Coffee Types and Type 2 Diabetes Mellitus: Large-Scale Cross-Phenotype Association Study and Mendelian Randomization Analysis.

Purpose: To explore whether coffee intake is associated with the risk of type 2 diabetes mellitus (T2DM) from a genetic perspective, and whether this association remains the same among different types of coffee consumers. Methods: We utilized the summary-level results of 12 genome-wide association studies. First, we used linkage disequilibrium score regression and cross-phenotype association analysis to estimate the genetic correlation and identify shared genes between coffee intake and T2DM in addition to some other T2DM-related phenotypes. Second, we used Mendelian randomization (MR) analysis to test whether there is a significant genetically predicted causal association between coffee intake and the risk of T2DM or other T2DM-related phenotypes. For all the analyses above, we also conducted a separate analysis for different types of coffee consumers, in addition to total coffee intake. Results: Genetically, choice for ground coffee was significantly negatively associated with the risk of T2DM and some other related risks. While coffee intake and choice for decaffeinated/instant coffee had significant positive correlation with these risks. Between these genetically related phenotypes, there were 1571 genomic shared regions, of which 134 loci were novel. Enrichment analysis showed that these shared genes were significantly enriched in antigen processing related biological processes. MR analysis indicated that higher genetically proxied choice for ground coffee can reduce the risk of T2DM (T2DM: b: -0.2, p-value: 4.70×10-10; T2DM adjusted for body mass index (BMI): b: -0.11, p-value: 4.60×10-5), and BMI (b: -0.08, p-value: 6.50×10-5). Conclusions: Compared with other types of coffee, ground coffee has a significant negative genetic and genetically predicated causal relationship with the risk of T2DM. And this association is likely to be mediated by immunity. The effect of different coffee types on T2DM is not equal, researchers on coffee should pay more attention to distinguishing between coffee types.