Common genetic variants near SLC2A2 and glycemic response to glimepiride in the GRADE comparative effectiveness clinical trial
Li, J. H.; Szczerbinski, L.; Tripputi, M.; Liu, H.; Nam, S.; Mujica, E.; Emmanouilidou, A.; Wangden, T. Y.; Citko-Rojewska, A.; Konopka, P.; Czajkowski, M.; Huerta-Chagoya, A.; Vora, M.; Leong, A.; Meigs, J. B.; Ng, M. Y.; Loos, R. J. F.; Pigeyre, M.; Gerstein, H. C.; Moura, F. A.; Lai, Y.-P.; Bhatt, D. L.; Marston, N. A.; Ruff, C. T.; Sabatine, M. S.; Dawed, A. Y.; Pearson, E. R.; Satin, L. S.; den Hoed, M.; Kretowski, A.; Kahn, S. E.; Younes, N.; Mercader, J. M.; Florez, J. C.; GRADE Research Group,
Show abstract
Optimizing second-line therapy for type 2 diabetes is challenging due to interindividual variability in response. We conducted a pharmacogenomic genome-wide association study (GWAS) in the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness (GRADE) Study to identify genetic predictors of glycemic response to insulin glargine, glimepiride, liraglutide, and sitagliptin, when added to metformin in a diverse population. We identified 21 genome-wide significant loci associated with treatment response. rs1905505, a non-coding variant near SLC2A2, the gene encoding the glucose transporter GLUT2, was enriched in Africans/African Americans and conferred a 36% increased risk of treatment failure on glimepiride (p=4.83x10). Carriers had impaired {beta}-cell function, evidenced by a lower C-peptide index during OGTT, and diminished glucose-lowering response to an acute sulfonylurea challenge. Genetic manipulation in zebrafish confirmed that slc2a2 disruption attenuates the glucose-lowering effect of glimepiride. In conclusion, genetic variation influences glycemic response to medications, with SLC2A2 emerging as a key determinant of sulfonylurea response. Clinical Trial registration number: NCT01794143
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