Imperial College London

DrAbbasDehghan

Faculty of MedicineSchool of Public Health

Reader in Cardiometabolic Disease Epidemiology
 
 
 
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Contact

 

+44 (0)20 7594 3347a.dehghan CV

 
 
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Location

 

157Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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269 results found

Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T, Colicino E, Waite LL, Joehanes R, Guan W, Brody JA, Elks C, Marioni R, Jhun MA, Agha G, Bressler J, Ward-Caviness CK, Chen BH, Huan T, Bakulski K, Salfati EL, Wahl S, Schramm K, Sha J, Hernandez DG, Just AC, Smith JA, Sotoodehnia N, Pilling LC, Pankow JS, Tsao PS, Liu C, Zhao W, Guarrera S, Michopoulos VJ, Smith AK, Peters MJ, Melzer D, Vokonas P, Fornage M, Prokisch H, Bis JC, Chu AY, Herder C, Grallert H, Yao C, Shah S, McRae AF, Lin H, Horvath S, Fallin D, Hofman A, Wareham NJ, Wiggins KL, Feinberg AP, Starr JM, Visscher PM, Murabito JM, Kardia SLR, Absher DM, Binder EB, Singleton AB, Bandinelli S, Peters A, Waldenberger M, Matullo G, Schwartz JD, Demerath EW, Uitterlinden AG, van Meurs JBJ, Franco OH, Chen Y-DI, Levy D, Turner ST, Deary IJ, Ressler KJ, Dupuis J, Ferrucci L, Ong KK, Assimes TL, Boerwinkle E, Koenig W, Arnett DK, Baccarelli AA, Benjamin EJ, Dehghan Aet al., 2016, DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases, Genome Biology, Vol: 17, ISSN: 1474-7596

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in thepathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated withchronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactiveprotein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population(n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry andreplicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterizethe molecular and clinical relevance of the findings, we examined the association with gene expression,genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associatedwith whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearbygenetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolicentity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individualvariation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novelgenetic loci underlying inflammation that may serve as targets for the development of novel therapeuticinterventions for inflammation.

Journal article

Gregson JM, Freitag DF, Surendran P, Stitziel NO, Chowdhury R, Burgess S, Kaptoge S, Gao P, Staley JR, Willeit P, Nielsen SF, Caslake M, Trompet S, Polfus LM, Kuulasmaa K, Kontto J, Perola M, Blankenberg S, Veronesi G, Gianfagna F, Männistö S, Kimura A, Lin H, Reilly DF, Gorski M, Mijatovic V, CKDGen consortium, Munroe PB, Ehret GB, International Consortium for Blood Pressure, Thompson A, Uria-Nickelsen M, Malarstig A, Dehghan A, CHARGE inflammation working group, Vogt TF, Sasaoka T, Takeuchi F, Kato N, Yamada Y, Kee F, Müller-Nurasyid M, Ferrières J, Arveiler D, Amouyel P, Salomaa V, Boerwinkle E, Thompson SG, Ford I, Wouter Jukema J, Sattar N, Packard CJ, Shafi Majumder AA, Alam DS, Deloukas P, Schunkert H, Samani NJ, Kathiresan S, MICAD Exome consortium, Nordestgaard BG, Saleheen D, Howson JM, Di Angelantonio E, Butterworth AS, Danesh J, EPIC-CVD consortium and the CHD Exome consortiumet al., 2016, Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles., European Journal of Preventive Cardiology, Vol: 24, Pages: 492-504, ISSN: 2047-4873

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2 activity was decreased by 64% ( p = 2.4 × 10-25) with carriage of any of the four loss-of-function variants, by 45% ( p < 10-300) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10-12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2 activity by 65% ( p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a

Journal article

Chaker L, Sedaghat S, Hoorn EJ, Den Elzen WPJ, Gussekloo J, Hofman A, Ikram MA, Franco OH, Dehghan A, Peeters RPet al., 2016, The association of thyroid function and the risk of kidney function decline: a population-based cohort study, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 175, Pages: 653-660, ISSN: 0804-4643

