{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:18:33Z","timestamp":1790882313965,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T00:00:00Z","timestamp":1652745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1123603"],"award-info":[{"award-number":["1123603"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Low vitamin D status is often associated with systemic low-grade inflammation as reflected by elevated C-reactive protein (CRP) levels. We investigated the causality and direction of the association between vitamin D status and CRP using linear and non-linear Mendelian randomization (MR) analyses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>MR analyses were conducted using data from 294\u200a970 unrelated participants of White-British ancestry from the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] and CRP concentrations were instrumented using 35 and 46 genome-wide significant variants, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In non-linear MR analysis, genetically predicted serum 25(OH)D had an L-shaped association with serum CRP, where CRP levels decreased sharply with increasing 25(OH)D concentration for participants within the deficiency range (&amp;lt;25\u2009nmol\/L) and levelled off at \u223c50\u2009nmol\/L of 25(OH)D (Pnon-linear\u2009=\u20091.49E-4). Analyses using several pleiotropy-robust methods provided consistent results in stratified MR analyses, confirming the inverse association between 25(OH)D and CRP in the deficiency range (P\u2009=\u20091.10E-05) but not with higher concentrations. Neither linear or non-linear MR analysis supported a causal effect of serum CRP level on 25(OH)D concentration (Plinear\u2009=\u20090.32 and Pnon-linear\u2009=\u20090.76).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The observed association between 25(OH)D and CRP is likely to be caused by vitamin D deficiency. Correction of low vitamin D status may reduce chronic inflammation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ije\/dyac087","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T11:16:58Z","timestamp":1649935018000},"page":"260-271","source":"Crossref","is-referenced-by-count":105,"title":["Vitamin D deficiency and C-reactive protein: a bidirectional Mendelian randomization study"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7088-0777","authenticated-orcid":false,"given":"Ang","family":"Zhou","sequence":"first","affiliation":[{"name":"Australian Center for Precision Health, University of South Australia Cancer Research Institute , Adelaide, Australia"},{"name":"South Australian Health and Medical Research Institute , Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina","family":"Hypp\u00f6nen","sequence":"additional","affiliation":[{"name":"Australian Center for Precision Health, University of South Australia Cancer Research Institute , Adelaide, Australia"},{"name":"South Australian Health and Medical Research Institute , Adelaide, Australia"},{"name":"Population, Policy and Practice, UCL Institute of Child Health , London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"2023020819452167900_dyac087-B1","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41591-019-0675-0","article-title":"Chronic inflammation in the etiology of disease across the life span","volume":"25","author":"Furman","year":"2019","journal-title":"Nat Med"},{"key":"2023020819452167900_dyac087-B2","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/ni.3828","article-title":"Biomarkers of chronic inflammation in disease development and prevention: challenges and opportunities","volume":"18","author":"Liu","year":"2017","journal-title":"Nat Immunol"},{"key":"2023020819452167900_dyac087-B3","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1017\/S0007114512005119","article-title":"A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies","volume":"109(Suppl 1)","author":"Calder","year":"2013","journal-title":"Br J Nutr"},{"key":"2023020819452167900_dyac087-B4","doi-asserted-by":"crossref","first-page":"2097.","DOI":"10.3390\/nu12072097","article-title":"Immunologic effects of vitamin D on human health and disease","volume":"12","author":"Charoenngam","year":"2020","journal-title":"Nutrients"},{"key":"2023020819452167900_dyac087-B5","doi-asserted-by":"crossref","first-page":"e0141770.","DOI":"10.1371\/journal.pone.0141770","article-title":"The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies","volume":"10","author":"Calton","year":"2015","journal-title":"PLoS One"},{"key":"2023020819452167900_dyac087-B6","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.metabol.2014.05.002","article-title":"Association between serum vitamin D concentrations and inflammatory markers in the general adult population","volume":"63","author":"Mellenthin","year":"2014","journal-title":"Metabolism"},{"key":"2023020819452167900_dyac087-B7","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1515\/cclm-2012-0157","article-title":"Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study","volume":"50","author":"Murr","year":"2012","journal-title":"Clin Chem Lab