Abstract P157: Genetically Determine Gut Microbiome Abundance, Obese, and Incident Type 2 Diabetes

Introduction: Gut microbiota has been linked to the body’s adiposity and the development of type 2 diabetes (T2D). A recent genome-wide association study identified that genetic variants at the ABO locus (SNPs rs8176645 and rs550057) were associated with the abundance of gut microbiome (i.e., Bifidobacterium bifidum and Collinsella aerofaciens, respectively). Hypothesis: We assessed the hypothesis that the genetically determined gut microbiome abundance was associated with incident T2D, and such association could be modified by obese status. Methods: A total of 339,465 European ancestry participants who are initially free of T2D at baseline and have available information on genetic variants from the UK Biobank population were included in this study. The genetic risk score (GRS) was constructed by the risk alleles of the two genetic variants at the ABO locus. Cox proportional hazard models were used to estimate the associations between the genetic variants/GRS and incident T2D. Results: During a median of 11.8 years of follow-up, 11,566 incident T2D were documented. We observed that the gut microbiome-related variants rs8176645 and rs550057 were both significantly associated with incident T2D after adjustment for sex, age, body mass index (BMI), Townsend deprivation index, smoking, drinking, regular physical activity, and diet score at baseline (hazard ratio [HR] per copy of risk allele A of rs8176645 1.05, 95% CI [1.02-1.09], P -value=0.001; HR per copy of risk allele T of rs550057 1.06, 95% CI [1.03-1.09], P -value<0.001; respectively). The GRS also showed a significant association with T2D incidence in the fully adjusted model (HR=1.03, 95% CI [1.01-1.05], P -value<0.001). In addition, we found that BMI significantly modified the associations between GRS and T2D, which were more pronounced in non-obese participants ( P -interaction=0.008). Conclusion: Our findings indicate that the genetically determined gut microbiome abundance significantly predicts T2D risk, independent of traditional risk factors.