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AIMS/HYPOTHESIS: Metformin, a mainstay of treatment for type 2 diabetes, can cause vitamin B deficiency. 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.METHODS: Individuals with metformin-induced vitamin B deficiency (n=487) and metformin-tolerant control individuals (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.RESULTS: Analysis identified a genome-wide significant non-synonymous SNP in the cubilin gene (CUBN, rs1801222/p.S253F) associated with metformin-induced vitamin B deficiency (additive model; adjusted p=1.86×10; 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 deficiency occurred in 0.84-1.20% of non-metformin-exposed individuals regardless of rs1801222 genotype. However, a large interaction with metformin use was observed, with vitamin B 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 deficient by 11 years vs 21 years for 10% of the GG group.CONCLUSIONS/INTERPRETATION: The observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B deficiency. While clinical monitoring of serum vitamin B 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.