stirrups KE, Bork-Jensen J, Gjesing AP, Kontto J, Perola M, Shaw-Hawkins S, Havulinna AS, Zhang H, Donnelly LA, Groves CJ, Rayner NW, Neville MJ, Robertson NR, Yiorkas AM, Herzig KH, Kajantie E, Zhang W, Willems SM, Lannfelt L, Malerba G, Soranzo N, Trabetti E, Verweij N, Evangelou E, Moayyeri A, Vergnaud AC, Nelson CP, Poveda A, Varga TV, Caslake M, de Craen AJ, Trompet S, Luan J, Scott RA, Harris SE, Liewald DC, Marioni R, Menni C, Farmaki AE, Hallmans G, Renström F, Huffman JE, Hassinen M, Burgess S, Vasan RS, Felix JF, CHARGE-Heart Failure Consortium, Uria-Nickelsen M, Malarstig A, Reilly DF, Hoek M, Vogt TF, Lin H, Lieb W, EchoGen Consortium, Traylor M, Markus HS, METASTROKE Consortium, Highland HM, Justice AE, Marouli E, GIANT Consortium, Lindström J, Uusitupa M, Komulainen P, Lakka TA, Rauramaa R, Polasek O, Rudan I, Rolandsson O, Franks PW, Dedoussis G, Spector TD, EPIC-InterAct Consortium, Jousilahti P, Männistö S, Deary IJ, Starr JM, Langenberg C, Wareham NJ, Brown MJ, Dominiczak AF, Connell JM, Jukema JW, Sattar N, Ford I, Packard CJ, Esko T, Mägi R, Metspalu A, de Boer RA, van der Meer P, van der Harst P, Lifelines Cohort Study, Gambaro G, Ingelsson E, Lind L, de Bakker PI, Numans ME, Brandslund I, Christensen C, Petersen ER, Korpi-Hyövälti E, Oksa H, Chambers JC, Kooner JS, Blakemore AI, Franks S, Jarvelin MR, Husemoen LL, Linneberg A, Skaaby T, Thuesen B, Karpe F, Tuomilehto J, Doney AS, Morris AD, Palmer CN, Holmen OL, Hveem K, Willer CJ, Tuomi T, Groop L, Käräjämäki A, Palotie A, Ripatti S, Salomaa V, Alam DS, Majumder AA, Di Anget al., 2016, Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension, Nature Genetics, Vol: 48, Pages: 1151-1161, ISSN: 1546-1718

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 ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/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.

Journal article

Ehret GB, Ferreira T, Chasman DI, Jackson AU, Schmidt EM, Johnson T, Thorleifsson G, Luan J, Donnelly LA, Kanoni S, Petersen AK, Pihur V, Strawbridge RJ, Shungin D, Hughes MF, Meirelles O, Kaakinen M, Bouatia-Naji N, Kristiansson K, Shah S, Kleber ME, Guo X, Lyytikäinen LP, Fava C, Eriksson N, Nolte IM, Magnusson PK, Salfati EL, Rallidis LS, Theusch E, Smith AJ, Folkersen L, Witkowska K, Pers TH, Joehanes R, Kim SK, Lataniotis L, Jansen R, Johnson AD, Warren H, Kim YJ, Zhao W, Wu Y, Tayo BO, Bochud M, CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Absher D, Adair LS, Amin N, Arking DE, Axelsson T, Baldassarre D, Balkau B, Bandinelli S, Barnes MR, Barroso I, Bevan S, Bis JC, Bjornsdottir G, Boehnke M, Boerwinkle E, Bonnycastle LL, Boomsma DI, Bornstein SR, Brown MJ, Burnier M, Cabrera CP, Chambers JC, Chang IS, Cheng CY, Chines PS, Chung RH, Collins FS, Connell JM, Döring A, Dallongeville J, Danesh J, de Faire U, Delgado G, Dominiczak AF, Doney AS, Drenos F, Edkins S, Eicher JD, Elosua R, Enroth S, Erdmann J, Eriksson P, Esko T, Evangelou E, Evans A, Fall T, Farrall M, Felix JF, Ferrières J, Ferrucci L, Fornage M, Forrester T, Franceschini N, Franco OH, Franco-Cereceda A, Fraser RM, Ganesh SK, Gao H, Gertow K, Gianfagna F, Gigante B, Giulianini F, Goel A, Goodall AH, Goodarzi MO, Gorski M, Gräßler J, Groves CJ, Gudnason V, Gyllensten U, Hallmans G, Hartikainen AL, Hassinen M, Havulinna AS, Hayward C, Hercberg S, Herzig KH, Hicks AA, Hingorani AD, Hirschhorn JN, Hofman A, Holmen J, Holmen OL, Hottenga JJ, Howard P, Hsiung CA, Hunt SC, Ikram MA, Illig T, Iribarren C, Jensen RA, Kähönen M, Kang HM, Kathiresan S, Keating BJ, Khaw KT, Kim YK, Kim E, Kivimaki M, Klopp N, Kolovou G, Komulainen P, Kooner JS, Kosova G, Krauss RM, Kuh D, Kutalik Z, Kuusisto J, Kvaløy K, Lakka TA, Lee NR, Lee IT, Lee WJ, Levy D, Li X, Liang KW, Lin H, Lin L, Lindström J, Lobbens S, Männistö S, Müller G, Müller-Nurasyid M, Mach F, Markus HS, Marouli Eet al., 2016, The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals, Nature Genetics, Vol: 48, Pages: 1171-1184, ISSN: 1546-1718

