Supplementary Materials

The PDF file includes:

  • Materials and Methods
  • Fig. S1. Flowchart and participant selection criteria of the ANDIS discovery cohort for metformin response.
  • Fig. S2. Flowchart and participant selection criteria of the ANDIS replication cohort for metformin response.
  • Fig. S3. Flowchart and selection criteria of ANDiU and OPTIMED participants for investigation of glycemic response to metformin therapy: “The European replication cohort for metformin response.”
  • Fig. S4. Combined MRSs discriminate between glycemic responders and nonresponders to metformin in drug-naïve participants with T2D from the ANDIS discovery and the European replication cohorts.
  • Fig. S5. Combined MRSs discriminate between glycemic responders and nonresponders to metformin in drug-naïve participants with T2D from the ANDIS discovery and the ANDIS replication cohorts.
  • Fig. S6. ROC curves for response and intolerance to metformin incorporating different clinical baseline phenotypes in all subjects from discovery and replication cohorts for metformin response and intolerance.
  • Fig. S7. ROC curves for response to metformin incorporating additional clinical baseline phenotypes in ANDIS participants from the discovery and replication cohorts for metformin response combined.
  • Fig. S8. Combined MRSs discriminate between tolerant and intolerant participants to metformin in drug-naïve participants with T2D from the ANDIS discovery and the European replication cohorts.
  • Fig. S9. Combined MRSs discriminate between tolerant and intolerant participants to metformin in drug-naïve participants with T2D from the ANDIS discovery and the ANDIS replication cohorts.
  • Fig. S10. Correlations between DNA methylation in blood and DNA methylation in adipose tissue (n = 28) from the same participant (monozygotic twin cohort).
  • Fig. S11. In vitro methylation of the SAP130 promoter resulted in decreased transcriptional activity.
  • Table S1. Clinical characteristics of the full discovery and replication cohorts for metformin response including drug-naïve and newly diagnosed participants with T2D from the ANDIS cohort.
  • Table S2. Clinical characteristics of case-control discovery and replication cohorts including patients who fulfill the criteria of being glycemic responders and nonresponders to metformin therapy.
  • Table S3. CpG sites with a significant association (FDR < 5%) between DNA methylation in whole blood before taking metformin and the change in HbA1c after ~1.5 years on metformin in drug-naïve participants with T2D from the discovery cohort (n = 63) (Excel).
  • Table S4. Comparison of the 2577 significant CpG sites (FDR < 5%) with an association between DNA methylation and the ∆HbA1c after ~1.5 years in drug-naïve participants with T2D from the discovery cohort, with two other linear models (Excel).
  • Table S5. CpG sites with DNA methylation associated with the change in HbA1c (ΔHbA1c) in both the discovery cohort and in the ANDIS replication cohort for metformin response (Excel).
  • Table S6. CpG sites exhibiting differences in DNA methylation in whole blood between glycemic responders (n = 26) and nonresponders (n = 21) to metformin therapy in drug-naïve participants with T2D from the discovery cohort (Excel).
  • Table S7. Comparison of the 7916 significant CpG sites (FDR < 5%) between metformin responders and nonresponders in drug-naïve participants with T2D from the discovery cohort, with three other linear models (Excel).
  • Table S8. Methylated CpG sites associated with response to metformin in the discovery cohort and in the ANDIS replication cohort for metformin response (Excel).
  • Table S9. Methylated CpG sites associated with response to metformin in the discovery cohort and in the European replication cohort for metformin response (Excel).
  • Table S10. Methylated CpG sites associated with response to metformin in the discovery cohort and in both the ANDIS and the European replication cohorts for metformin response (Excel).
  • Table S11. Clinical characteristics of drug-naïve and newly diagnosed patients with T2D included in the metformin intolerance discovery and replication cohorts.
  • Table S12. CpG sites exhibiting differences in DNA methylation in whole blood between metformin-intolerant (n = 17) and metformin-tolerant (n = 66) drug-naïve participants with T2D from the discovery cohort (Excel).
  • Table S13. Comparison of the 9676 significant CpG sites (FDR < 5%) between metformin-tolerant and metformin-intolerant drug-naïve participants with T2D from the discovery cohort, with two other linear models (Excel).
  • Table S14. CpG sites with DNA methylation associated with intolerance to metformin in the discovery cohort and in the ANDIS replication cohort for metformin intolerance (Excel).
  • Table S15. CpG sites with DNA methylation associated with intolerance to metformin in the discovery cohort and in the European replication cohort for metformin intolerance (Excel).
  • Table S16. CpG sites with DNA methylation associated with intolerance to metformin in the discovery cohort and in both the ANDIS and the European replication cohorts for metformin intolerance (Excel).
  • Table S17. Assessing discrimination between glycemic responders and nonresponders to metformin using SNPs and MRSs associated with metformin response.
  • Table S18. Assessing discrimination between tolerant and intolerant participants to metformin using SNPs and MRSs associated with metformin intolerance.
  • Table S19. Clinical characteristics of all study participants in the monozygotic twin cohort (MZ).
  • Table S20. Available data from the monozygotic twin cohort used for cross-tissue methylation analysis in human tissues in the present study.
  • Table S21. Promoter sequence upstream of SAP130 inserted into the CpG-free firefly luciferase reporter vector (pCpGL-basic) and used for luciferase experiments.
  • Legends for data files S1 and S2
  • References (5970)

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