Untargeted urinary metabolomics by CREBRF rs373863828 (p.Arg457Gln) variant among individuals without type 2 diabetes

Background/Objectives : The CREBRF rs373863828-A (p.Arg457Gln) variant is associated with increased body mass index (BMI) but paradoxically reduced odds of type 2 diabetes (T2D). This study used untargeted urinary metabolomics to investigate metabolic pathways influenced by the CREBRF variant in Māori and Pacific peoples without T2D. Methods : Untargeted metabolomic analysis was conducted on urine samples from 980 adult participants of Māori and Pacific descent from the Genetics of Gout, Diabetes, and Kidney disease (GoGDK) study, all of whom did not have T2D or significant kidney disease. Of these, 325 (33.2%) were carriers of the CREBRF variant. Urine samples were analysed using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Linear modelling using the limma package was used to identify differentially expressed metabolites between carriers and non-carriers, with and without adjustment for BMI. Results were stratified by sex, and pathway enrichment analysis was performed using MetaboAnalyst 6.0. Results : Four metabolites differed significantly between carriers and non-carriers before BMI adjustment (false discovery rate [FDR]-adjusted P < 0.05), including N-acetylhistamine (log ₂ FC = 0.25, adjusted p = 0.002) and dimethylglycine (log ₂ FC = 0.19, p = 0.002). Two metabolic pathways were significantly enriched: glycine, serine, and threonine metabolism (adjusted p = 0.047; impact score = 0.19), and histidine metabolism (adjusted p = 0.047; impact score = 0.19). After BMI adjustment, no metabolites remained significant. Conclusions : Urinary metabolomic differences between CREBRF rs373863828-A carriers and non-carriers appear to be driven by differences in BMI. These findings highlight the need to further explore the role of body composition in mediating the metabolic effects of CREBRF .