Search

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 Pleucine-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. [ABSTRACT FROM AUTHOR]

Summary: Background: The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile. Aims: To investigate the effects of the NAFLD risk alleles on the all‐cause and cause‐specific mortality in 5581 Chinese adults. Methods: The genome‐wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data. Results: Genome‐wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 C>G variant (P = 8.6 × 10−7). Further analyses validated the associations of TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants with NAFLD. During 29 425.1 person‐years of follow‐up, the overall mortality was 816 per 100 000 person‐years, where 299 deaths were attributable to cardiovascular disease and 85 to liver disease. The PNPLA3 rs738409 C>G variant was independently associated with increased liver‐specific mortality (P for trend = 0.034) but reduced cardiovascular mortality (P for trend = 0.047). A composite genetic‐predisposition score of PNPLA3, TM6SF2, and MBOAT7 risk alleles presented similar opposite effects on liver‐specific and cardiovascular mortality. Moreover, interactions of the NAFLD risk alleles with adiposity for liver‐specific mortality were found (Pinteraction < 0.05). The reduced serum VLDL1 concentration was responsible for the increased liver‐specific mortality related to NAFLD risk alleles. Conclusion: The PNPLA3 rs738409 C>G variant and its combination with TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants increase liver‐specific mortality but reduce cardiovascular mortality in overweight/obese Chinese. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Xia et al papers. To view these articles, visit https://doi.org/10.1111/apt.16772 and https://doi.org/10.1111/apt.16818 [ABSTRACT FROM AUTHOR]