ProfessorAbbasDehghan

Brahimaj A, Ligthart S, Ghanbari M, Ikram MA, Hofman A, Franco OH, Kavousi M, Dehghan Aet al., 2017, Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study, European Journal of Epidemiology, Vol: 32, Pages: 217-226, ISSN: 0393-2990

The immune response involved in each phase oftype 2 diabetes (T2D) development might be different. Weaimed to identify novel inflammatory markers that predictprogression from normoglycemia to pre-diabetes, incidentT2D and insulin therapy. We used plasma levels of 26inflammatory markers in 971 subjects from the RotterdamStudy. Among them 17 are novel and 9 previously studied.Cox regression models were built to perform survivalanalysis. Main Outcome Measures: During a follow-up ofup to 14.7 years (between April 1, 1997, and Jan 1, 2012)139 cases of pre-diabetes, 110 cases of T2D and 26 cases ofinsulin initiation were identified. In age and sex adjustedCox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH(1.24), IL18 (1.22) and CRP (1.32) were associated withincident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE(1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27),IL1ra (1.24) and CRP (1.64) were associated with incidentT2D. In multivariate models, IL13 (0.77), EN-RAGE(1.23) and CRP (1.26) remained associated with pre-diabetes.IL13 (0.67), IL17 (0.76) and CRP (1.32) remainedassociated with T2D. IL13 (0.55) was the only markerassociated with initiation of insulin therapy in diabetics.Various inflammatory markers are associated with progressionfrom normoglycemia to pre-diabetes (IL13, ENRAGE,CRP), T2D (IL13, IL17, CRP) or insulin therapystart (IL13). Among them, EN-RAGE is a novel inflammatorymarker for pre-diabetes, IL17 for incident T2D andIL13 for pre-diabetes, incident T2D and insulin therapystart.

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Brahimaj A, Ligthart S, Ikram MA, Hofman A, Franco OH, Sijbrands EJG, Kavousi M, Dehghan Aet al., 2017, Serum Levels of Apolipoproteins and Incident Type 2 Diabetes: A Prospective Cohort Study, DIABETES CARE, Vol: 40, Pages: 346-351, ISSN: 0149-5992

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• Citations: 34

Muka T, Nano J, Jaspers L, Meun C, Bramer WM, Hofman A, Dehghan A, Kavousi M, Laven JSE, Franco OHet al., 2017, Associations of Steroid Sex Hormones and Sex Hormone-Binding Globulin With the Risk of Type 2 Diabetes in Women: A Population-Based Cohort Study and Meta-analysis, DIABETES, Vol: 66, Pages: 577-586, ISSN: 0012-1797

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• Citations: 86

Li M, Li Y, Weeks O, Mijatovic V, Teumer A, Huffman JE, Tromp G, Fuchsberger C, Gorski M, Lyytikäinen L-P, Nutile T, Sedaghat S, Sorice R, Tin A, Yang Q, Ahluwalia TS, Arking DE, Bihlmeyer NA, Böger CA, Carroll RJ, Chasman DI, Cornelis MC, Dehghan A, Faul JD, Feitosa MF, Gambaro G, Gasparini P, Giulianini F, Heid I, Huang J, Imboden M, Jackson AU, Jeff J, Jhun MA, Katz R, Kifley A, Kilpeläinen TO, Kumar A, Laakso M, Li-Gao R, Lohman K, Lu Y, Mägi R, Malerba G, Mihailov E, Mohlke KL, Mook-Kanamori DO, Robino A, Ruderfer D, Salvi E, Schick UM, Schulz C-A, Smith AV, Smith JA, Traglia M, Yerges-Armstrong LM, Zhao W, Goodarzi MO, Kraja AT, Liu C, Wessel J, CHARGE Glycemic-T2D Working Group, CHARGE Blood Pressure Working Group, Boerwinkle E, Borecki IB, Bork-Jensen J, Bottinger EP, Braga D, Brandslund I, Brody JA, Campbell A, Carey DJ, Christensen C, Coresh J, Crook E, Curhan GC, Cusi D, de Boer IH, de Vries APJ, Denny JC, Devuyst O, Dreisbach AW, Endlich K, Esko T, Franco OH, Fulop T, Gerhard GS, Glümer C, Gottesman O, Grarup N, Gudnason V, Hansen T, Harris TB, Hayward C, Hocking L, Hofman A, Hu FB, Husemoen LLN, Jackson RD, Jørgensen T, Jørgensen ME, Kähönen M, Kardia SLR, König W, Kooperberg C, Kriebel J, Launer LJ, Lauritzen T, Lehtimäki T, Levy D, Linksted P, Linneberg A, Liu Y, Loos RJF, Lupo A, Meisinger C, Melander O, Metspalu A, Mitchell P, Nauck M, Nürnberg P, Orho-Melander M, Parsa A, Pedersen O, Peters A, Peters U, Polasek O, Porteous D, Probst-Hensch NM, Psaty BM, Qi L, Raitakari OT, Reiner AP, Rettig R, Ridker PM, Rivadeneira F, Rossouw JE, Schmidt F, Siscovick D, Soranzo N, Strauch K, Toniolo D, Turner ST, Uitterlinden AG, Ulivi S, Velayutham D, Völker U, Völzke H, Waldenberger M, Wang JJ, Weir DR, Witte D, Kuivaniemi H, Fox CS, Franceschini N, Goessling W, Köttgen A, Chu AYet al., 2017, SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function., J Am Soc Nephrol, Vol: 28, Pages: 981-994

