The causal associations of circulating amino acids with blood pressure: a Mendelian randomization study

Abstract

Background: Circulating levels of amino acids were associated with blood pressure (BP) in observational studies. However, the causation of such associations has been hypothesized but is difficult to prove in human studies. Here, we aimed to use two-sample Mendelian randomization analyses to evaluate the potential causal associations of circulating levels of amino acids with BP and risk of hypertension.

Methods: We generated genetic instruments for circulating levels of nine amino acids by conducting meta-analyses of genome-wide association study (GWAS) in UK Biobank participants with metabolomic data (n = 98,317) and another published metabolomics GWAS (n = 24,925). Data on the associations of the genetic variants with BP and hypertension were obtained in the UK Biobank participants without metabolomic data (n = 286,390). The causal effects were estimated using inverse-variance weighted method.

Results: Significant evidence consistently supported the causal effects of increased branched-chain amino acids (BCAAs, i.e., leucine, isoleucine, and valine) levels on higher BP and risk of hypertension (all P < 0.006 after Bonferroni correction except for P_{leucine-on-diastolicBP} = 0.008). For example, per standard deviation higher of genetically predicted isoleucine levels were associated with 2.71 ± 0.78 mmHg higher systolic BP and 1.24 ± 0.34 mmHg higher diastolic BP, as well as with 7% higher risk of hypertension (odds ratio: 1.07, [95% CI: 1.04-1.10]). In addition, per standard deviation higher of genetically predicted glycine level was associated with lower systolic BP (- 0.70 ± 0.17 mmHg, P = 4.04 × 10^-5) and a lower risk of hypertension (0.99 [0.98-0.99], P = 6.46 × 10^-5). In the reverse direction, genetically predicted higher systolic BP was associated with lower circulating levels of glycine (- 0.025±0.008, P = 0.001).

Conclusions: This study provides evidence for causal impacts of genetically predicted circulating BCAAs and glycine levels on BP. Meanwhile, genetically predicted higher BP was associated with lower glycine levels. Further investigations are warranted to clarify the underlying mechanisms.

Keywords: Amino acids; Blood pressure; Hypertension; Mendelian randomization; Metabolomics.

Fig. 1

Flowchart of the analytical populations. Genetic variants for circulating levels of amino acids were calculated from a meta-analysis of GWAS using post-QC UK Biobank samples with metabolomics data (n = 98,317) and a published GWAS by Kettunen et al. (n = 24,925). Corresponding genetic effect sizes for these SNPs on BP traits and hypertension were calculated from the rest part of the UK Biobank population (n = 286,390). Causal effects of circulating levels of amino acids on BP and hypertension were estimated using a two-sample Mendelian randomization approach

Fig. 2

The evaluated causal effects of circulating levels of amino acids (per 1-SD increase) on systolic blood pressure (SBP), diastolic blood pressure (DBP), and risk of hypertension. Causal estimates are obtained using the inverse variance weighted method. Results are presented as mmHg change for BP traits and odds ratio for hypertension per one SD increase in genetically predicted circulating amino acids level. Leu, leucine; Ile, isoleucine; Val, valine; Ala, alanine; Phe, phenylalanine; Tyr, tyrosine; His, histidine; Gln, glutamine; Gly, glycine; OR, odds ratio and CI, confidence interval

Fig. 3

The evaluated causal effects of circulating levels of glycine (per 1-SD increase) on systolic blood pressure (SBP), diastolic blood pressure (DBP), and risk of hypertension using different genetic instrumental variables. Each row represents the raw glycine-related IV, including CPS1 loci, and the IV excluding CPS1 loci, respectively. Causal effects are estimated using the inverse-variance weighted method. Gly, glycine; Gly_rmCPS1, glycine-IV removing CPS1 locus; OR, odds ratio and CI, confidence interval