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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]

Background: The associations between visceral adipose tissue (VAT) and bone mineral density (BMD) or fracture have been controversial and the causality of the associations remains to be assessed. This study aimed to explore the associations of VAT^ (predicted value of VAT mass) with BMD and fracture risk in men and women, and to examine their potential causation by two-sample Mendelian randomization (MR) analyses. Methods: UK Biobank is a large, population-based prospective cohort study that recruited more than 500,000 participants aged 40–69 in the United Kingdom from 2006 to 2010. In this study, we used a validated and reliable prediction model to estimate the VAT amount of the participants. On this basis, linear and nonlinear multivariable statistical models were used to explore the association of VAT^ with BMD and fracture risk in different groups of sex and BMI. In observational analyses, the multivariable linear regression model and Cox proportional-hazards model were used to assess VAT^ association with BMD and fracture risk, respectively. Inverse variance weighting was used as the main result of MR analysis. Results: In 190,836 men, an inverted U-shaped association was observed between VAT^ and heel BMD (P for nonlinearity < 0.001), with a turning point of VAT^ = 1.25 kg. Per kg increase in VAT^ was associated with a 0.13 standard deviation (SD) increase in heel BMD (P = 1.5 × 10−16) among men with lower amounts of VAT^, and associated with a 0.05 SD decrease in heel BMD (P = 1.3 × 10−15) among men with higher amounts of VAT^. In 193,592 women, per kg increase in VAT^ was monotonically associated with a 0.16 SD increase in heel BMD (P = 1.2 × 10−136, P for VAT^-sex interaction = 8.4 × 10−51). During a median follow-up of 8.2 years, VAT^ was associated with lower risks of hip fractures in the overall men and women (P for VAT^-sex interaction = 1.9 × 10−4 for total fractures; 1.5 × 10−4 for other fractures). There were significant interactions of VAT^ and BMI on heel BMD and fracture risks in men only (P for VAT^-BMI interaction = 5.9 × 10−31 for heel BMD; 2.7 × 10−4 for total fractures; 5.7 × 10−3 for hip fractures; 6.8 × 10−3 for other fractures). In two-sample MR analyses, evidence of causality was not observed between VAT^ and DXA-derived BMD or fractures. Conclusions: These novel findings demonstrated gender-dependent associations of VAT^ with BMD and fracture risk, with the association in men being modified by adiposity. Evidence of causality was not observed, suggesting that the observational association of VAT^ with BMD and fracture risk could be the result of confounding. [ABSTRACT FROM AUTHOR]

Background: COVID-19 is an infectious disease characterized by multiple respiratory and extrapulmonary manifestations, including gastrointestinal symptoms. Although recent studies have linked gut microbiota to infectious diseases such as influenza, little is known about the role of the gut microbiota in COVID-19 pathophysiology.Methods: To better understand the host-gut microbiota interactions in COVID-19, we characterized the gut microbial community and gut barrier function using metagenomic and metaproteomic approaches in 63 COVID-19 patients and 8 non-infected controls. Both immunohematological parameters and transcriptional profiles were measured to reflect the immune response in COVID-19 patients.Results: Altered gut microbial composition was observed in COVID-19 patients, which was characterized by decreased commensal species and increased opportunistic pathogenic species. Severe illness was associated with higher abundance of four microbial species (i.e., Burkholderia contaminans, Bacteroides nordii, Bifidobacterium longum, and Blautia sp. CAG 257), six microbial pathways (e.g., glycolysis and fermentation), and 10 virulence genes. These severity-related microbial features were further associated with host immune response. For example, the abundance of Bu. contaminans was associated with higher levels of inflammation biomarkers and lower levels of immune cells. Furthermore, human-origin proteins identified from both blood and fecal samples suggested gut barrier dysfunction in COVID-19 patients. The circulating levels of lipopolysaccharide-binding protein increased in patients with severe illness and were associated with circulating inflammation