{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T05:05:47Z","timestamp":1784091947428,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Academy of Medical Sciences Springboard","award":["SBF002\\1097"],"award-info":[{"award-number":["SBF002\\1097"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["U105960371"],"award-info":[{"award-number":["U105960371"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","award":["19544"],"award-info":[{"award-number":["19544"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Genetic variants at the vitamin D binding protein (\n                      <jats:italic>GC<\/jats:italic>\n                      ), cytochrome P450 family 2 subfamily R member 1 (\n                      <jats:italic>CYP2R1<\/jats:italic>\n                      ), and 7-dehydrocholesterol reductase (\n                      <jats:italic>DHCR7<\/jats:italic>\n                      ) loci have been associated with serum 25-hydroxy vitamin D (25(OH)D) concentration, but their role in interpreting the response to vitamin D supplementation is unclear. Here, we investigated associations between common variants at these loci and plasma 25(OH)D concentrations in a randomised dose-ranging trial of vitamin D supplementation in healthy older people.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The study involved 323 participants of the Vitamin D supplementation in Older People (VDOP) trial, randomly assigned to either 12,000, 24,000, or 48,000 IU colecalciferol monthly for 12\u202fmonths. Plasma 25(OH)D concentrations were measured by liquid chromatography-mass spectrometry. Variants rs7041 and rs2282679 (\n                      <jats:italic>GC<\/jats:italic>\n                      ), rs10741657 (\n                      <jats:italic>CYP2R1<\/jats:italic>\n                      ), and rs12785878 (\n                      <jats:italic>DHCR7<\/jats:italic>\n                      ) were genotyped by Sanger sequencing. Associations between genotype and 25(OH)D at baseline and post-supplementation were assessed by linear regression analysis with baseline 25(OH)D as a covariate and dose as fixed factor for post-supplementation data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At baseline, plasma 25(OH)D concentration was associated with the minor allele rs7041-A (\n                      <jats:italic>GC<\/jats:italic>\n                      ). Post-supplementation, an allele-dose effect was observed with two variants at the\n                      <jats:italic>GC<\/jats:italic>\n                      locus. Common homozygotes for rs2282679 and rs7041 had higher 25(OH)D concentrations at all supplement dosages, with lower frequency of 25(OH)D concentrations &amp;lt;50\u202fnmol\/L compared to other genotypes (OR(95%CI)\u202f=\u202f2.97(1.56\u20135.65) and 2.84(1.28\u20136.32), respectively).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Common genetic variants at the\n                      <jats:italic>GC<\/jats:italic>\n                      locus influence plasma 25(OH)D concentrations and the response to vitamin D supplementation. Genotyping of\n                      <jats:italic>GC<\/jats:italic>\n                      may aid interpreting 25(OH)D concentrations in people who are undergoing supplementation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1880174","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:21:54Z","timestamp":1784089314000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic determinants of response to vitamin D supplementation"],"prefix":"10.3389","volume":"13","author":[{"given":"Nerea","family":"Alonso","sequence":"first","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh","place":["Edinburgh, United Kingdom"]},{"name":"Clinical Institute of Medical and Chemical Laboratory Diagnostics (CIMCL), Medical University of Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inez","family":"Schoenmakers","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Norwich Medical School, University of East Anglia","place":["Norwich, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kuenzer","sequence":"additional","affiliation":[{"name":"Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariane","family":"Willems","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry J.","family":"Aspray","sequence":"additional","affiliation":[{"name":"NIHR Newcastle Biomedical Research Centre, Campus for Ageing and Vitality","place":["Newcastle upon Tyne, United Kingdom"]},{"name":"Institute for Cellular Medicine, Newcastle University","place":["Newcastle upon Tyne, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart H.","family":"Ralston","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Cancer, University of Edinburgh","place":["Edinburgh, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s11914-012-0098-z","article-title":"Vitamin D and bone","volume":"10","author":"Bikle","year":"2012","journal-title":"Curr Osteoporos Rep"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/B978-0-12-809965-0.00007-0","volume-title":"Vitamin D Volume 1: Biochemistry, Physiology and Diagnostics. 