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Clinical risk factors have been identified but genetic factors remain undiscovered. Our objective was to identify and validate genetic predisposing factors and establish clinical utility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Individuals with metformin-induced vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      deficiency (\n                      <jats:italic>n<\/jats:italic>\n                      =487) and metformin-tolerant control individuals (\n                      <jats:italic>n<\/jats:italic>\n                      =6686) were identified in UK Biobank. Genome-wide association analysis was undertaken using logistic regression. Replication was undertaken in three cohorts: a Scottish cohort; the Diabetes Prevention Program Outcomes Study (DPPOS); and a separate cohort from Liverpool. In the Liverpool cohort, plasma metformin levels were also measured.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Analysis identified a genome-wide significant non-synonymous SNP in the cubilin gene (\n                      <jats:italic>CUBN,<\/jats:italic>\n                      rs1801222\/p.S253F) associated with metformin-induced vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      deficiency (additive model; adjusted\n                      <jats:italic>p<\/jats:italic>\n                      =1.86\u00d710\n                      <jats:sup>\u221210<\/jats:sup>\n                      ; OR 1.56 [95% CI 1.36, 1.79] for AG vs GG genotype; OR 2.43 [95% CI 1.85, 3.20] for AA vs GG genotype), which was replicated in both the Scottish and the DPPOS cohorts. Vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      deficiency occurred in 0.84\u20131.20% of non-metformin-exposed individuals regardless of rs1801222 genotype. However, a large interaction with metformin use was observed, with vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      deficiency occurring at 6.02% in GG, 7.96% in GA and 12.84% in AA genotype groups. When followed up from metformin initiation, 10% with the AA genotype were vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      deficient by 11 years vs 21 years for 10% of the GG group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      The observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      deficiency. While clinical monitoring of serum vitamin B\n                      <jats:sub>12<\/jats:sub>\n                      levels in patients on metformin is inconsistently done, this finding highlights the potential clinical utility of targeted monitoring for certain subsets of individuals, including those genetically at high risk.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06655-5","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:22:49Z","timestamp":1768450969000},"page":"953-965","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a genetic risk factor for metformin-induced vitamin B12 deficiency"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-791X","authenticated-orcid":false,"given":"Faye D.","family":"Baldwin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7959-8110","authenticated-orcid":false,"given":"Khaled F.","family":"Bedair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6977-9337","authenticated-orcid":false,"given":"Andrea L.","family":"Jorgensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5792-5408","authenticated-orcid":false,"given":"Lewis","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1196-1822","authenticated-orcid":false,"given":"Innocent G.","family":"Asiimwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6415-6560","authenticated-orcid":false,"given":"Colin N. 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Funding for dissemination of this work was awarded as part of the HDR UK publication fund. We follow and adhere to the STROPs (STrengthening the Reporting Of Pharmacogenetic Studies) guidelines throughout the writing of this research. IA and MP are also supported by the Medical Research Council grant (MR\/V033867\/1), Multimorbidity Mechanism and Therapeutics Research Collaborative. JHL received individual support from National Institute of Diabetes and Digestive and Kidney (NIDDK) K23DK131345. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD\/16\/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust [216767\/Z\/19\/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award \u2018STratifying Resilience and Depression Longitudinally\u2019 [STRADL] Reference 104036\/Z\/14\/Z). CH was supported by the MRC Human Genetics Unit quinquennial programme grant \u2018QTL in Health and Disease\u2019 (MC_UU_00007\/10). The DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. Research reported in this publication was supported by the NIDDK of the National Institutes of Health (NIH) under award numbers DPPOS NIDDK grant no. U01 DK048489 by providing funding during DPP and DPPOS to the clinical centres and the coordinating centre for the design and conduct of the study, and collection, management, analysis and interpretation of the data. A complete list of centres, investigators and staff can be found in the\n                      \n                      .","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"All the persons listed as authors fulfil all three criteria for authorship as per the ICMJE uniform requirements. Specifically they all made substantial contributions to the conception or design of the work, the acquisition, analysis or interpretation of data, and drafting of the article or reviewing it critically for important intellectual content. All listed authors gave final approval of the version to be published. DFC is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}