biomarkers and immune cells. Besides, proteins of disease-related bacteria (e.g., B. longum) were detectable in blood samples from patients.Conclusions: Our results suggest that the dysbiosis of the gut microbiome and the dysfunction of the gut barrier might play a role in the pathophysiology of COVID-19 by affecting host immune homeostasis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate associations of oily and nonoily fish consumption and fish oil supplements with incident type 2 diabetes (T2D).Research Design and Methods: We included 392,287 middle-aged and older participants (55.0% women) in the UK Biobank who were free of diabetes, major cardiovascular disease, and cancer and had information on habitual intake of major food groups and use of fish oil supplements at baseline (2006-2010). Of these, 163,706 participated in one to five rounds of 24-h dietary recalls during 2009-2012.Results: During a median 10.1 years of follow-up, 7,262 incident cases of T2D were identified. Compared with participants who reported never consumption of oily fish, the multivariable-adjusted hazard ratios of T2D were 0.84 (95% CI 0.78-0.91), 0.78 (0.72-0.85), and 0.78 (0.71-0.86) for those who reported <1 serving/week, weekly, and ≥2 servings/week of oily fish consumption, respectively (P-trend < 0.001). Consumption of nonoily fish was not associated with risk of T2D (P-trend = 0.45). Participants who reported regular fish oil use at baseline had a 9% (95% CI 4-14%) lower risk of T2D compared with nonusers. Baseline regular users of fish oil who also reported fish oil use during at least one of the 24-h dietary recalls had an 18% (8-27%) lower risk of T2D compared with constant nonusers.Conclusions: Our findings suggest that consumption of oily fish but not nonoily fish was associated with a lower risk of T2D. Use of fish oil supplements, especially constant use over time, was also associated with a lower risk of T2D. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence shows that circulating levels of trimethylamine N-oxide, which is generated from the metabolism of dietary choline, may predict cardiovascular disease among Caucasians. Acute coronary syndrome (ACS), one common presentation of cardiovascular disease, is a spectrum of signs and symptoms due to acute decreased blood flow in the coronary arteries. The relationship between the metabolites from choline pathway and ACS remains unclear. We aimed to assess the associations of circulating metabolites from the choline pathway with ACS among a Chinese population, who consume a different dietary pattern than their Western counterparts. Methods: We recruited 501 participants who were admitted to the Department of Cardiology, Zhongshan Hospital,Shanghai China between March 2017 and June 2018, including 254 ACS cases and 247 controls. Liquid chromatography-tandem mass spectrometry was used to measure circulating concentrations of metabolites in the choline pathway, including betaine, choline, trimethylamine, and trimethylamine N-oxide. A composite metabolite score using a weighted sum of these four metabolites, and the betaine/choline ratio were calculated. Multivariable logistic regressions were applied to estimate the association of metabolites with ACS, with adjustment of age, sex, body mass index, smoking index, history of diseases, and kidney function. Results: After adjusting for traditional risk factors, per 1-standard deviation (SD) increment in choline was positively associated with the odds of ACS [odds ratio (OR), 95% confidence interval (CI), 1.77(1.44–2.18)], and the other metabolites were not associated with ACS at a statistical significance level. Compared with participants in the lowest quartile of the metabolite score, those in the highest quartile had higher odds of ACS [OR (95% CI), 3.18(1.85–5.54), p < 0.001 for trend]. Per 1-SD increment in metabolite score was positively associated with higher odds of ACS [OR (95% CI), 1.80 (1.37–2.40)], and per 1-SD increment in the betaine/choline ratio was inversely associated with the odds of ACS [OR (95% CI), 0.49 (0.39–0.60)]. Conclusions: Among our Chinese participants, trimethylamine N-oxide was not associated with ACS, while a composite metabolite score of metabolites from the choline pathway was associated with increased odds of ACS. The choline pathway metabolites may be related to the pathophysiology of ACS among Chinese. [ABSTRACT FROM AUTHOR]