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.

Journal article

Koyama T, Yoshita K, Okuda N, Saitoh S, Sakata K, Okayama A, Nakagawa H, Miyagawa N, Miura K, Elliott P, Chan Q, Stamler J, Ueshima Het al., 2016, The relationship between overall nutrient intake and total fat intake among Japanese people: The INTERLIPID Study Japan, Asia Pacific Journal of Clinical Nutrition, ISSN: 1440-6047

Backgroundand Objectives: Total fat intake is linked to the intake of other nutrients. Little data are available on the extent to which total fat affects diet quality in Japanese people. We investigated the relationship between total fat intake and other nutrient intake using INTERLIPID/ INTERMAP data on Japanese people living in Japan. Methodsand Study Design: The participants included 371 men and 401 women with a healthy body mass index and between the ages of 40 and 59 from 4 population samples in Japan. Nutrient intake data were based on fourin-depth 24-hour dietary recalls per person.Results: Analysis of covariance adjusted for age revealed that total fat intake was positively related to intakes of calcium, thiamine, riboflavin, meat, eggs, and milks and dairy products for both sexes. Totalfat intake was inversely associated with carbohydrate and cereals intake for both sexes. On average, men with total fat intake between 25.0 and 27.4% of total energy had saturated fatty acids above 7%, which is the upper limit recommended for preventing lifestyle-related diseases. Men with total fat intake less than 20% of total energy had a higher risk of not meeting the Dietary Reference Intakes for Japanese (2015) for some nutrients.Conclusions: Total fat intake was positively associated with calcium, thiamine, and riboflavin intakes and inversely associated with carbohydrate intake. Our results suggest that in 40–59-year-old men with a healthy body mass index, total fat intake between 20 and 27% of total energy may best support adequate intake of othernutrients.

Journal article

Lewis MR, Pearce JTM, Spagou K, Green M, Dona AC, Yuen AHY, David M, Berry DJ, Chappell K, Horneffer-van der Sluis C, Shaf R, Lovestone S, Elliott P, Shockcor J, Lindon JC, Cloarec O, Takats Z, Holmes E, Nicholson JKet al., 2016, Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping, Analytical Chemistry, Vol: 88, Pages: 9004-9013, ISSN: 1520-6882

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 and mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. Yet, 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, exceptional measurement precision is exemplified with independent epidemiological sample sets of approximately 650 and 1000 participant samples. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) samples distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC sample dilution. Analysis of the remaining features within the repeated QC sample measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch

Journal article

Oude Griep LM, Seferidi P, Stamler J, Van Horn L, Chan Q, Tzoulaki I, Steffen LM, Miura K, Ueshima H, Okuda N, Zhao L, Soedamah-Muthu SS, Daviglus ML, Elliott P, INTERMAP Research Groupet al., 2016, Relation of unprocessed, processed red meat and poultry consumption to blood pressure in East Asian and Western adults, Journal of Hypertension, Vol: 34, Pages: 1721-1729, ISSN: 1473-5598

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 (INTERMAP).Design: INTERMAP included 4,680 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 multi-pass 24-hr dietary recalls, and two timed 24-hr 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 systolic/diastolic BP 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, systolic/diastolic BP 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.

Journal article

Bentham J, Di Cesare M, Stevens GA, Zhou B, Bixby H, Cowan M, Fortunato L, Bennett J, Danaei G, Hajifathalian K, Lu Y, Riley LM, Laxmaiah A, Kontis V, Paciorek CJ, Riboli E, Ezzati M, Chan Q, Elliott P, Gunter M, Hihtaniemi IT, Murphy N, Norat T, Riboli E, Vineis P, NCD Risk Factor Collaboration NCD-RisCet al., 2016, A century of trends in adult human height, eLife, Vol: 5, ISSN: 2050-084X

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.

