Integrated gene-based and pathway analyses using UK Biobank data identify novel genes for chronic respiratory diseases

BackgroundChronic respiratory diseases have become a non-negligible cause of death globally. Although smoking and environmental exposures are primary risk factors for chronic respiratory diseases, genetic factors also play an important role in determining individual’s susceptibility to diseases. Here we performed integrated gene-based and pathway analyses to systematically illuminate the heritable characteristics of chronic respiratory diseases.MethodsUK (United Kingdom) Biobank is a very large, population-based prospective study with over 500,000 participants, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases. Utilizing the GWAS-summarized data downloaded from UK Biobank, we conducted gene-based analysis to obtain associations of susceptibility genes with asthma, chronic obstructive pulmonary disease (COPD) and pneumonia using FUSION and MAGMA software. Across the identified susceptibility regions, functional annotation integrating multiple functional data sources was performed to explore potential regulatory mechanisms with INQUISIT algorithm. To further detect the biological process involved in the development of chronic respiratory diseases, we undertook pathway enrichment analysis with the R package (clusterProfiler).ResultsA total of 195 susceptibility genes were identified significantly associated with chronic respiratory diseases (Pbonferroni < 0.05), and 24/195 located out of known susceptibility regions (e.g. WDPCP in 2p15). Within the identified susceptibility regions, functional annotation revealed an aggregation of credible variants in promoter-like and enhancer-like histone modification regions and such regulatory mechanisms were specific to lung tissues. Furthermore, 110 genes with INQUISIT score ≥1 may influence diseases susceptibility through exerting effects on coding sequences, proximal promoter and distal enhancer regulations. Pathway enrichment results showed that these genes were enriched in immune-related processes and nicotinic acetylcholine receptors pathways.ConclusionsThis study implemented an integrated gene-based and pathway strategy to explore the underlying biological mechanisms and our findings may serve as promising targets for future clinical treatments of chronic respiratory diseases

Association of healthy lifestyle with incident cardiovascular diseases among hypertensive and normotensive Chinese adults

Background: Whether lifestyle improvement benefits in reducing cardiovascular diseases (CVD) events extend to hypertensive patients and whether these benefits differ between hypertensive and normotensive individuals is unclear. This study aimed to investigate the associations of an overall healthy lifestyle with the subsequent development of CVD among participants with hypertension and normotension. Methods: Using data from the Suzhou subcohort of the China Kadoorie Biobank study of 51,929 participants, this study defined five healthy lifestyle factors as nonsmoking or quitting for reasons other than illness; nonexcessive alcohol intake; relatively higher physical activity level; a relatively healthy diet; and having a standard waist circumference and body mass index. We estimated the associations of these lifestyle factors with CVD, ischemic heart disease (IHD) and ischemic stroke (IS). Results: During a follow-up of 10.1 years, this study documented 6,151 CVD incidence events, 1,304 IHD incidence events, and 2,243 IS incidence events. Compared to those with 0–1 healthy lifestyle factors, HRs for those with 4–5 healthy factors were 0.71 (95% CI: 0.62, 0.81) for CVD, 0.56 (95% CI: 0.42, 0.75) for IHD, and 0.63 (95% CI: 0.51, 0.79) for IS among hypertensive participants. However, we did not observe this association among normotensive participants. Stratified analyses showed that the association between a healthy lifestyle and IHD risk was stronger among younger participants, and the association with IS risk was stronger among hypertensive individuals with lower household incomes. Conclusion: Adherence to a healthy lifestyle pattern is associated with a lower risk of cardiovascular diseases among hypertensive patients, but this benefit is not as pronounced among normotensive patients

Separation of matrine and oxymatrine from Sophora flavescens extract through cation exchange resin coupled with macroporous absorption resin

