Are serum concentrations of vitamin B-12 causally related to cardiometabolic risk factors and disease? A Mendelian randomization study.

Background: Several observational studies have shown that low serum vitamin B-12 is associated with increased body mass index (BMI) and adverse cardiometabolic outcomes. However, it is unclear if these associations reflect a causal effect of vitamin B-12 on cardiometabolic risk factors and diseases, latent confounding, or reverse causality.

Objectives: The aims of this study were to investigate 1) the possible causal relation between vitamin B-12 and indicators of body fat, lipid, and glucose variables; type 2 diabetes (T2D); and cardiovascular disease by using a 2-sample Mendelian randomization (MR) method and 2) the possible pleiotropic role of fucosyltransferase 2 (FUT2).

Design: We selected 11 single nucleotide polymorphisms (SNPs) robustly associated with serum concentrations of vitamin B-12 in a previous genomewide association study (GWAS) in 45,576 individuals. We performed 2-sample MR analyses of the relation between vitamin B-12 and cardiometabolic risk factors and diseases with the use of publicly available GWAS summary statistics for 15 outcomes in ≤339,224 individuals. The robustness of results was tested with sensitivity analyses by using MR Egger regression and weighted-median estimation, and by performing additional analyses excluding a variant in the FUT2 gene, which may be pleiotropic.

Results: We found a suggestive causal relation between vitamin B-12 and fasting glucose and β cell function [homeostatic model assessment (HOMA) of β cell function (HOMA-B)]. However, we found no evidence that serum concentrations of vitamin B-12 were causally related to BMI, waist-to-hip ratio, plasma leptin, body fat, fasting insulin, insulin resistance (from HOMA of insulin resistance), glycated hemoglobin, triglycerides, T2D, coronary artery disease, or HDL, LDL, or total cholesterol.

Conclusions: We found no evidence that serum concentrations of vitamin B-12 are causally related to body weight or the majority of cardiometabolic outcomes investigated. However, vitamin B-12 may have a causal effect on fasting glucose and HOMA-B, although these results will require replication in large independent data sets. This trialwas registered at https://www.isrctn.com/ISRCTN47414943 as ISRCTN47414943.