Journal article

Elliott P, Burgess AP, fouquet NC, Seri S, Hawken MB, Heard A, Neasham D, Little MPet al., 2016, Acute Exposure to Terrestrial Trunked Radio (TETRA) has effects on theelectroencephalogram and electrocardiogram, consistent with vagal nervestimulation., Environmental Research, Vol: 150, Pages: 461-469, ISSN: 1096-0953

BackgroundTerrestrial Trunked Radio (TETRA) is a telecommunications system widely used by police and emergency services around the world. The Stewart Report on mobile telephony and health raised questions about possible health effects associated with TETRA signals. This study investigates possible effects of TETRA signals on the electroencephalogram and electrocardiogram in human volunteers.MethodsBlinded randomized provocation study with a standardized TETRA signal or sham exposure. In the first of two experiments, police officers had a TETRA set placed first against the left temple and then the upper-left quadrant of the chest and the electroencephalogram was recorded during rest and active cognitive processing. In the second experiment, volunteers were subject to chest exposure of TETRA whilst their electroencephalogram and heart rate variability derived from the electrocardiogram were recorded.ResultsIn the first experiment, we found that exposure to TETRA had consistent neurophysiological effects on the electroencephalogram, but only during chest exposure, in a pattern suggestive of vagal nerve stimulation. In the second experiment, we observed changes in heart rate variability during exposure to TETRA but the electroencephalogram effects were not replicated.ConclusionsObserved effects of exposure to TETRA signals on the electroencephalogram (first experiment) 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 on the electroencephalogram, it seems unlikely that this will have a significant impact on health. Long-term monitoring of the health of the police force in relation to TETRA use is on-going.

Journal article

Bakolis I, Kelly R, Fecht D, Best N, Millett C, Garwood K, Elliott P, Hansell A, Hodgson Set al., 2016, Protective Effects of Smoke-free Legislation on Birth Outcomes in England: A Regression Discontinuity Design, Epidemiology, Vol: 27, Pages: 810-818, ISSN: 1531-5487

Background: Environmental tobacco smoke has an adverse impact on preterm birth and birthweight. England introduced a new law to make virtually all enclosed public places andworkplaces smoke free on July 1 2007. We investigated the effect of smoke-free legislation onbirth outcomes in England using Hospital Episode Statistics (HES) maternity data.Methods: We used regression discontinuity, a quasi-experimental study design, which canfacilitate valid causal inference, to analyse short-term effects of smoke-free legislation on birthweight, low birth weight, gestational age, preterm birth and small for gestational age.Results: We analysed 1,800,906 pregnancies resulting in singleton live-births in Englandbetween January 1 2005 and December 31 2009. In the one to five months following theintroduction of the smoking-free legislation, for those entering their third trimester, the risk oflow birth weight decreased by between 8% (95% CI: 4%-12%) and 14% (95% CI: 5%-23%),very low birth weight between 28% (95% CI: 19%-36%) and 32% (95% CI: 21%-41%), pretermbirth between 4% (95% CI: 1%-8%) and 9% (95% CI: 2%-16%), and small for gestational agebetween 5% (95% CI: 2%-8%) and 9% (95% CI: 2%-15%). The impact of the smoke-freelegislation varied by maternal age, deprivation, ethnicity and region.Conclusions: The introduction of smoke-free legislation in England had an immediate beneficialimpact on birth outcomes overall, although this benefit was not observed across all age, ethnic, ordeprivation groups.

Journal article

Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ, Rivas MA, Perry JR, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SC, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MC, Palmer ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VK, Park KS, Saleheen D, So WY, Tam CH, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, van der Schouw YT, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA, Thameem F, Wilson G, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney AS, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM, Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maget al., 2016, The genetic architecture of type 2 diabetes., Nature, Vol: 536, Pages: 41-47, ISSN: 0028-0836

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.