Med"},{"key":"2023020819452167900_dyac087-B8","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/S2213-8587(17)30357-1","article-title":"Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials","volume":"5","author":"Autier","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023020819452167900_dyac087-B9","doi-asserted-by":"crossref","first-page":"k601.","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"2023020819452167900_dyac087-B10","doi-asserted-by":"crossref","first-page":"e0131740","DOI":"10.1371\/journal.pone.0131740","article-title":"Vitamin D and C-reactive protein: a Mendelian randomization study","volume":"10","author":"Liefaard","year":"2015","journal-title":"PLoS One"},{"key":"2023020819452167900_dyac087-B11","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1093\/ajcn\/nqaa056","article-title":"Could Vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study","volume":"111","author":"Palaniswamy","year":"2020","journal-title":"Am J Clin Nutr"},{"key":"2023020819452167900_dyac087-B12","doi-asserted-by":"crossref","first-page":"561.","DOI":"10.3390\/nu10050561","article-title":"Emerging evidence of thresholds for beneficial effects from vitamin D supplementation","volume":"10","author":"Scragg","year":"2018","journal-title":"Nutrients"},{"key":"2023020819452167900_dyac087-B13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/nure.12090","article-title":"Guidelines for optimizing design and analysis of clinical studies of nutrient effects","volume":"72","author":"Heaney","year":"2014","journal-title":"Nutr Rev"},{"key":"2023020819452167900_dyac087-B14","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/gepi.22041","article-title":"Semiparametric methods for estimation of a nonlinear exposure-outcome relationship using instrumental variables with application to Mendelian randomization","volume":"41","author":"Staley","year":"2017","journal-title":"Genet Epidemiol"},{"key":"2023020819452167900_dyac087-B15","first-page":"ehab809","article-title":"Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk","author":"Zhou","year":"2021","journal-title":"Eur Heart J"},{"key":"2023020819452167900_dyac087-B16","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S2213-8587(21)00263-1","article-title":"Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses","volume":"9","author":"Sofianopoulou","year":"2021","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023020819452167900_dyac087-B17","doi-asserted-by":"crossref","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med"},{"key":"2023020819452167900_dyac087-B18","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"2023020819452167900_dyac087-B19","author":"Fry"},{"key":"2023020819452167900_dyac087-B20","author":"UK Biobank"},{"key":"2023020819452167900_dyac087-B21","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1038\/s41467-020-15421-7","article-title":"Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration","volume":"11","author":"Revez","year":"2020","journal-title":"Nat Commun"},{"key":"2023020819452167900_dyac087-B22","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/s41467-017-02662-2","article-title":"Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels","volume":"9","author":"Jiang","year":"2018","journal-title":"Nat Commun"},{"key":"2023020819452167900_dyac087-B23","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1093\/ije\/dyt093","article-title":"Use of allele scores as instrumental variables for Mendelian randomization","volume":"42","author":"Burgess","year":"2013","journal-title":"Int J Epidemiol"},{"key":"2023020819452167900_dyac087-B24","first-page":"ehab870","article-title":"Genetic evidence for vitamin D and cardiovascular disease: choice of variants is critical","author":"Burgess","year":"2021","journal-title":"Eur Heart J"},{"key":"2023020819452167900_dyac087-B25","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":"Berry","year":"2012","journal-title":"PLoS One"},{"key":"2023020819452167900_dyac087-B26","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":"Vimaleswaran","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2023020819452167900_dyac087-B27","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":"Vimaleswaran","year":"2013","journal-title":"PLoS Med"},{"key":"2023020819452167900_dyac087-B28","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.ajhg.2018.09.009","article-title":"Genome analyses of &gt;200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders","volume":"103","author":"Ligthart","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2023020819452167900_dyac087-B29","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1002\/ijc.32947","article-title":"Mendelian randomisation analysis of circulating adipokines and C-reactive protein on breast cancer risk","volume":"147","author":"Robinson","year":"2020","journal-title":"Int J Cancer"},{"key":"2023020819452167900_dyac087-B30","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1093\/aje\/kwr026","article-title":"Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses","volume":"173","author":"Palmer","year":"2011","journal-title":"Am J Epidemiol"},{"key":"2023020819452167900_dyac087-B31","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1093\/ije\/dyp334","article-title":"Illustrating bias due to conditioning on a collider","volume":"39","author":"Cole","year":"2010","journal-title":"Int J Epidemiol"},{"key":"2023020819452167900_dyac087-B32","doi-asserted-by":"crossref","first-page":"15611561","DOI":"10.1038\/s41467-019-09381-w","article-title":"Adjustment