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

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Kieboom BCT, Ligthart S, Dehghan A, Kurstjens S, de Baaij JHF, Franco OH, Hofman A, Zietse R, Stricker BH, Hoorn EJet al., 2017, Serum magnesium and the risk of prediabetes: a population-based cohort study, Diabetologia, Vol: 60, Pages: 843-853, ISSN: 0012-186X

Aims/hypothesis: Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk. Methods: Within the population-based Rotterdam Study, we used Cox models, adjusted for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use, to study the association between serum magnesium and prediabetes/diabetes. In addition, we performed two mediation analyses: (1) to study if common genetic variation in eight magnesium-regulating genes influence diabetes risk through serum magnesium levels; and (2) to quantify the proportion of the effect of serum magnesium levels on diabetes that is mediated through insulin resistance (quantified by HOMA-IR). Results: A total of 8555 participants (mean age, 64.7 years; median follow-up, 5.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were included. A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25] ). Genetic variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6 significantl

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Braun KVE, Dhana K, de Vries PS, Voortman T, van Meurs JBJ, Uitterlinden AG, Hofman A, Hu FB, Franco OH, Dehghan Aet al., 2017, Epigenome-wide association study (EWAS) on lipids: the Rotterdam Study, Clinical Epigenetics, Vol: 9, ISSN: 1868-7083

BackgroundDNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants.ResultsGenome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-corrected p value lower than 1.08 × 10−7 was considered statistically significant. Five CpG sites annotated to genes including DHCR24, CPT1A, ABCG1, and SREBF1 were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated to CPT1A (cg00574958 and cg17058475), ABCG1 (cg06500161), and SREBF1 (cg11024682). Two CpG sites were associated with HDL-C, including ABCG1 (cg06500161) and DHCR24 (cg17901584). No significant associations were observed with LDL-C or total cholesterol.ConclusionsWe report an association of HDL-C levels with methylation of a CpG site near DHCR24, a protein-coding gene involved in cholesterol biosynthesis, which has previously been reported to be associated with other metabolic traits. Furthermore, we confirmed previously reported associations of methylation of CpG sites within CPT1A, ABCG1, and SREBF1 and lipids. These results provide insight in the mechanisms that are involved in lipid metabolism.