Journal article

Chami N, Chen MH, Slater AJ, Eicher JD, Evangelou E, Tajuddin SM, Love-Gregory L, Kacprowski T, Schick UM, Nomura A, Giri A, Lessard S, Brody JA, Schurmann C, Pankratz N, Yanek LR, Manichaikul A, Pazoki R, Mihailov E, Hill WD, Raffield LM, Burt A, Bartz TM, Becker DM, Becker LC, Boerwinkle E, Bork-Jensen J, Bottinger EP, O'Donoghue ML, Crosslin DR, de Denus S, Dubé MP, Elliott P, Engström G, Evans MK, Floyd JS, Fornage M, Gao H, Greinacher A, Gudnason V, Hansen T, Harris TB, Hayward C, Hernesniemi J, Highland HM, Hirschhorn JN, Hofman A, Irvin MR, Kähönen M, Lange E, Launer LJ, Lehtimäki T, Li J, Liewald DC, Linneberg A, Liu Y, Lu Y, Lyytikäinen LP, Mägi R, Mathias RA, Melander O, Metspalu A, Mononen N, Nalls MA, Nickerson DA, Nikus K, O'Donnell CJ, Orho-Melander M, Pedersen O, Petersmann A, Polfus L, Psaty BM, Raitakari OT, Raitoharju E, Richard M, Rice KM, Rivadeneira F, Rotter JI, Schmidt F, Smith AV, Starr JM, Taylor KD, Teumer A, Thuesen BH, Torstenson ES, Tracy RP, Tzoulaki I, Zakai NA, Vacchi-Suzzi C, van Duijn CM, van Rooij FJ, Cushman M, Deary IJ, Velez Edwards DR, Vergnaud AC, Wallentin L, Waterworth DM, White HD, Wilson JG, Zonderman AB, Kathiresan S, Grarup N, Esko T, Loos RJ, Lange LA, Faraday N, Abumrad NA, Edwards TL, Ganesh SK, Auer PL, Johnson AD, Reiner AP, Lettre Get al., 2016, Exome genotyping identifies pleiotropic variants associated with red blood cell traits, American Journal of Human Genetics, Vol: 99, Pages: 8-21, ISSN: 1537-6605

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.

Journal article

Tajuddin SM, Schick UM, Eicher JD, Chami N, Giri A, Brody JA, Hill WD, Kacprowski T, Li J, Lyytikäinen LP, Manichaikul A, Mihailov E, O'Donoghue ML, Pankratz N, Pazoki R, Polfus LM, Smith AV, Schurmann C, Vacchi-Suzzi C, Waterworth DM, Evangelou E, Yanek LR, Burt A, Chen MH, van Rooij FJ, Floyd JS, Greinacher A, Harris TB, Highland HM, Lange LA, Liu Y, Mägi R, Nalls MA, Mathias RA, Nickerson DA, Nikus K, Starr JM, Tardif JC, Tzoulaki I, Velez Edwards DR, Wallentin L, Bartz TM, Becker LC, Denny JC, Raffield LM, Rioux JD, Friedrich N, Fornage M, Gao H, Hirschhorn JN, Liewald DC, Rich SS, Uitterlinden A, Bastarache L, Becker DM, Boerwinkle E, de Denus S, Bottinger EP, Hayward C, Hofman A, Homuth G, Lange E, Launer LJ, Lehtimäki T, Lu Y, Metspalu A, O'Donnell CJ, Quarells RC, Richard M, Torstenson ES, Taylor KD, Vergnaud AC, Zonderman AB, Crosslin DR, Deary IJ, Dörr M, Elliott P, Evans MK, Gudnason V, Kähönen M, Psaty BM, Rotter JI, Slater AJ, Dehghan A, White HD, Ganesh SK, Loos RJ, Esko T, Faraday N, Wilson JG, Cushman M, Johnson AD, Edwards TL, Zakai NA, Lettre G, Reiner AP, Auer PLet al., 2016, Large-scale exome-wide association analysis identifies loci for white blood cell traits and pleiotropy with immune-mediated diseases, American Journal of Human Genetics, Vol: 99, Pages: 22-39, ISSN: 1537-6605

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.