Journal article

Nano J, Muka T, Cepeda M, Voortman T, Dhana K, Brahimaj A, Dehghan A, Franco OHet al., 2016, Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: A systematic review and meta-analysis of observational evidence, DIABETES & METABOLISM, Vol: 42, Pages: 389-397, ISSN: 1262-3636

Journal article

Chen BH, Hivert M-F, Peters MJ, Pilling LC, Hogan JD, Pham LM, Harries LW, Fox CS, Bandinelli S, Dehghan A, Hernandez DG, Hofman A, Hong J, Joehanes R, Johnson AD, Munson PJ, Rybin DV, Singleton AB, Uitterlinden AG, Ying S, Melzer D, Levy D, van Meurs JBJ, Ferrucci L, Florez JC, Dupuis J, Meigs JB, Kolaczyk EDet al., 2016, Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations, DIABETES, Vol: 65, Pages: 3794-3804, ISSN: 0012-1797

Journal article

Natarajan P, Bis JC, Bielak LF, Cox AJ, Dorr M, Feitosa MF, Franceschini N, Guo X, Hwang S-J, Isaacs A, Jhun MA, Kavousi M, Li-Gao R, Lyytikainen L-P, Marioni RE, Schminke U, Stitziel NO, Tada H, van Setten J, Smith AV, Vojinovic D, Yanek LR, Yao J, Yerges-Armstrong LM, Amin N, Baber U, Borecki IB, Carr JJ, Chen Y-DI, Cupples LA, de Jong PA, de Koning H, de Vos BD, Demirkan A, Fuster V, Franco OH, Goodarzi MO, Harris TB, Heckbert SR, Heiss G, Hoffmann U, Hofman A, Isgum I, Jukema JW, Kahonen M, Kardia SLR, Kral BG, Launer LJ, Massaro J, Mehran R, Mitchell BD, Jr THM, de Mutsert R, Newman AB, Nguyen K-D, North KE, O'Connell JR, Oudkerk M, Pankow JS, Peloso GM, Post W, Province MA, Raffield LM, Raitakari OT, Reilly DF, Rivadeneira F, Rosendaal F, Sartori S, Taylor KD, Teumer A, Trompet S, Turner ST, Uitterlinden AG, Vaidya D, van der Lugt A, Volker U, Wardlaw JM, Wassel CL, Weiss S, Wojczynski MK, Becker DM, Becker LC, Boerwinkle E, Bowden DW, Deary IJ, Dehghan A, Felix SB, Gudnason V, Lehtimaki T, Mathias R, Mook-Kanamori DO, Psaty BM, Rader DJ, Rotter JI, Wilson JG, van Duijn CM, Volzke H, Kathiresan S, Peyser PA, O'Donnell CJet al., 2016, Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 9, Pages: 511-+, ISSN: 1942-325X

Journal article

Khan SR, Chaker L, Ruiter R, Aerts JGJV, Hofman A, Dehghan A, Franco OH, Stricker BHC, Peeters RPet al., 2016, Thyroid Function and Cancer Risk: The Rotterdam Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 101, Pages: 5030-5036, ISSN: 0021-972X

Journal article

Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh GK, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Liu T, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott R, Luan J, Bobak M, Malyutina SA, Pajak A, Kubinova R, Tamosiunas A, Pikhart H, Husemoen LLN, Grarup N, Pedersen O, Hansen T, Linneberg A, Simonsen KS, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Kirchner HL, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Donnell MO, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Christen T, Mook-Kanamori DO, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Doerr M, Lerch MM, Voelker U, Voelzke H, Ward J, Pell JP, Smith DJ, Meade T, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Balkau B, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Ridker PM, Chasman DI, Reiner AP, Lange LA, Ritchie MD, Asselbergs FW, Casas J-P, Keating BJ, Preiss D, Hingorani AD, Sattar Net al., 2016, PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study, Lancet Diabetes and Endocrinology, Vol: 5, Pages: 97-105, ISSN: 2213-8587

Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductionsin both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modesthyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets theirsubstantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk.Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials,case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol,fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, usinga standardised analysis plan, meta-analyses, and weighted gene-centric scores.Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analysesof four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lowerLDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight(1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50).Based on the collected data, we did not identify associations with HbA1c (0·03%, –0·01 to 0·08), fasting insulin (0·00%,–0·06 to 0·07), and BMI (0·11 kg/m², –0·09 to 0·30).Interpretation: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higherfasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diab

Journal article

Zhou B, Bentham J, Di Cesare M, Bixby H, Danaei G, Cowan MJ, Paciorek CJ, Singh G, Hajifathalian K, Bennett JE, Taddei C, Bilano V, Carrillo-Larco RM, Djalalinia S, Khatibzadeh S, Lugero C, Peykari N, Zhang WZ, Lu Y, Stevens GA, Riley LM, Bovet P, Elliott P, Gu D, Ikeda N, Jackson RT, Joffres M, Kengne AP, Laatikainen T, Lam TH, Laxmaiah A, Liu J, Miranda JJ, Mondo CK, Neuhauser HK, Sundstrom J, Smeeth L, Soric M, Woodward M, Ezzati Met al., 2016, Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1,479 population-based measurement studies with 19.1 million participants, The Lancet, Vol: 389, Pages: 37-55, ISSN: 0140-6736

BackgroundRaised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. We estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher.MethodsFor this analysis, we pooled national, subnational, or community population-based studies that had measured blood pressure in adults aged 18 years and older. We used a Bayesian hierarchical model to estimate trends from 1975 to 2015 in mean systolic and mean diastolic blood pressure, and the prevalence of raised blood pressure for 200 countries. We calculated the contributions of changes in prevalence versus population growth and ageing to the increase in the number of adults with raised blood pressure.FindingsWe pooled 1479 studies that had measured the blood pressures of 19·1 million adults. Global age-standardised mean systolic blood pressure in 2015 was 127·0 mm Hg (95% credible interval 125·7–128·3) in men and 122·3 mm Hg (121·0–123·6) in women; age-standardised mean diastolic blood pressure was 78·7 mm Hg (77·9–79·5) for men and 76·7 mm Hg (75·9–77·6) for women. Global age-standardised prevalence of raised blood pressure was 24·1% (21·4–27·1) in men and 20·1% (17·8–22·5) in women in 2015. Mean systolic and mean diastolic blood pressure decreased substantially from 1975 to 2015 in high-income western and Asia Pacific countries, moving these countries from having some of the highest worldwide blood pressure in 1975 to the lowest in 2015. Mean blood pressure also decreased in women in central and eastern Europe, Latin America and the Caribbean, and, more recently, central Asia, Middle East, and north Africa, but the es

Journal article

Hanewinckel R, Drenthen J, Ligthart S, Dehghan A, Franco OH, Hofman A, Ikram MA, van Doorn PAet al., 2016, Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 87, Pages: 1336-1342, ISSN: 0022-3050

Journal article

Chaker L, Baumgartner C, den Elzen WPJ, Collet T-H, Ikram MA, Blum MR, Dehghan A, Drechsler C, Luben RN, Portegies MLP, Lervasi G, Medici M, Stott DJ, Dullaart RP, Ford I, Bremner A, Newman AB, Wanner C, Sgarbi JA, Dorr M, Longstreth WT, Psaty BM, Ferrucci L, Maciel RMB, Westendorp RG, Jukema JW, Ceresini G, Imaizumi M, Hofman A, Bakker SJL, Franklyn JA, Khaw K-T, Bauer DC, Walsh JP, Razvi S, Gussekloo J, Volzke H, Franco OH, Cappola AR, Rodondi N, Peeters RPet al., 2016, Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 101, Pages: 4270-4282, ISSN: 0021-972X

Journal article

Sedaghat S, de Vries PS, Boender J, Sonneveld MAH, Hoorn EJ, Hofman A, de Maat MPM, Franco OH, Ikram MA, Leebeek FWG, Dehghan Aet al., 2016, von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study, AMERICAN JOURNAL OF KIDNEY DISEASES, Vol: 68, Pages: 726-732, ISSN: 0272-6386

Journal article

Brouwer-Brolsma EM, van Woudenbergh GJ, Elferink SJWHO, Singh-Povel CM, Hofman A, Dehghan A, Franco OH, Feskens EJMet al., 2016, Intake of different types of dairy and its prospective association with risk of type 2 diabetes: The Rotterdam Study, NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES, Vol: 26, Pages: 987-995, ISSN: 0939-4753

Journal article

de Vries PS, van Herpt TTW, Ligthart S, Hofman A, Ikram MA, van Hoek M, Sijbrands EJG, Franco OH, de Maat MPM, Leebeek FWG, Dehghan Aet al., 2016, ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study, Diabetologia, Vol: 60, Pages: 280-286, ISSN: 0012-186X

Aims/hypothesis ADAMTS13 is a protease that breaks downvon Willebrand factor (VWF) multimers into smaller, lessactive particles. VWF has been associated with an increasedrisk of incident type 2 diabetes mellitus. Here, we determinewhether ADAMTS13 activity and VWF antigen are associatedwith incident diabetes.Methods This study included 5176 participants from theRotterdam Study, a prospective population-based cohortstudy. Participants were free of diabetes at baseline andfollowed up for more than 20 years. Cox proportional hazardsmodels were used to examine the association of ADAMTS13activity and VWF antigen with incident diabetes.Results ADAMTS13 activity was associated with an increasedrisk of incident diabetes (HR 1.17 [95% CI 1.08,1.27]) after adjustment for known risk factors and VWF antigenlevels. Although ADAMTS13 activity was positively associatedwith fasting glucose and insulin, the association withincident diabetes did not change when we adjusted for thesecovariates. ADAMTS13 activity was also associated with incidentprediabetes (defined on the basis of both fasting andnon-fasting blood glucose) after adjustment for known riskfactors (HR 1.11 [95% CI 1.03, 1.19]), while the VWF antigenlevel was not. VWF antigen was associated with incident diabetes,but this association was attenuated after adjustment forknown risk factors.Conclusions/interpretation ADAMTS13 activity appears tobe an independent risk factor for incident prediabetes and type2 diabetes. As the association between ADAMTS13 and diabetesdid not appear to be explained by its cleavage of VWF,ADAMTS13 may have an independent role in the developmentof diabetes.

Journal article

Brahimaj A, Muka T, Kavousi M, Laven JSE, Dehghan A, Franco OHet al., 2016, Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study, Diabetologia, Vol: 60, Pages: 98-106, ISSN: 0012-186X

Aims/hypothesis Previous literature documents controversialresults for the impact of dehydroepiandrosterone (DHEA) inglucose metabolism. We aimed to assess the associations betweenserum levels of DHEA and its main derivatives DHEAsulphate (DHEAS) and androstenedione, as well as the ratio ofDHEAS to DHEA, and risk of type 2 diabetes.Methods We used data on serum levels of DHEA, DHEASand androstenedione from 5189 middle-aged and elderly menand women from the prospective population-based RotterdamStudy. Type 2 diabetes was defined as a fasting blood glucose≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l.Results During a median follow-up of 10.9 years, 643 patientswith incident type 2 diabetes were identified. After adjustingfor age, sex, cohort, fasting status, fasting glucose and insulin,and BMI, both serum DHEA levels (per 1 unit natural logtransformed,HR 0.76, 95% CI 0.67, 0.87) and serum DHEASlevels (per 1 unit natural log-transformed, HR 0.82, 95% CI0.73, 0.92) were inversely associated with risk of type 2 diabetesin the total population. Further adjustment for alcohol,smoking, physical activity, prevalent cardiovascular disease,serum total cholesterol, use of lipid-lowering medications,systolic BP, treatment for hypertension, C-reactive protein,oestradiol and testosterone did not substantially affect the associationbetween DHEA and incident type 2 diabetes (per 1unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99),but abolished the association between DHEAS and type 2diabetes. Androstenedione was not associated with risk oftype 2 diabetes, nor was DHEAS to DHEA ratio.Conclusions/interpretation DHEA serum levels might be anindependent marker of type 2 diabetes.

