TY - JOUR
T1 - A Polygenic Score for Type 2 Diabetes Risk is Associated with Both the Acute and Sustained Response to Sulfonylureas
AU - Li, Josephine H.
AU - Szczerbinski, Lukasz
AU - Dawed, Adem Y.
AU - Kaur, Varinderpal
AU - Todd, Jennifer N.
AU - Pearson, Ewan R.
AU - Florez, Jose C.
N1 - Funding Information:
Funding. This work was conducted with support from National Institute of Diabetes and Digestive and Kidney Diseases awards R01 DK088214, R03 DK077675, and P30 DK036836, the Joslin Diabetes Center from its philanthropic donors, and the Harvard Catalyst: the Harvard University Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, 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 National Institute of Diabetes and Digestive and Kidney Diseases grant T32DK007028. E.R.P. holds a Wellcome Trust New Investigator Award (102820/Z/ 13/Z). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. J.H.L., L.S., V.K., and J.C.F. conceived and designed the experiments in SUGAR-MGH. J.H.L., A.Y.D., E.R.P., and J.C.F. conceived and designed the replication analyses in GoDARTS. V.K. and J.C.F. recruited participants in SUGAR-MGH. J.H.L., L.S., A.Y.D., and V.K. analyzed the data. All authors took part in interpreting the data. J.H.L. and J.C.F. prepared the manuscript. All authors read and edited the manuscript. J.C.F. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in poster form at the 79th Scientific Sessions of the American Diabetes Association, San Francisco, CA, 7–11 June 2019.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease pre-disposition 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, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and 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 hemoglobin A
1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside 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.
AB - There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease pre-disposition 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, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and 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 hemoglobin A
1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside 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.
UR - http://www.scopus.com/inward/record.url?scp=85099073092&partnerID=8YFLogxK
U2 - 10.2337/db20-0530
DO - 10.2337/db20-0530
M3 - Article
C2 - 33106254
SN - 0012-1797
VL - 70
SP - 293
EP - 300
JO - Diabetes
JF - Diabetes
IS - 1
ER -