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de Vries PS, Sabater-Lleal M, Chasman DI, Trompet S, Ahluwalia TS, Teumer A, Kleber ME, Chen M-H, Wang JJ, Attia JR, Marioni RE, Steri M, Weng L-C, Pool R, Grossmann V, Brody JA, Venturini C, Tanaka T, Rose LM, Oldmeadow C, Mazur J, Basu S, Franberg M, Yang Q, Ligthart S, Hottenga JJ, Rumley A, Mulas A, de Craen AJM, Grotevendt A, Taylor KD, Delgado GE, Kifley A, Lopez LM, Berentzen TL, Mangino M, Bandinelli S, Morrison AC, Hamsten A, Tofler G, de Maat MPM, Draisma HHM, Lowe GD, Zoledziewska M, Sattar N, Lackner KJ, Voelker U, McKnight B, Huang J, Holliday EG, McEvoy MA, Starr JM, Hysi PG, Hernandez DG, Guan W, Rivadeneira F, McArdle WL, Slagboom PE, Zeller T, Psaty BM, Uitterlinden AG, de Geus EJC, Stott DJ, Binder H, Hofman A, Franco OH, Rotter JI, Ferrucci L, Spector TD, Deary IJ, Maerz W, Greinacher A, Wild PS, Cucca F, Boomsma DI, Watkins H, Tang W, Ridker PM, Jukema JW, Scott RJ, Mitchell P, Hansen T, O'Donnell CJ, Smith NL, Strachan DP, Dehghan Aet al., 2017, Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study, PLoS ONE, Vol: 12, ISSN: 1932-6203

An increasing number of genome-wide association (GWA) studies are now using the higherresolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectationthat 1000G imputation will lead to the discovery of additional associated loci when comparedto HapMap imputation. In order to assess the improvement of 1000G over HapMapimputation in identifying associated loci, we compared the results of GWA studies of circulatingfibrinogen based on the two reference panels. Using both HapMap and 1000G imputationwe performed a meta-analysis of 22 studies comprising the same 91,953 individuals.We identified six additional signals using 1000G imputation, while 29 loci were associatedusing both HapMap and 1000G imputation. One locus identified using HapMap imputationwas not significant using 1000G imputation. The genome-wide significance threshold of5×10−8 is based on the number of independent statistical tests using HapMap imputation,and 1000G imputation may lead to further independent tests that should be corrected for.When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10−8),the number of loci significant only using HapMap imputation increased to 4 while the numberof loci significant only using 1000G decreased to 5. In conclusion, 1000G imputationenabled the identification of 20% more loci than HapMap imputation, although the advantageof 1000G imputation became less clear when a stricter Bonferroni correction was used.More generally, our results provide insights that are applicable to the implementation ofother dense reference panels that are under development.

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van Rooij FJA, Qayyum R, Smith AV, Zhou Y, Trompet S, Tanaka T, Keller MF, Chang L-C, Schmidt H, Yang M-L, Chen M-H, Hayes J, Johnson AD, Yanek LR, Mueller C, Lange L, Floyd JS, Ghanbari M, Zonderman AB, Jukema JW, Hofman A, van Duijn CM, Desch KC, Saba Y, Ozel AB, Snively BM, Wu J-Y, Schmidt R, Fornage M, Klein RJ, Fox CS, Matsuda K, Kamatani N, Wild PS, Stott DJ, Ford I, Slagboom PE, Yang J, Chu AY, Lambert AJ, Uitterlinden AG, Franco OH, Hofer E, Ginsburg D, Hu B, Keating B, Schick UM, Brody JA, Li JZ, Chen Z, Zeller T, Guralnik JM, Chasman DI, Peters LL, Kubo M, Becker DM, Li J, Eiriksdottir G, Rotter JI, Levy D, Grossmann V, Patel KV, Chen C-H, Ridker PM, Tang H, Launer LJ, Rice KM, Li-Gao R, Ferrucci L, Evans MK, Choudhuri A, Trompouki E, Abraham BJ, Yang S, Takahashi A, Kamatani Y, Kooperberg C, Harris TB, Jee SH, Coresh J, Tsai F-J, Longo DL, Chen Y-T, Felix JF, Yang Q, Psaty BM, Boerwinkle E, Becker LC, Mook-Kanamori DO, Wilson JG, Gudnason V, O'Donnell CJ, Dehghan A, Cupples LA, Nalls MA, Morris AP, Okada Y, Reiner AP, Zon LI, Ganesh SKet al., 2017, Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for <i>RBPMS</i> in Erythropoiesis, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 100, Pages: 51-63, ISSN: 0002-9297