Journal article

Chaker L, Wolters FJ, Bos D, Korevaar TIM, Hofman A, van der Lugt A, Koudstaal PJ, Franco OH, Dehghan A, Vernooij MW, Peeters RP, Ikram MAet al., 2016, Thyroid function and the risk of dementia The Rotterdam Study, NEUROLOGY, Vol: 87, Pages: 1688-1695, ISSN: 0028-3878

Journal article

Braun KVE, Voortman T, Dhana K, Troup J, Bramer WM, Troup J, Chowdhury R, Dehghan A, Muka T, Franco OHet al., 2016, The role of DNA methylation in dyslipidaemia: A systematic review, PROGRESS IN LIPID RESEARCH, Vol: 64, Pages: 178-191, ISSN: 0163-7827

Journal article

Chaker L, Ligthart S, Korevaar TIM, Hofman A, Franco OH, Peeters RP, Dehghan Aet al., 2016, Thyroid function and risk of type 2 diabetes: a population-based prospective cohort study, BMC Medicine, Vol: 14, ISSN: 1741-7015

BackgroundThe association of thyroid function with risk of type 2 diabetes remains elusive. We aimed to investigate the association of thyroid function with incident diabetes and progression from prediabetes to diabetes in a population-based prospective cohort study.MethodsWe included 8452 participants (mean age 65 years) with thyroid function measurement, defined by thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and longitudinal assessment of diabetes incidence. Cox-models were used to investigate the association of TSH and FT4 with diabetes and progression from prediabetes to diabetes. Multivariable models were adjusted for age, sex, high-density lipoprotein cholesterol, and glucose at baseline, amongst others.ResultsDuring a mean follow-up of 7.9 years, 798 diabetes cases occurred. Higher TSH levels were associated with a higher diabetes risk (hazard ratio [HR] 1.13; 95 % confidence interval [CI], 1.08–1.18, per logTSH), even within the reference range of thyroid function (HR 1.24; 95 % CI, 1.06–1.45). Higher FT4 levels were associated with a lower diabetes risk amongst all participants (HR 0.96; 95 % CI, 0.93–0.99, per 1 pmol/L) and in participants within the reference range of thyroid function (HR 0.96; 95 % CI, 0.92–0.99). The risk of progression from prediabetes to diabetes was higher with low-normal thyroid function (HR 1.32; 95 % CI, 1.06–1.64 for TSH and HR 0.91; 95 % CI, 0.86–0.97 for FT4). Absolute risk of developing diabetes type 2 in participants with prediabetes decreased from 35 % to almost 15 % with higher FT4 levels within the normal range.ConclusionsLow and low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes. Future studies should investigate whether screening for and treatment of (subclinical) hypothyroidism is beneficial in subjects at risk of developing diabetes.

Journal article

Iotchkova V, Huang J, Morris JA, Jain D, Barbieri C, Walter K, Min JL, Chen L, Astle W, Cocca M, Deelen P, Elding H, Farmaki A-E, Franklin CS, Franberg M, Gaunt TR, Hofman A, Jiang T, Kleber ME, Lachance G, Luan J, Malerba G, Matchan A, Mead D, Memari Y, Ntalla I, Panoutsopoulou K, Pazoki R, Perry JRB, Rivadeneira F, Sabater-Lleal M, Sennblad B, Shin S-Y, Southam L, Traglia M, van Dijk F, van Leeuwen EM, Zaza G, Zhang W, Amin N, Butterworth A, Chambers JC, Dedoussis G, Dehghan A, Franco OH, Franke L, Frontini M, Gambaro G, Gasparini P, Hamsten A, Issacs A, Kooner JS, Kooperberg C, Langenberg C, Marz W, Scott RA, Swertz MA, Toniolo D, Uitterlinden AG, van Duijn CM, Watkins H, Zeggini E, Maurano MT, Timpson NJ, Reiner AP, Auer PL, Soranzo Net al., 2016, Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps, Nature Genetics, Vol: 48, Pages: 1303-1312, ISSN: 1061-4036

Large-scale whole genome sequence datasets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole genome sequence data from the UK10K and the 1000 Genomes Projects into 35,981 study participants of European ancestry, followed by association analysis with twenty quantitative cardiometabolic and hematologic traits. We describe 17 novel associations, including six rare (minor allele frequency [MAF]<1%) or low frequency variants (1%<MAF<5%) with platelet count (PLT), red cell indices (MCH, MCV) and high-density lipoprotein (HDL) cholesterol. Applying fine-mapping analysis to 233 known and novel loci associated with the twenty traits, we resolve associations of 59 loci to credible sets of 20 or less variants, and describe trait enrichments within regions of predicted regulatory function. These findings augment understanding of the allelic architecture of risk factors for cardiometabolic and hematologic diseases, and provide additional functional insights with the identification of potentially novel biological targets.

