Genetic risk for metformin-associated B12 deficiency

door | jan 16, 2026 | B12, UK Biobank, wetenschap | 0 Reacties

Scientists have identified the first DNA variant associated with a higher risk of developing B12 deficiency when a person is treated with metformin.

The analysis, which was done by the authors, identified a genome-wide non-synonymous SNP in the cubilin gene (CUBN, rs1801222/p.S253F), which was significantly associated with metformin-induced vitamin B12 deficiency. This finding was replicated in three Scottish cohorts, in the Diabetes Prevention Program Outcomes Study (DPPOS) cohort, and in a small clinical cohort from Liverpool. Vitamin B12 deficiency occurred in 0.84–1.20% of individuals who were not exposed to metformin regardless of their rs1801222 genotype. However, a large interaction with metformin use was observed, with vitamin B12 deficiency developing at 6.02% in GG, 7.96% in GA and 12.84% in AA genotype groups.

Co-author Ewan Pearson: “The 14% of white population with AA genotype are 2.5 times more likely to require B12 replacement GG. Equates to 10% requiring B12 replacement by 11 years after starting metformin with AA genotype vs 21 years for GG. A large effect!”

It should be noted that the primary analysis was conducted among participants in the UK Biobank. Individuals were identified with a diagnosis of vitamin B12 deficiency and/or a record of B12 injection prescriptions, and metformin use was extensively documented. However, clinical diagnosis of B12 deficiency is often only done on the basis of abnormal B12 measurements, and -for instance- measurements of methylmalonic acid are rarely done. Furthermore, people who are using (multi)vitamin supplementation may not so easily be recognized as truly B12-deficient. So, the incidence of B12 deficiency may be higher than reported in the paper. Nevertheless, this is great work in the beautiful dataset of UK Biobank, and confirmed in other cohorts, such as Generation Scotland, GoDARTS, and SHARE, and DPPOS. Researchers are eagerly awaiting the time when UK Biobank data will also be enriched with serum B12, MMA, and homocysteine measurements for all participants.

Full source: https://link.springer.com/article/10.1007/s00125-025-06655-5

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Steatose lever en HVZ

door | nov 2, 2024 | gezondheidszorg, UK Biobank, wetenschap

 

Background & aims: Noninvasive tools (NITs) are currently used to stratify the risk of having or developing hepatic steatosis or fibrosis. Their performance and a proteomic-enabled improvement in forecasting long-term cardio-renal-metabolic morbidity, malignancies, as well as cause-specific and all-cause mortality, are lacking. Therefore, the performance of established NITs needs to be investigated in identifying cardio-renal-metabolic morbidity, malignancies, cause-specific and overall mortality and improve their performance with novel, proteomic-enabled NITs, including growth differentiation factor 15 (GDF-15), allowing multipurpose utilization.

Methods: 502,359 UK Biobank participants free of the study outcomes at baseline with a 14-year median follow-up were grouped into three categories: a) general population, b) potentially metabolic dysfunction-associated steatotic liver disease (MASLD) population, c) individuals with type 2 diabetes mellitus. The investigated NITs include Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis 4 Index (FIB-4), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and metabolic dysfunction-associated fibrosis (MAF-5) score.

Results: Adding GDF-15 to the existing NITs led to significantly increased prognostic performance compared to the traditional NITs in almost all instances, reaching substantially high C-indices, ranging between 0.601 and 0.808, with an overall >0.2 improvement in C-index. Overall, with the GDF-15 enhanced NITs, up to more than seven times fewer individuals need to be screened to identify more incident cases of adverse outcomes compared to the traditional NITs. The cumulative incidence of all outcomes, based on the continuous value percentiles of NITs, is increasing exponentially in the upper quintile of the GDF-15 enhanced NITs.

Conclusions: The herein-developed GDF-15 enhanced indices demonstrate higher screening effectiveness and significantly improved prognostic abilities, which are reduced to practice through an easy-to-use web-based calculator tool (https://clinicalpredictor.shinyapps.io/multimorbidity-mortality-risk/).

 

Het resultaat van een mooie samenwerking tussen UMCG (Klinische Farmacie & Farmacologie, en Endocrinologie), Ancora Health, en Harvard Medical School.

Download het volledige artikel hier: https://www.metabolismjournal.com/article/S0026-0495(24)00275-0/fulltext