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OBJECTIVE: To assess whether increased genetic risk of type 2 diabetes (T2D) is associated with the development of hyperglycemia after glucocorticoid treatment.RESEARCH DESIGN AND METHODS: We performed a retrospective analysis of individuals with no diagnosis of diabetes who received a glucocorticoid dose of ≥10 mg prednisone. We analyzed the association between hyperglycemia and a T2D global extended polygenic score, which was constructed through a meta-analysis of two published genome-wide association studies.RESULTS: Of 546 individuals who received glucocorticoids, 210 developed hyperglycemia and 336 did not. T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (odds ratio 1.4 per SD of polygenic score; P = 0.038).CONCLUSIONS: Individuals with increased genetic risk of T2D have a higher risk of glucocorticoid-induced hyperglycemia. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment.