S. Chang,1 Y. Gong,1 C. W. McDonough,1 N. Nasiri Kenari,1 T. Langaee,1 A. L. Beitelshees,2 J. G. Gums,1 A. B. Chapman,3 S. T. Turner,4 J. A. Johnson,1 R. M. Cooper-DeHoff1; 1University of Florida, Gainesville, FL, 2University of Maryland, Baltimore, MD, 3Emory University, Atlanta, GA, 4Mayo Clinic, Rochester, MN
BACKGROUND: Lower MT levels and variations in the MT receptor gene are associated with glucose dysregulation. Atenolol treatment affects glucose and MT levels. This study investigated whether atenolol associated change in glucose level is mediated via alteration in MT levels, or the pharmacogenetic effects of MT candidate genes.
METHODS: This study included 232 hypertensive Whites from PEAR who received atenolol 100 mg monotherapy for 9 weeks. Urinary 6-sulfatoxymelatonin (aMT6s) is a main MT metabolite, and when normalized to urinary creatinine can be used as a surrogate for plasma MT levels. Urinary aMT6s was measured with ELISA before and after atenolol treatment. Genotype of polymorphisms in 18 MT candidate genes were determined on the Illumina 50K HumanCVD BeadChip. Linear regression of Δ glucose and Δ aMT6s was performed controlling for age, sex, BMI, and baseline levels of glucose and insulin in non-night workers. For pharmacogenetic association with Δ glucose, principal components for ancestry were added, and a p < 4.6 x 10-4 was deemed statistically significant.
RESULTS: After atenolol treatment, patients had increased glucose levels (median: +2.8 mg/dl, P= 0.0008) and decreased aMT6s levels (median: -2.8 ng/mg, P<0.0001), but the Δ aMT6s was not associated with the Δ glucose (p = 0.10). rs11649514, an intronic SNP in PRKCB, was associated with atenolol-related Δ glucose (p = 9.9 x 10-5) with each A allele associated with an average 4.8 mg/dl increase in glucose.
CONCLUSION: In White hypertensive patients treated with atenolol, decreased MT level was observed but was not associated with the post-atenolol glucose dysregulation. PRKCB, a gene involved in the MT-insulin regulatory pathway may play a role in mediating clinically meaningful atenolol-related hyperglycemia or diabetes.