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studies","volume":"23","author":"Smith G Davey","year":"2014","journal-title":"Hum Mol Genet"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"e37465","DOI":"10.1371\/journal.pone.0037465","article-title":"Evaluation of genetic markers as instruments for Mendelian randomization studies on vitamin D","volume":"7","author":"DJ Berry","year":"2012","journal-title":"PLoS ONE"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"S Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature10405","article-title":"Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk","volume":"478","author":"GB Ehret","year":"2011","journal-title":"Nature"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"e1002607","DOI":"10.1371\/journal.pgen.1002607","article-title":"Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals","volume":"8","author":"Z Dastani","year":"2012","journal-title":"PLoS Genet"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1093\/ije\/dyn065","article-title":"Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation","volume":"37","author":"NA Patsopoulos","year":"2008","journal-title":"Int J Epidemiol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"JP Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"JP Higgins","year":"2002","journal-title":"Stat Med"},{"key":"ref35","unstructured":"Ross AC. Dietary reference intakes for calcium and vitamin D. Washington (District of Columbia): Institute of Medicine. Available: <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.iom.edu\/Reports\/2010\/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx\" xlink:type=\"simple\">http:\/\/www.iom.edu\/Reports\/2010\/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx<\/ext-link>. Accessed 22 July 2015."},{"key":"ref36","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s00223-012-9660-z","article-title":"Genetic regulation of vitamin D levels","volume":"92","author":"Z Dastani","year":"2013","journal-title":"Calcif Tissue Int"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1172\/JCI5244","article-title":"Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein","volume":"103","author":"FF Safadi","year":"1999","journal-title":"J Clin Invest"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1210\/jcem-61-5-969","article-title":"Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels","volume":"61","author":"DD Bikle","year":"1985","journal-title":"J Clin Endocrinol Metab"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nsb754","article-title":"A structural basis for the unique binding features of the human vitamin D-binding protein","volume":"9","author":"C Verboven","year":"2002","journal-title":"Nat Struct Biol"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.bbrc.2004.09.073","article-title":"Metabolism of vitamin D by human microsomal CYP2R1","volume":"324","author":"R Shinkyo","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12865-014-0035-2","article-title":"Vitamin D-binding protein controls T cell responses to vitamin D","volume":"15","author":"M Kongsbak","year":"2014","journal-title":"BMC Immunol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/cdd.2012.161","article-title":"Vitamin D-binding protein interacts with A\u03b2 and suppresses A\u03b2-mediated pathology","volume":"20","author":"M Moon","year":"2013","journal-title":"Cell Death Differ"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3390\/toxins7010129","article-title":"Increased circulating levels of vitamin D binding protein in MS patients","volume":"7","author":"AO Rinaldi","year":"2015","journal-title":"Toxins (Basel)"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1007\/s12035-012-8387-1","article-title":"Vitamin D-binding protein in cerebrospinal fluid is associated with multiple sclerosis progression","volume":"47","author":"M Yang","year":"2013","journal-title":"Mol Neurobiol"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.jsbmb.2014.06.007","article-title":"Serum lipoprotein composition and vitamin D metabolite levels in clinically isolated syndromes: results from a multi-center study","volume":"143","author":"RW Browne","year":"2014","journal-title":"J Steroid Biochem Mol Biol"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/ng.2797","article-title":"Discovery and refinement of loci associated with lipid levels","volume":"45","author":"CJ Willer","year":"2013","journal-title":"Nat Genet"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1093\/brain\/awv080","article-title":"Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis","volume":"138","author":"MM Van Luijn","year":"2015","journal-title":"Brain"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"e1000369","DOI":"10.1371\/journal.pgen.1000369","article-title":"Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D","volume":"5","author":"SV Ramagopalan","year":"2009","journal-title":"PLoS Genet"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1186\/1745-6215-14-272","article-title":"Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial","volume":"14","author":"K O\u2019Connell","year":"2013","journal-title":"Trials"},{"key":"ref50","unstructured":"Thouvenot E, Suehs CM. Efficacy of cholecalciferol (vitamin D3) for delaying the diagnosis of MS after a clinically isolated syndrome (D-Lay-MS). <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ClinicalTrials.gov\" xlink:type=\"simple\">ClinicalTrials.gov<\/ext-link>. Available: <ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01817166?term=vitamin+d+multiple+sclerosis&rank=13\" xlink:type=\"simple\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01817166?term=vitamin+d+multiple+sclerosis&amp;rank=13<\/ext-link>. Accessed 22 July 2015."},{"key":"ref51","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1136\/jmedgenet-2014-102438","article-title":"Mendelian randomisation applied to drug development in cardiovascular disease: a review","volume":"52","author":"LE Mokry","year":"2015","journal-title":"J Med Genet"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"\u201cMendelian randomization\u201d: can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"GD Smith","year":"2003","journal-title":"Int J Epidemiol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"e1001751","DOI":"10.1371\/journal.pmed.1001751","article-title":"The causal effect of vitamin D binding protein (DBP) levels on calcemic and cardiometabolic diseases: a Mendelian randomization study","volume":"11","author":"A Leong","year":"2014","journal-title":"PLoS Med"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S2213-8587(14)70184-6","article-title":"Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a Mendelian randomisation study","volume":"3","author":"Z Ye","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.2337\/db10-1656","article-title":"Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes","volume":"60","author":"JD Cooper","year":"2011","journal-title":"Diabetes"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S2213-8587(14)70113-5","article-title":"Association of vitamin D status with arterial blood pressure and hypertension risk: a Mendelian randomisation study","volume":"2","author":"KS Vimaleswaran","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"e1001383","DOI":"10.1371\/journal.pmed.1001383","article-title":"Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts","volume":"10","author":"KS Vimaleswaran","year":"2013","journal-title":"PLoS Med"}],"updated-by":[{"DOI":"10.1371\/journal.pmed.1001981","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2016,3,2]],"date-time":"2016-03-02T00:00:00Z","timestamp":1456876800000}}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pmed.1001866","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T18:53:32Z","timestamp":1718045612000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1001866"}},"subtitle":[],"editor":[{"given":"Paolo Antonio","family":"Muraro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,8,25]]},"references-count":57,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2015,8,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1001866","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,25]]}}}