1","author":"Bouillon","year":"2018"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1210\/jc.2010-2704","article-title":"The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know","volume":"96","author":"Ross","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.cca.2021.03.002","article-title":"Recommendations on the measurement and the clinical use of vitamin D metabolites and vitamin D binding protein - a position paper from the IFCC committee on bone metabolism","volume":"517","author":"Makris","year":"2021","journal-title":"Clin Chim Acta"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.jada.2011.01.004","article-title":"The 2011 dietary reference intakes for calcium and vitamin D: what dietetics practitioners need to know","volume":"111","author":"Ross","year":"2011","journal-title":"J Am Diet Assoc"},{"key":"ref6","year":"2024"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1210\/clinem\/dgae290","article-title":"Vitamin D for the prevention of disease: an Endocrine Society clinical practice guideline","volume":"109","author":"Demay","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/S0140-6736(10)60588-0","article-title":"Common genetic determinants of vitamin D insufficiency: a genome-wide association study","volume":"376","author":"Wang","year":"2010","journal-title":"Lancet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"360","DOI":"10.3390\/nu14020360","article-title":"Vitamin D receptor (VDR) gene polymorphisms modify the response to vitamin D supplementation: a systematic review and Meta-analysis","volume":"14","author":"Usategui-Martin","year":"2022","journal-title":"Nutrients"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3373","DOI":"10.1210\/jc.2014-1714","article-title":"25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype","volume":"99","author":"Jones","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1515\/jomb-2017-0015","article-title":"Association between two common polymorphisms of vitamin D binding protein and the risk of coronary artery disease: a case-control study","volume":"36","author":"Tarighi","year":"2017","journal-title":"J Med Biochem"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1056\/NEJMoa1306357","article-title":"Vitamin D-binding protein and vitamin D status of black Americans and white Americans","volume":"369","author":"Powe","year":"2013","journal-title":"N Engl J Med"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2226","DOI":"10.1210\/jc.2016-1104","article-title":"Free 25-Hydroxyvitamin D: impact of vitamin D binding protein assays on racial-genotypic associations","volume":"101","author":"Nielson","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1530\/eje-15-1089","article-title":"Effects of vitamin D binding protein phenotypes and vitamin D supplementation on serum total 25(OH)D and directly measured free 25(OH)D","volume":"174","author":"Sollid","year":"2016","journal-title":"Eur J Endocrinol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"8363","DOI":"10.1074\/jbc.M115.699546","article-title":"Cholesterol-mediated degradation of 7-Dehydrocholesterol reductase switches the balance from cholesterol to vitamin D synthesis","volume":"291","author":"Prabhu","year":"2016","journal-title":"J Biol Chem"},{"key":"ref16","doi-asserted-by":"publisher","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":"ref17","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.ajhg.2017.06.014","article-title":"Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis","volume":"101","author":"Manousaki","year":"2017","journal-title":"Am J Hum Genet"},{"key":"ref18","doi-asserted-by":"publisher","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":"ref19","doi-asserted-by":"publisher","first-page":"5483","DOI":"10.1210\/jc.2019-00630","article-title":"Genetic variation of the vitamin D binding protein affects vitamin D status and response to supplementation in infants","volume":"104","author":"Enlund-Cerullo","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"13977","DOI":"10.1002\/jcp.28083","article-title":"A variant in CYP2R1 predicts circulating vitamin D levels after supplementation with high-dose of vitamin D in healthy adolescent girls","volume":"234","author":"Khayyatzadeh","year":"2019","journal-title":"J Cell Physiol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2941","DOI":"10.1210\/jc.2017-00682","article-title":"Response to antenatal cholecalciferol supplementation is associated with common vitamin D-related genetic variants","volume":"102","author":"Moon","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.clnesp.2024.01.009","article-title":"Influence of the BsmI polymorphism of the vitamin D receptor gene on the levels of vitamin D, inflammatory and oxidative stress profile in patients with cystic fibrosis supplemented with Colecalciferol megadose","volume":"60","author":"Queiroz","year":"2024","journal-title":"Clin Nutr ESPEN"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"e0261097","DOI":"10.1371\/journal.pone.0261097","article-title":"Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis","volume":"16","author":"Mimpen","year":"2021","journal-title":"PLoS One"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1016\/j.clinbiochem.2009.03.008","article-title":"Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation","volume":"42","author":"Fu","year":"2009","journal-title":"Clin Biochem"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1024\/0300-9831\/a000762","article-title":"Genetic variations of vitamin D receptor and vitamin D supplementation interaction in relation to serum vitamin D and metabolic traits: a systematic review and meta-analysis","volume":"93","author":"Ghiasvand","year":"2023","journal-title":"Int J Vitam Nutr Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/s41430-022-01218-y","article-title":"Variability in response to vitamin D supplementation according to