000164050 001__ 164050 000164050 005__ 20240229133154.0 000164050 0247_ $$2doi$$a10.1371/journal.pmed.1003394 000164050 0247_ $$2pmid$$apmid:33064751 000164050 0247_ $$2ISSN$$a1549-1277 000164050 0247_ $$2ISSN$$a1549-1676 000164050 0247_ $$2altmetric$$aaltmetric:92540022 000164050 037__ $$aDKFZ-2020-02218 000164050 041__ $$aeng 000164050 082__ $$a610 000164050 1001_ $$00000-0001-6560-4890$$aZheng, Ju-Sheng$$b0 000164050 245__ $$aThe association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis. 000164050 260__ $$aLawrence, Kan.$$bPLoS$$c2020 000164050 3367_ $$2DRIVER$$aarticle 000164050 3367_ $$2DataCite$$aOutput Types/Journal article 000164050 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1611213547_29169 000164050 3367_ $$2BibTeX$$aARTICLE 000164050 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000164050 3367_ $$00$$2EndNote$$aJournal Article 000164050 520__ $$aPrior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis.We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities.Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D. 000164050 536__ $$0G:(DE-HGF)POF3-323$$a323 - Metabolic Dysfunction as Risk Factor (POF3-323)$$cPOF3-323$$fPOF III$$x0 000164050 588__ $$aDataset connected to CrossRef, PubMed, 000164050 7001_ $$aLuan, Jian'an$$b1 000164050 7001_ $$aSofianopoulou, Eleni$$b2 000164050 7001_ $$00000-0003-2375-1440$$aSharp, Stephen J$$b3 000164050 7001_ $$00000-0003-3789-7651$$aDay, Felix R$$b4 000164050 7001_ $$aImamura, Fumiaki$$b5 000164050 7001_ $$aGundersen, Thomas E$$b6 000164050 7001_ $$aLotta, Luca A$$b7 000164050 7001_ $$00000-0001-7758-4911$$aSluijs, Ivonne$$b8 000164050 7001_ $$aStewart, Isobel D$$b9 000164050 7001_ $$00000-0001-8789-8869$$aShah, Rupal L$$b10 000164050 7001_ $$00000-0002-4605-435X$$avan der Schouw, Yvonne T$$b11 000164050 7001_ $$aWheeler, Eleanor$$b12 000164050 7001_ $$aArdanaz, Eva$$b13 000164050 7001_ $$aBoeing, Heiner$$b14 000164050 7001_ $$aDorronsoro, Miren$$b15 000164050 7001_ $$00000-0003-0481-2893$$aDahm, Christina C$$b16 000164050 7001_ $$00000-0003-1678-9328$$aDimou, Niki$$b17 000164050 7001_ $$aEl-Fatouhi, Douae$$b18 000164050 7001_ $$00000-0002-0520-7604$$aFranks, Paul W$$b19 000164050 7001_ $$00000-0001-5033-5966$$aFagherazzi, Guy$$b20 000164050 7001_ $$aGrioni, Sara$$b21 000164050 7001_ $$00000-0002-9637-3869$$aHuerta, José María$$b22 000164050 7001_ $$00000-0001-6517-1300$$aHeath, Alicia K$$b23 000164050 7001_ $$00000-0002-7109-8864$$aHansen, Louise$$b24 000164050 7001_ $$00000-0002-0573-1852$$aJenab, Mazda$$b25 000164050 7001_ $$aJakszyn, Paula$$b26 000164050 7001_ $$0P:(DE-He78)4b2dc91c9d1ac33a1c0e0777d0c1697a$$aKaaks, Rudolf$$b27$$udkfz 000164050 7001_ $$0P:(DE-He78)0907a10ba1dc8f53f04907f54f6fdcfe$$aKühn, Tilman$$b28$$udkfz 000164050 7001_ $$aKhaw, Kay-Tee$$b29 000164050 7001_ $$00000-0002-8532-456X$$aLaouali, Nasser$$b30 000164050 7001_ $$00000-0002-5758-9069$$aMasala, Giovanna$$b31 000164050 7001_ $$aNilsson, Peter M$$b32 000164050 7001_ $$aOvervad, Kim$$b33 000164050 7001_ $$00000-0003-4788-503X$$aOlsen, Anja$$b34 000164050 7001_ $$aPanico, Salvatore$$b35 000164050 7001_ $$aQuirós, J Ramón$$b36 000164050 7001_ $$aRolandsson, Olov$$b37 000164050 7001_ $$00000-0002-9972-9779$$aRodríguez-Barranco, Miguel$$b38 000164050 7001_ $$00000-0002-8008-5096$$aSacerdote, Carlotta$$b39 000164050 7001_ $$aSpijkerman, Annemieke M W$$b40 000164050 7001_ $$00000-0002-0284-8959$$aTong, Tammy Y N$$b41 000164050 7001_ $$00000-0003-2666-414X$$aTumino, Rosario$$b42 000164050 7001_ $$00000-0002-8452-8472$$aTsilidis, Konstantinos K$$b43 000164050 7001_ $$aDanesh, John$$b44 000164050 7001_ $$00000-0001-6795-6080$$aRiboli, Elio$$b45 000164050 7001_ $$aButterworth, Adam S$$b46 000164050 7001_ $$00000-0002-5017-7344$$aLangenberg, Claudia$$b47 000164050 7001_ $$00000-0002-5041-248X$$aForouhi, Nita G$$b48 000164050 7001_ $$00000-0003-1422-2993$$aWareham, Nicholas J$$b49 000164050 773__ $$0PERI:(DE-600)2164823-2$$a10.1371/journal.pmed.1003394$$gVol. 17, no. 10, p. e1003394 -$$n10$$pe1003394 -$$tPLoS medicine$$v17$$x1549-1676$$y2020 000164050 909CO $$ooai:inrepo02.dkfz.de:164050$$pVDB 000164050 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)4b2dc91c9d1ac33a1c0e0777d0c1697a$$aDeutsches Krebsforschungszentrum$$b27$$kDKFZ 000164050 9101_ $$0I:(DE-588b)2036810-0$$6P:(DE-He78)0907a10ba1dc8f53f04907f54f6fdcfe$$aDeutsches Krebsforschungszentrum$$b28$$kDKFZ 000164050 9131_ $$0G:(DE-HGF)POF3-323$$1G:(DE-HGF)POF3-320$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lHerz-Kreislauf-Stoffwechselerkrankungen$$vMetabolic Dysfunction as Risk Factor$$x0 000164050 9141_ $$y2020 000164050 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bPLOS MED : 2018$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0310$$2StatID$$aDBCoverage$$bNCBI Molecular Biology Database$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0320$$2StatID$$aDBCoverage$$bPubMed Central$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Peer review$$d2020-02-27 000164050 915__ $$0LIC:(DE-HGF)CCBYNV$$2V:(DE-HGF)$$aCreative Commons Attribution CC BY (No Version)$$bDOAJ$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2020-02-27 000164050 915__ $$0StatID:(DE-HGF)1110$$2StatID$$aDBCoverage$$bCurrent Contents - 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