for index event bias in genome-wide association studies of subsequent events","volume":"10","author":"Dudbridge","year":"2019","journal-title":"Nat Commun"},{"key":"2023020819452167900_dyac087-B33","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/gepi.21998","article-title":"Bias due to participant overlap in two-sample Mendelian randomization","volume":"40","author":"Burgess","year":"2016","journal-title":"Genet Epidemiol"},{"key":"2023020819452167900_dyac087-B34","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41467-018-08219-1","article-title":"Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis","volume":"10","author":"Haworth","year":"2019","journal-title":"Nat Commun"},{"key":"2023020819452167900_dyac087-B35","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome. Loos R, editor","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"2023020819452167900_dyac087-B36","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1038\/s41430-020-0558-y","article-title":"Vitamin D deficiency 2.0: an update on the current status worldwide","volume":"74","author":"Amrein","year":"2020","journal-title":"Eur J Clin Nutr"},{"key":"2023020819452167900_dyac087-B37","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.amjms.2021.06.005","article-title":"Low serum levels of 25-hydroxyvitamin D accompany severe COVID-19 because it is a negative acute phase reactant","volume":"362","author":"Antonelli","year":"2021","journal-title":"Am J Med Sci"},{"key":"2023020819452167900_dyac087-B38","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.2337\/dc20-1765","article-title":"Intratrial exposure to vitamin D and new-onset diabetes among adults with prediabetes: a secondary analysis from the vitamin D and type 2 diabetes (D2d) study","volume":"43","author":"Dawson-Hughes","year":"2020","journal-title":"Diabetes Care"},{"key":"2023020819452167900_dyac087-B39","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.3390\/ijms19061618","article-title":"Role of vitamin D beyond the skeletal function: a review of the molecular and clinical studies","volume":"19","author":"Umar","year":"2018","journal-title":"Int J Mol Sci"},{"key":"2023020819452167900_dyac087-B40","doi-asserted-by":"crossref","first-page":"34","DOI":"10.4161\/derm.24054","article-title":"Vitamin D status and sun exposure in Southeast Asia","volume":"5","author":"Nimitphong","year":"2013","journal-title":"Dermatoendocrinology"},{"key":"2023020819452167900_dyac087-B41","author":"Australian Government Department of Health","year":"2018"},{"key":"2023020819452167900_dyac087-B42","doi-asserted-by":"crossref","first-page":"P23","DOI":"10.1530\/EJE-18-0736","article-title":"Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society","volume":"180","author":"Lips","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"2023020819452167900_dyac087-B43","doi-asserted-by":"crossref","first-page":"e1002566","DOI":"10.1371\/journal.pmed.1002566","article-title":"Association of vitamin D with risk of type 2 diabetes: a Mendelian randomisation study in European and Chinese adults","volume":"15","author":"Lu","year":"2018","journal-title":"PLoS Med"},{"key":"2023020819452167900_dyac087-B44","doi-asserted-by":"crossref","first-page":"e1001866","DOI":"10.1371\/journal.pmed.1001866","article-title":"Vitamin D and risk of multiple sclerosis: a Mendelian randomization study","volume":"12","author":"Mokry","year":"2015","journal-title":"PLoS Med"},{"key":"2023020819452167900_dyac087-B45","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1093\/aje\/kwx246","article-title":"Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population","volume":"186","author":"Fry","year":"2017","journal-title":"Am J Epidemiol"},{"key":"2023020819452167900_dyac087-B46","doi-asserted-by":"crossref","first-page":"m131","DOI":"10.1136\/bmj.m131","article-title":"Comparison of risk factor associations in UK Biobank against representative, general population based studies with conventional response rates: prospective cohort study and individual participant meta-analysis","volume":"368","author":"Batty","year":"2020","journal-title":"BMJ"},{"key":"2023020819452167900_dyac087-B47","doi-asserted-by":"crossref","first-page":"l1042","DOI":"10.1136\/bmj.l1042","article-title":"Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear Mendelian randomisation analyses","volume":"364","author":"Sun","year":"2019","journal-title":"BMJ"}],"container-title":["International Journal of Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ije\/article-pdf\/52\/1\/260\/49127260\/dyac087.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ije\/article-pdf\/52\/1\/260\/49127260\/dyac087.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T19:53:13Z","timestamp":1675885993000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ije\/article\/52\/1\/260\/6586699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,17]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,5,17]]},"published-print":{"date-parts":[[2023,2,8]]}},"URL":"https:\/\/doi.org\/10.1093\/ije\/dyac087","relation":{},"ISSN":["0300-5771","1464-3685"],"issn-type":[{"value":"0300-5771","type":"print"},{"value":"1464-3685","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,5,17]]}}}