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

Chaker L, van den Berg ME, Niemeijer MN, Franco OH, Dehghan A, Hofman A, Rijnbeek PR, Deckers JW, Eijgelsheim M, Stricker BHC, Peeters RPet al., 2016, Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study, CIRCULATION, Vol: 134, Pages: 713-722, ISSN: 0009-7322

Journal article

Willeit P, Kaptoge S, Welsh P, Butterworth AS, Chowdhury R, Spackman SA, Pennells L, Gao P, Burgess S, Freitag DF, Sweeting M, Wood AM, Cook NR, Judd S, Trompet S, Nambi V, Olsen MH, Everett BM, Kee F, Arnlov J, Salomaa V, Levy D, Kauhanen J, Laukkanen JA, Kavousi M, Ninomiya T, Casas J-P, Daniels LB, Lind L, Kistorp CN, Rosenberg J, Mueller T, Rubattu S, Panagiotakos DB, Franco OH, de Lemos JA, Luchner A, Kizer JR, Kiechl S, Salonen JT, Wannamethee SG, de Boer RA, Nordestgaard BG, Andersson J, Jorgensen T, Melander O, Ballantyne CM, DeFilippi C, Ridker PM, Cushman M, Rosamond WD, Thompson SG, Gudnason V, Sattar N, Danesh J, Di Angelantonio Eet al., 2016, Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis, Lancet Diabetes and Endocrinology, Vol: 4, Pages: 840-849, ISSN: 2213-8595

BackgroundGuidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.MethodsIn this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.FindingsWe recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56–1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77–2·26) for the combination of coronary heart disease, stroke, and

Journal article

Polfus LM, Khajuria RK, Schick UM, Pankratz N, Pazoki R, Brody JA, Chen MH, Auer PL, Floyd JS, Huang J, Lange L, van Rooij FJA, Gibbs RA, Metcalf G, Muzny D, Veeraraghavan N, Walter K, Chen L, Yanek L, Becker LC, Peloso GM, Wakabayashi A, Kals M, Metspalu A, Esko T, Fox K, Wallace R, Franceschini N, Matijevic N, Rice KM, Bartz TM, Lyytikäinen LP, Kähönen M, Lehtimäki T, Raitakari OT, Li-Gao R, Mook-Kanamori DO, Lettre G, van Duijn CM, Franco OH, Rich SS, Rivadeneira F, Hofman A, Uitterlinden AG, Wilson JG, Psaty BM, Soranzo N, Dehghan A, Boerwinkle E, Zhang X, Johnson AD, O'Donnell CJ, Johnsen JM, Reiner AP, Ganesh SK, Sankaran VGet al., 2016, Erratum: Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis (American Journal of Human Genetics (2016) 99(2) (481–488)(S0002929716302208)(10.1016/j.ajhg.2016.06.016)), American Journal of Human Genetics, Vol: 99, Pages: 785-785, ISSN: 0002-9297

© 2016 American Society of Human Genetics (The American Journal of Human Genetics 99, 481–488; August 4, 2016) In the originally published version of this paper, Nora Franceschini's surname was misspelled. It has now been corrected online. The authors apologize for the error.

