Novel plasma biomarker of atenolol-induced hyperglycemia identified through a metabolomics-genomics integrative approach

Abstract

Introduction While atenolol is an effective antihypertensive agent, its use is also associated with adverse events including hyperglycemia and incident diabetes that may offset the benefits of blood pressure lowering. By combining metabolomic and genomic data acquired from hypertensive individuals treated with atenolol, it may be possible to better understand the pathways that most impact the development of an adverse glycemic state. Objective To identify biomarkers that can help predict susceptibility to blood glucose excursions during exposure to atenolol. Methods Plasma samples acquired from 234 Caucasian participants treated with atenolol in the Pharmacogenomic Evaluation of Antihypertensive Responses trial were analyzed by gas chromatography Time-Of-Flight Mass Spectroscopy. Metabolomics and genomics data were integrated by first correlating participant’s metabolomic profiles to change in glucose after treatment with atenolol, and then incorporating genotype information from genes involved in metabolite pathways associated with glucose response. Results Our findings indicate that the baseline level of β-alanine was associated with glucose change after treatment with atenolol (Q = 0.007, β = 2.97 mg/dL). Analysis of genomic data revealed that carriers of the G allele for SNP rs2669429 in gene DPYS, which codes for dihydropyrimidinase, an enzyme involved in β-alanine formation, had significantly higher glucose levels after treatment with atenolol when compared with non-carriers (Q = 0.05, β = 2.76 mg/dL). This finding was replicated in participants who received atenolol as an add-on therapy (P = 0.04, β = 1.86 mg/dL). Conclusion These results suggest that β-alanine and rs2669429 may be predictors of atenolol-induced hyperglycemia in Caucasian individuals and further investigation is warranted.

Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics

“…Over the past decade, pharmacogenomics studies have identified several promising genetic signatures associated with variability in response to thiazide diuretics . Additionally, pharmacometabolomics has been successful in identifying novel pathways and biomarkers influencing patients’ variability in response to different drugs . Recently, using an untargeted metabolomics approach, we were able to identify several novel metabolites significantly associated with the BP response to HCTZ .…”

“…7,10,11 Additionally, pharmacometabolomics has been successful in identifying novel pathways and biomarkers influencing patients' variability in response to different drugs. [12][13][14] Recently, using an untargeted metabolomics approach, we were able to identify several novel metabolites significantly associated with the BP response to HCTZ. 15 Also, pharmacolipidomics represents a promising approach to identify novel biomarkers of drug response and yield mechanistic insights for several drugs.…”

Biomarkers of food intake and nutrient status are associated with glucose tolerance status and development of type 2 diabetes in older Swedish women

“…Recently we found that b-alanine was increased after beef intake compared with fish because of a high amount of b-alanine in beef mince compared with fish (17), suggesting that b-alanine may reflect beef intake. Other studies have linked b-alanine and carnosine (b-alanine conjugated with the amino acid histidine) with T2D, which may also explain this result (43)(44)(45).…”

Current Concepts in Pharmacometabolomics, Biomarker Discovery, and Precision Medicine

“…Pharmacometabolomics and pharmacogenomics were combined to discover that purine pathway enzymes and genes were involved in the variation of patients' response to aspirin [75]. The pharmacometabolomics and pharmacogenomics combined approach revealed that β-alanine and rs2669429 may be predictors of atenolol-induced hyperglycaemia [92]. The broad utility of the concept that pharmacometabolomics informs pharmacogenomics has been demonstrated in a series of related studies [78,[81][82][83][84][85][86].…”