Journal article

Eicher JD, Chami N, Kacprowski T, Nomura A, Chen MH, Yanek LR, Tajuddin SM, Schick UM, Slater AJ, Pankratz N, Polfus L, Schurmann C, Giri A, Brody JA, Lange LA, Manichaikul A, Hill WD, Pazoki R, Elliot P, Evangelou E, Tzoulaki I, Gao H, Vergnaud AC, Mathias RA, Becker DM, Becker LC, Burt A, Crosslin DR, Lyytikäinen LP, Nikus K, Hernesniemi J, Kähönen M, Raitoharju E, Mononen N, Raitakari OT, Lehtimäki T, Cushman M, Zakai NA, Nickerson DA, Raffield LM, Quarells R, Willer CJ, Peloso GM, Abecasis GR, Liu DJ, Global Lipids Genetics Consortium, Deloukas P, Samani NJ, Schunkert H, Erdmann J, CARDIoGRAM Exome Consortium, Myocardial Infarction Genetics Consortium, Fornage M, Richard M, Tardif JC, Rioux JD, Dube MP, de Denus S, Lu Y, Bottinger EP, Loos RJ, Smith AV, Harris TB, Launer LJ, Gudnason V, Velez Edwards DR, Torstenson ES, Liu Y, Tracy RP, Rotter JI, Rich SS, Highland HM, Boerwinkle E, Li J, Lange E, Wilson JG, Mihailov E, Mägi R, Hirschhorn J, Metspalu A, Esko T, Vacchi-Suzzi C, Nalls MA, Zonderman AB, Evans MK, Engström G, Orho-Melander M, Melander O, O'Donoghue ML, Waterworth DM, Wallentin L, White HD, Floyd JS, Bartz TM, Rice KM, Psaty BM, Starr JM, Liewald DC, Hayward C, Deary IJ, Greinacher A, Völker U, Thiele T, Völzke H, van Rooij FJ, Uitterlinden AG, Franco OH, Dehghan A, Edwards TL, Ganesh SK, Kathiresan S, Faraday N, Auer PL, Reiner AP, Lettre G, Johnson ADet al., 2016, Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals, American Journal of Human Genetics, Vol: 99, Pages: 40-55, ISSN: 1537-6605

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Journal article

Scheelbeek PF, Khan AE, Mojumder S, Elliott P, Vineis Pet al., 2016, Drinking Water Sodium and Elevated Blood Pressure of Healthy Pregnant Women in Salinity-Affected Coastal Areas, Hypertension, Vol: 68, Pages: 464-470, ISSN: 1524-4563

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.

Journal article

Tzoulaki I, Elliott P, Kontis V, Ezzati Met al., 2016, Worldwide Exposures to Cardiovascular Risk Factors and Associated Health Effects: Current Knowledge and Data Gaps, Circulation, Vol: 133, Pages: 2314-2333, ISSN: 0009-7322

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.

Journal article

Nakamura Y, Ueshima H, Okuda N, Miura K, Kita Y, Miyagawa N, Yoshita K, Nakagawa H, Sakata K, Saitoh S, Okamura T, Okayama A, Choudhry SR, Rodriguez B, Masaki KH, Chan Q, Elliott P, Stamler Jet al., 2016, Relationship of three different types of low-carbohydrate diet to cardiometabolic risk factors in a Japanese population: the INTERMAP/INTERLIPID Study, EUROPEAN JOURNAL OF NUTRITION, Vol: 55, Pages: 1515-1524, ISSN: 1436-6207

Journal article

Scott WR, Zhang W, Loh M, Tan S-T, Lehne B, Afzal U, Peralta J, Saxena R, Ralhan S, Wander GS, Bozaoglu K, Sanghera DK, Elliott P, Scott J, Chambers JC, Kooner JSet al., 2016, Investigation of Genetic Variation Underlying Central Obesity amongst South Asians, PLOS One, Vol: 11, ISSN: 1932-6203

ArticleAuthorsMetricsCommentsRelated ContentAbstractIntroductionMaterials and MethodsResultsDiscussion and ConclusionSupporting InformationAcknowledgmentsAuthor ContributionsReferencesReader Comments (0)Media Coverage (0)FiguresAbstractSouth Asians are 1/4 of the world’s population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10−6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our find

Journal article

Vergnaud A-C, Aresu M, McRobie D, Singh D, Spear J, Heard A, Elliott Pet al., 2016, Validation of objective records and misreporting of personal radio use in a cohort of British Police forces (the Airwave Health Monitoring Study), ENVIRONMENTAL RESEARCH, Vol: 148, Pages: 367-375, ISSN: 0013-9351

Journal article

Blaise B, Correia G, Tin A, Young J, Vergnaud A, Lewis M, Pearce J, Elliott P, Nicholson J, Holmes E, Ebbels TMDet al., 2016, A novel method for power analysis and sample size determination in metabolic phenotyping, Analytical Chemistry, Vol: 88, Pages: 5179-5188, ISSN: 1520-6882

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 framework allows us to investigate the complex relationship between sample size, power, and effect size for real multivariate data sets. For instance, we demonstrate for an example pilot data set that certain features achieve a power of 0.8 for a sample size of 20 samples or that a cross-validated predictivity QY2 of 0.8 is reached with an effect size of 0.2 and 200 samples. We exemplify the approach for both nuclear magnetic resonance and liquid chromatography–mass spectrometry data from humans and the model organism C. elegans.

Journal article

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