A simple method for separation of matrine and oxymatrine from Sophora flavescens was developed with cation exchange resin coupled with macroporous resin. Based on the adsorption characteristics of matrine and oxymatrine, 001×732 cation exchange resin was used to absorb target alkaloids for removing most of the foreign matter, while BS-65 macroporous resin was chosen to purify these alkaloids. The result showed that the equilibrium adsorption data of matrine and oxymatrine on 001×732 resin and BS-65 resin at 30°C was fitted to Langmuir isotherm and Freundlich isotherm, respectively. The contents of matrine and oxymatrine were increased from 0.73% and 2.2% in the crude extract of the root of Sophora flavescens to 67.2% and 66.8% in the final eluent products with the recoveries of 90.3% and 86.9%, respectively

Vitamin D status and chronic obstructive pulmonary disease risk: a prospective UK Biobank study

Background Low vitamin D status has been linked to an increased risk for various inflammatory diseases. Conflicting results have been reported regarding chronic obstructive pulmonary disease (COPD). This study aims to investigate the associations of serum 25-hydroxyvitamin D (25(OH)D) concentrations with COPD risk and survival.Methods We included 403 648 participants with serum 25(OH)D measurements and free of COPD at baseline from UK Biobank. Follow-up was until 30 September 2021. Multivariable-adjusted cox regression models were applied to estimate HRs and 95% CIs for the associations of season-standardised 25(OH)D concentrations with COPD risk and survival. The restricted cubic splines were used to assess dose–response relationship. Kaplan-Meier estimation was used to create graphs of the survival curves.Results During a median follow-up of 12.3 (IQR: 11.4–13.2) years, 11 008 cases of COPD were recorded. We observed a non-linear inverse association between 25(OH)D concentrations and COPD risk. Compared with participants in the fourth quintile of 25(OH)D, those in the lowest quintile were associated with a 23% higher risk (HR, 1.23; 95% CI, 1.16 to 1.31). Stronger associations were observed for the risk in men and current smokers (Both p for interaction <0.05). In survival analyses, compared with the fourth quintile, cases in the lowest quintile had a 38% higher risk for overall death (HR, 1.38; 95% CI, 1.22 to 1.56).Conclusion Our findings indicate that serum 25(OH)D concentrations are non-linearly negatively associated with incidence and mortality of COPD, suggesting a potential protective role of vitamin D in the pathogenesis of COPD

Associations of serum aminotransferase and the risk of all-cause and cause-specific mortality in Chinese type 2 diabetes: a community-based cohort study

Objective Investigating the associations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with all-cause, cardiovascular disease (CVD) and cancer mortality in a large cohort of community-dwelling patients with type 2 diabetes mellitus (T2DM).Design Community-based prospective cohort study conducted between 2013 and 2014.Setting 44 selected townships in Changshu and Huai’an City, Jiangsu province, China.Participants 20340 participants with T2DM were recruited in Jiangsu province, China.Methods We use Cox proportional hazard models to estimate the HR and 95% CIs of associations of serum ALT and AST levels with all-cause and cause-specific mortality. Restricted cubic splines were used to explore the dose-response relationships between ALT and AST levels with mortality.Results ALT and AST levels were inversely associated with CVD mortality, compared with the lowest quintile (Q1), the multivariable HRs of the highest quintile (Q5) was 0.82 (95% CI: 0.66 to 1.01, p for trend=0.022) and 0.78 (95% CI: 0.63 to 0.96, p for trend=0.022), respectively. Furthermore, the HRs for ALT levels in all-cause mortality were 0.90 (95% CI: 0.79 to 1.01, p for trend=0.018), and the HRs for AST levels in cancer mortality were 1.29 (95% CI: 1.02 to 1.63, p for trend=0.023). Stronger inverse effects of ALT and AST levels on all-cause mortality were observed in the older subgroup and in those with dyslipidaemia (all p for interaction <0.05). Further analysis based on gender showed that the associations between serum aminotransferases and the mortality risk were more significant in women and substantially attenuated in men.Conclusion Our findings suggested patients with T2DM with lower levels of ALT and AST had an increased risk of CVD mortality, which needs confirmation in future clinical trials