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A polygenic score for type 2 diabetes risk is associated with both the acute and sustained response to sulfonylureas

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posted on 26.10.2020, 17:09 by Ada Admin, Josephine H. Li, Lukasz Szczerbinski, Adem Y. Dawed, Varinderpal Kaur, Jennifer N. Todd, Ewan R. Pearson, Jose C. Florez
There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to anti-diabetes medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose (FG), and fasting insulin (FI), comprised of 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic endpoints, adjusting for age, sex, race, and body mass index (BMI). A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year HbA1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research, Tayside and Scotland (GoDARTS) study (p=0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.


This work was conducted with support from National Institutes of Health/NIDDK awards R01 DK088214, R03 DK077675, and P30 DK036836; from the Joslin Clinical Research Center from its philanthropic donors; and the Harvard Catalyst: The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Awards M01-RR-01066, 1 UL1 RR025758-04 and 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). J.H.L. received individual support from NIH T32DK007028. E.R.P. holds a Wellcome Trust New Investigator Award (102820/Z/13/Z).