# Identification of a genetic risk factor for metformin-induced vitamin B12 deficiency

## TL;DR

This study finds a genetic variant that increases the risk of vitamin B12 deficiency in people taking metformin for diabetes.

## Contribution

The study identifies a specific genetic risk factor (CUBN rs1801222) for metformin-induced vitamin B12 deficiency and validates it across multiple cohorts.

## Key findings

- The CUBN gene variant rs1801222 is strongly associated with metformin-induced vitamin B12 deficiency.
- Individuals with the AA genotype have a significantly higher risk of deficiency compared to those with the GG genotype.
- The genetic risk interacts strongly with metformin use, with higher deficiency rates observed in AA genotype carriers.

## Abstract

Metformin, a mainstay of treatment for type 2 diabetes, can cause vitamin B12 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.

Individuals with metformin-induced vitamin B12 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.

Analysis identified a genome-wide significant non-synonymous SNP in the cubilin gene (CUBN, rs1801222/p.S253F) associated with metformin-induced vitamin B12 deficiency (additive model; adjusted p=1.86×10−10; 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 B12 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 B12 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 B12 deficient by 11 years vs 21 years for 10% of the GG group.

The observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B12 deficiency. While clinical monitoring of serum vitamin B12 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.

The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-025-06655-5.