vitamin D metabolism related gene polymorphisms in healthy adults","volume":"77","author":"Ammar","year":"2023","journal-title":"Eur J Clin Nutr"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"242","DOI":"10.3390\/nu17020242","article-title":"Vitamin metabolism and its dependency on genetic variations among healthy adults: a systematic review for precision nutrition strategies","volume":"17","author":"Bosch","year":"2025","journal-title":"Nutrients"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/ajcn\/nqy280","article-title":"Randomized controlled trial of vitamin D supplementation in older people to optimize bone health","volume":"109","author":"Aspray","year":"2019","journal-title":"Am J Clin Nutr"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1186\/1745-6215-14-299","article-title":"Vitamin D supplementation in older people (VDOP): study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3","volume":"14","author":"Schoenmakers","year":"2013","journal-title":"Trials"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e65715","DOI":"10.7554\/eLife.65715","article-title":"Epigenetic analysis of Paget's disease of bone identifies differentially methylated loci that predict disease status","volume":"10","author":"Diboun","year":"2021","journal-title":"eLife"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1002\/jbmr.3928","article-title":"Loss-of-function mutations in the ALPL gene presenting with adult onset osteoporosis and low serum concentrations of Total alkaline phosphatase","volume":"35","author":"Alonso","year":"2020","journal-title":"J Bone Miner Res"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1093\/bioinformatics\/btm091","article-title":"Enhancements and modifications of primer design program Primer3","volume":"23","author":"Koressaar","year":"2007","journal-title":"Bioinformatics"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e115","DOI":"10.1093\/nar\/gks596","article-title":"Primer3--new capabilities and interfaces","volume":"40","author":"Untergasser","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2739","DOI":"10.1093\/hmg\/ddq155","article-title":"Genome-wide association study of circulating vitamin D levels","volume":"19","author":"Ahn","year":"2010","journal-title":"Hum Mol Genet"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cca.2006.03.011","article-title":"Biological and clinical aspects of the vitamin D binding protein (Gc-globulin) and its polymorphism","volume":"372","author":"Speeckaert","year":"2006","journal-title":"Clin Chim Acta"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s00439-011-1099-1","article-title":"Associations between common variants in GC and DHCR7\/NADSYN1 and vitamin D concentration in Chinese Hans","volume":"131","author":"Lu","year":"2012","journal-title":"Hum Genet"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"e28623","DOI":"10.1371\/journal.pone.0028623","article-title":"Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D levels among African Americans","volume":"6","author":"Signorello","year":"2011","journal-title":"PLoS One"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.bone.2014.12.068","article-title":"Vitamin D binding protein genotype is associated with plasma 25OHD concentration in west African children","volume":"74","author":"Braithwaite","year":"2015","journal-title":"Bone"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/jbmr.1735","article-title":"Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers","volume":"28","author":"Carpenter","year":"2013","journal-title":"J Bone Miner Res"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1007\/s00198-014-2905-0","article-title":"Predictors of 25(OH)D half-life and plasma 25(OH)D concentration in the Gambia and the UK","volume":"26","author":"Jones","year":"2015","journal-title":"Osteoporos Int"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.nutres.2022.09.003","article-title":"Vitamin D binding protein gene polymorphisms are associated with lower plasma 25-hydroxy-cholecalciferol concentrations in Ethiopian lactating women","volume":"107","author":"Hart","year":"2022","journal-title":"Nutr Res"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"5365","DOI":"10.1080\/07391102.2023.2226742","article-title":"Differential glycosylation in mutant vitamin D-binding protein decimates the binding stability of vitamin D","volume":"42","author":"Usama","year":"2024","journal-title":"J Biomol Struct Dyn"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"105918","DOI":"10.1016\/j.jsbmb.2021.105918","article-title":"Analysis of the effect of vitamin D supplementation and sex on Vdr, Cyp2r1 and Cyp27b1 gene expression in Wistar rats' tissues","volume":"212","author":"Oczkowicz","year":"2021","journal-title":"J Steroid Biochem Mol Biol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.jsbmb.2013.10.004","article-title":"DNA methylation levels of CYP2R1 and CYP24A1 predict vitamin D response variation","volume":"144","author":"Zhou","year":"2014","journal-title":"J Steroid Biochem Mol Biol"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1880174\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:21:56Z","timestamp":1784089316000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1880174\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":44,"alternative-id":["10.3389\/fnut.2026.1880174"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1880174","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]},"article-number":"1880174"}}