In utero metabolomic signatures of refined grain intake and risk of gestational diabetes: A metabolome-wide association study

Background: Epidemiologic evidence has linked refined grain intake to a higher risk of gestational diabetes (GDM), but the biological underpinnings remain unclear. Objectives: We aimed to identify and validate refined grain-related metabolomic biomarkers for GDM risk. Methods: In a metabolome-wide association study of 91 cases with GDM and 180 matched controls without GDM (discovery set) nested in the prospective Pregnancy Environment and Lifestyle Study (PETALS), refined grain intake during preconception and early pregnancy and serum untargeted metabolomics were assessed at gestational weeks 10–13. We identified refined grain-related metabolites using multivariable linear regression and examined their prospective associations with GDM risk using conditional logistic regression. We further examined the predictivity of refined grain-related metabolites selected by least absolute shrinkage and selection operator regression in the discovery set and validation set (a random PETALS subsample of 38 individuals with and 336 without GDM). Results: Among 821 annotated serum (87.4% fasting) metabolites, 42 were associated with refined grain intake, of which 17 (70.6% in glycerolipids, glycerophospholipids, and sphingolipids clusters) were associated with subsequent GDM risk (all false discovery rate-adjusted P values <0.05). Adding 7 of 17 metabolites to a conventional risk factor-based prediction model increased the C-statistic for GDM risk in the discovery set from 0.71 (95% CI: 0.64, 0.77) to 0.77 (95% CI: 0.71, 0.83) and in the validation set from 0.77 (95% CI: 0.69, 0.86) to 0.81 (95% CI: 0.74, 0.89), both with P-for-difference <0.05. Conclusions: Clusters of glycerolipids, glycerophospholipids, and sphingolipids may be implicated in the association between refined grain intake and GDM risk, as demonstrated by the significant associations of these metabolites with both refined grains and GDM risk and the incremental predictive value of these metabolites for GDM risk beyond the conventional risk factors. These findings provide evidence on the potential biological underpinnings linking refined grain intake to the risk of GDM and help identify novel disease-related dietary biomarkers to inform diet-related preventive strategies for GDM.