Journal article

Chaker L, Korevaar TIM, Medici M, Uitterlinden AG, Hofman A, Dehghan A, Franco OH, Peeters RPet al., 2016, Thyroid Function Characteristics and Determinants: The Rotterdam Study, THYROID, Vol: 26, Pages: 1195-1204, ISSN: 1050-7256

Journal article

van der Laan SW, Fall T, Soumare A, Teumer A, Sedaghat S, Baumert J, Zabaneh D, van Setten J, Isgum I, Galesloot TE, Arpegard J, Amouyel P, Trompet S, Waldenberger M, Doerr M, Magnusson PK, Giedraitis V, Larsson A, Morris AP, Felix JF, Morrison AC, Franceschini N, Bis JC, Kavousi M, O'Donnell C, Drenos F, Tragante V, Munroe PB, Malik R, Dichgans M, Worrall BB, Erdmann J, Nelson CP, Samani NJ, Schunkert H, Marchini J, Patel RS, Hingorani AD, Lind L, Pedersen NL, de Graaf J, Kiemeney LALM, Baumeister SE, Franco OH, Hofman A, Uitterlinden AG, Koenig W, Meisinger C, Peters A, Thorand B, Jukema JW, Eriksen BO, Toft I, Wilsgaard T, Onland-Moret NC, van der Schouw YT, Debette S, Kumari M, Svensson P, van der Harst P, Kivimaki M, Keating BJ, Sattar N, Dehghan A, Reiner AP, Ingelsson E, den Ruijter HM, de Bakker PIW, Pasterkamp G, Arnlov J, Holmes MV, Asselbergs FWet al., 2016, Cystatin C and Cardiovascular Disease A Mendelian Randomization Study, Journal of the American College of Cardiology, Vol: 68, Pages: 934-945, ISSN: 0735-1097

BackgroundEpidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation.ObjectivesThe aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.MethodsWe incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.ResultsCystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10−14). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10−211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10−5). A causal effect of cystatin C was not detected for any individual component of CVD.ConclusionsMendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.

Journal article

Dehghan A, 2016, Mass spectrometry in epidemiological studies: What are the key considerations?, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 31, Pages: 715-716, ISSN: 0393-2990

Journal article

Amin N, Jovanova O, Adams HHH, Dehghan A, Kavousi M, Vernooij MW, Peeters RP, de Vrij FMS, van der Lee SJ, van Rooij JGJ, Uitterlinden AG, Niessen WJ, Franco OH, Kushner SA, Ikram MA, Tiemeier H, van Duijn CMet al., 2016, Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms (vol 22, pg 537, 2017), MOLECULAR PSYCHIATRY, Vol: 22, Pages: 634-634, ISSN: 1359-4184

Journal article

Polfus LM, Khajuria RK, Schick UM, Pankratz N, Pazoki R, Brody JA, Chen M-H, Auer PL, Floyd JS, Huang J, Lange L, van Rooij FJA, Gibbs RA, Metcalf G, Muzny D, Veeraraghavan N, Walter K, Chen L, Yanek L, Becker LC, Peloso GM, Wakabayashi A, Kals M, Metspalu A, Esko T, Fox K, Wallace R, Franceschini N, Matijevic N, Rice KM, Bartz TM, Lyytikainen L-P, Kahonen M, Lehtimaki T, Raitakari OT, Li-Gao R, Mook-Kanamori DO, Lettre G, van Duijn CM, Franco OH, Rich SS, Rivadeneira F, Hofman A, Uitterlinden AG, Wilson JG, Psaty BM, Soranzo N, Dehghan A, Boerwinkle E, Zhang X, Johnson AD, O'Donnell CJ, Johnsen JM, Reiner AP, Ganesh SK, Sankaran VGet al., 2016, Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 99, Pages: 481-488, ISSN: 0002-9297

Journal article

Sedaghat S, Cremers LGM, de Groot M, Hofman A, van der Lugt A, Niessen WJ, Franco OH, Dehghan A, Ikram MA, Vernooij MWet al., 2016, Lower microstructural integrity of brain white matter is related to higher mortality, NEUROLOGY, Vol: 87, Pages: 927-934, ISSN: 0028-3878

Journal article

Bano A, Chaker L, Plompen EPC, Hofman A, Dehghan A, Franco OH, Janssen HLA, Murad SD, Peeters RPet al., 2016, Thyroid Function and the Risk of Nonalcoholic Fatty Liver Disease: The Rotterdam Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 101, Pages: 3204-3211, ISSN: 0021-972X

Journal article

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