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Published on: April 19, 2013
Common genetic variants near SLC2A2 and glycemic response to glimepiride in the GRADE comparative effectiveness
Josephine H Li1,2,3,4, Lukasz Szczerbinski2,3,4,5, Mark Tripputi6
1Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
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=4.83×10). Carriers had impaired β-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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