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• Citations: 32

Brænne I, Zeng L, Willenborg C, Tragante V, Kessler T, CARDIoGRAM Consortium, CARDIoGRAMplusC4D Consortium, Willer CJ, Laakso M, Wallentin L, Franks PW, Salomaa V, Dehghan A, Meitinger T, Samani NJ, Asselbergs FW, Erdmann J, Schunkert Het al., 2017, Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk., PLoS One, Vol: 12

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

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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

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Bano A, Chaker L, Darweesh SKL, Korevaar TIM, Mattace-Raso FUS, Dehghan A, Franco OH, van der Geest JN, Ikram MA, Peeters RPet al., 2016, Gait patterns associated with thyroid function: The Rotterdam Study, Scientific Reports, Vol: 6, ISSN: 2045-2322

Gait is an important health indicator and poor gait is strongly associated with disability and risk of falls. Thyroid dysfunction is suggested as a potential determinant of gait deterioration, but this has not been explored in a population-based study. We therefore investigated the association of thyroid function with gait patterns in 2645 participants from the Rotterdam Study with data available on TSH (thyroid-stimulating hormone), FT4 (free thyroxine) and gait, without known thyroid disease or dementia. The primary outcome was Global gait (standardized Z-score), while secondary outcomes included gait domains (Rhythm, Variability, Phases, Pace, Base of support, Tandem, Turning) and velocity. Gait was assessed by electronic walkway. Multivariable regression models revealed an inverted U-shaped association of TSH (p < 0.001), but no association of FT4 concentrations with Global gait (p = 0.2). TSH levels were positively associated with Base of support (p = 0.01) and followed an inverted U-shaped curve with Tandem (p = 0.002) and velocity (p = 0.02). Clinical and subclinical hypothyroidism were associated with worse Global gait than euthyroidism (β = −0.61; CI = −1.03, −0.18; p = 0.004 and β = −0.13; CI = −0.26, −0.00; p = 0.04, respectively). In euthyroid participants, higher thyroid function was associated with worse gait patterns. In conclusion, both low and high thyroid function are associated with alterations in Global gait, Tandem, Base of support and velocity.

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Wen K-X, Milic J, El-Khodor B, Dhana K, Nano J, Pulido T, Kraja B, Zaciragic A, Bramer WM, Troup J, Chowdhury R, Ikram MA, Dehghan A, Muka T, Franco OHet al., 2016, The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review, PLoS ONE, Vol: 11, ISSN: 1932-6203

ImportanceEpigenetic modifications of the genome, such as DNA methylation and histone modifications,have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer’sdisease (AD) and Parkinson’s disease (PD).ObjectiveTo systematically review studies investigating epigenetic marks in AD or PD.MethodsEleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus,PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and GoogleScholar) were searched until July 11th 2016 to identify relevant articles. We included all randomizedcontrolled trials, cohort, case-control and cross-sectional studies in humans thatexamined associations between epigenetic marks and ND. Two independent reviewers,with a third reviewer available for disagreements, performed the abstract and full text selection.Data was extracted using a pre-designed data collection form.ResultsOf 6,927 searched references, 73 unique case-control studies met our inclusion criteria.Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PDoutcomes). There was no consistent association between global DNA methylation patternand any ND. Studies reported epigenetic regulation of 31 genes (including cell communication,apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistentlyreported associations. Methylation of α-synuclein gene (SNCA) was also found to be associatedwith PD. Seven studies reported histone protein alterations in AD and PD.ConclusionMany studies have investigated epigenetics and ND. Further research should include largercohort or longitudinal studies, in order to identify clinically significant epigenetic changes.Identifying relevant epigenetic changes could lead to interventional strategies in ND.

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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.

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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

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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

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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

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• Citations: 19

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

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• Citations: 40

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

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• Citations: 17

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, Mosley TH, 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

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• Citations: 37

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

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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

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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

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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

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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

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• Citations: 18

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

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• Citations: 10

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.

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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.

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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

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• Citations: 65

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

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• Citations: 26

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.

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