Background: Gut microbiota has been implicated in the development of type 2 diabetes (T2D) . A recent genome-metagenome-wide study identified that genetic variants at the ABO locus (SNPs rs3758348, rs8176632, rs602662, and rs601338) were associated with the abundance of the gut microbiome. This study aimed to investigate whether the gut microbiota-related genetic variants at the ABO locus were associated with T2D and blood metabolome. We also analyzed the associations of the gut microbiota-related Metabolomic Risk Score (MRS) with incident T2D.

Methods: A total of 456,274 participants who are free of T2D at baseline and have available data on genetic variants from the UK Biobank population were included in this study. Plasma metabolome was profiled by a high-throughput NMR-based metabolic biomarker profiling platform among 109,0 participants. The MRS score was constructed with genetic variant-associated metabolites.

Results: We observed that the gut microbiota-related variant rs3758348 was significantly associated with T2D in the fully adjusted model (hazard ratio [HR] per copy of the C allele 1.06; [95% CI, 1.02-1.10]; P=0.0012 for trend) . We found that a total of 91 metabolites were significantly associated with rs3758348 (false discovery rate < 0.05) . Using elastic net regularized regressions, we generated a weighted MRS applying the 91 metabolites to predict the incidence risk of T2D. In multivariable Cox regressions, the weighted MRS showed a significant association with T2D incidence after adjusting for age, sex, BMI, alcohol status, smoking status, physical activity, and diet quality score (HR=1.49 [95% CI, 1.41-1.59], P<0.0001) .

Conclusion: Our study indicates that the gut microbiota-related genetic variant and metabolomic profile significantly predict T2D risk, independent of traditional risk factors.


R.Tang: None. X.Wang: None. H.Ma: None. X.Li: None. Y.Heianza: None. L.Qi: None.


National Heart, Lung, and Blood Institute (HL071981, HL034594, HL126024) , the National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383) , the Fogarty International Center (TW010790) , and Tulane Research Centers of Excellence Awards.

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