Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease

Mateusz Dziedzic; Ewelina Józefczuk; Tomasz J Guzik; Mateusz Siedlinski

doi:10.1161/HYPERTENSIONAHA.123.22649

Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease

Hypertension. 2024 Apr 8. doi: 10.1161/HYPERTENSIONAHA.123.22649. Online ahead of print.

Authors

Mateusz Dziedzic¹, Ewelina Józefczuk¹, Tomasz J Guzik^{1

2

3}, Mateusz Siedlinski^{1

2

3}

Affiliations

¹ Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland. (M.D., E.J., T.J.G., M.S.).
² Center for Medical Genomics OMICRON, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland. (T.J.G., M.S.).
³ Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, United Kingdom (T.J.G., M.S.).

PMID: 38587181
DOI: 10.1161/HYPERTENSIONAHA.123.22649

Abstract

Background: Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension (HTN) and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease.

Methods: The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D.

Results: The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile, Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.1226 [95% CI, 1.160-1.1296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively).

Conclusions: The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Keywords: Mendelian randomization analysis; UK Biobank; amino acids, branched-chain; glycine; hypertension.