Li_Supplemental_Material_R1_clean.pdf (261.81 kB)
Download fileA polygenic score for type 2 diabetes risk is associated with both the acute and sustained response to sulfonylureas
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posted on 2020-10-26, 17:09 authored by Ada AdminAda Admin, Josephine H. Li, Lukasz Szczerbinski, Adem Y. Dawed, Varinderpal Kaur, Jennifer N. Todd, Ewan R. Pearson, Jose C. FlorezThere 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.