Air pollutants, genetic susceptibility, and incident schizophrenia in later life: A prospective study in the UK Biobank.

OBJECTIVE: Air pollution has been linked to multiple psychiatric disorders, but little is known on its long-term association with schizophrenia. The interaction between air pollution and genetic susceptibility on incident schizophrenia has never been reported. We aimed to explore the associations between long-term air pollution exposure and late-onset schizophrenia and evaluate whether genetic susceptibility could modify the association. METHODS: This population-based prospective cohort study included 437,802 middle-aged and elderly individuals free of schizophrenia at baseline in the UK Biobank. Land use regression models were applied in the estimation of the annual average concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), fine particulate matter (PM2.5), and inhalable particulate matter (PM10) at residence. The associations between air pollutants and schizophrenia were evaluated by using Cox proportional hazard models. A polygenic risk score of schizophrenia was constructed for exploring potential interaction of air pollutants with genetic susceptibility. RESULTS: An interquartile range increase in PM2.5, PM10, NO2, and NOx was associated with the hazard ratios (HR) for incident schizophrenia at 1.19, 1.16, 1.22, and 1.09, respectively. The exposure-response curves for the association of air pollution with incident schizophrenia were approximately linear. There are additive interactions of air pollution score (APS), PM10, NO2, and NOx with genetic risk. Specifically, compared with participants with low genetic susceptibility and low APS, the HR was 3.23 for individuals with high genetic risk and high APS, among which 0.49 excess risk could be attributed to the additive interaction, accounting for 15 % of the schizophrenia risk. CONCLUSION: This large-scale, prospective cohort study conveys the first-hand evidence that long-term air pollution exposure could elevate schizophrenia incidence in later life, especially for individuals with higher genetic risks. The findings highlight the importance of improving air quality for preventing the late-onset schizophrenia in an aging era, especially among those with high genetic risks.

Air Pollution and Cardiac Arrest: A More Significant Intermediate Role of COPD than Cardiac Events.

No prior studies have linked long-term air pollution exposure to incident sudden cardiac arrest (SCA) or its possible development trajectories. We aimed to investigate the association between long-term exposure to air pollution and SCA, as well as possible intermediate diseases. Based on the UK Biobank cohort, Cox proportional hazard model was applied to explore associations between air pollutants and SCA. Chronic obstructive pulmonary disease (COPD) and major adverse cardiovascular events (MACE) were selected as intermediate conditions, and multistate model was fitted for trajectory analysis. During a median follow-up of 13.7 years, 2884 participants developed SCA among 458 237 individuals. The hazard ratios (HRs) for SCA were 1.04-1.12 per interquartile range increment in concentrations of fine particulate matter, inhalable particulate matter, nitrogen dioxide, and nitrogen oxides. Most prominently, air pollutants could induce SCA through promoting transitions from baseline health to COPD (HRs: 1.06-1.24) and then to SCA (HRs: 1.16-1.27). Less importantly, SCA could be developed through transitions from baseline health to MACE (HRs: 1.02-1.07) and further to SCA (HRs: 1.12-1.16). This study provides novel and compelling evidence that long-term exposure to air pollution could promote the development of SCA, with COPD serving as a more important intermediate condition than MACE.

Long-term exposure to ambient air pollution and incident gout: A prospective cohort study in the UK Biobank.

Gout is a chronic disorder characterized by the accumulation of uric acid in the body, leading to recurrent episodes of joint inflammation and pain. There remains a lack of studies investigating the association between long-term exposure to ambient air pollution and the incidence of gout. We conducted this prospective cohort study involving participants aged 38-70 from the UK Biobank who were enrolled in 2006-2010 and followed until 2023. Baseline residential concentrations of fine particulate matter (PM2.5), inhalable particulate matter (PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOx) were predicted using land-use regression models. Cox proportional hazards models were employed to examine the relationship between air pollution and incident gout events. A total of 443,587 individuals were included in the analyses and a total of 6589 incident gout cases were identified over a follow-up of 6,130,439 person-years. There were significant associations between higher levels of air pollution and an increased incidence risk of gout. Higher risk of incident gout was associated with each interquartile range increase in concentrations of PM2.5 (hazard ratio:1.05, 95% confidence intervals: 1.02-1.09), PM10 (1.04, 1.00-1.07), NO2 (1.08, 1.05-1.12) and NOx (1.04, 1.02-1.07). The magnitude of associations was larger at higher concentrations. The association was more prominent among older adults, smokers, and individuals with lower and moderate physical activity. This prospective cohort study provides novel and compelling evidence of increased risk of incident gout associated with long-term air pollution exposures.

Associations between fine particulate air pollution with small-airway inflammation: A nationwide analysis in 122 Chinese cities.

Alveolar nitric oxide is a non-invasive indicator of small-airway inflammation, a key pathophysiologic mechanism underlying lower respiratory diseases. However, no epidemiological studies have investigated the impact of fine particulate matter (PM2.5) exposure on the concentration of alveolar nitric oxide (CANO). To explore the associations between PM2.5 exposure in multiple periods and CANO, we conducted a nationwide cross-sectional study in 122 Chinese cities between 2019 and 2021. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched long-term, mid-term, and short-term PM2.5 exposure for 28,399 individuals based on their home addresses. Multivariable linear regression models were applied to estimate the associations between PM2.5 at multiple exposure windows and CANO. Stratified analyses were also performed to identify potentially vulnerable subgroups. We found that per interquartile range (IQR) unit higher in 1-year average, 1-month average, and 7-day average PM2.5 concentration was significantly associated with increments of 17.78% [95% confidence interval (95%CI): 12.54%, 23.26%], 8.76% (95%CI: 7.35%, 10.19%), and 4.00% (95%CI: 2.81%, 5.20%) increment in CANO, respectively. The exposure-response relationship curves consistently increased with the slope becoming statistically significant beyond 20 µg/m3. Males, children, smokers, individuals with respiratory symptoms or using inhaled corticosteroids, and those living in Southern China were more vulnerable to PM2.5 exposure. In conclusion, our study provided novel evidence that PM2.5 exposure in long-term, mid-term, and short-term periods could significantly elevate small-airway inflammation represented by CANO. Our results highlight the significance of CANO measurement as a non-invasive tool for early screening in the management of PM2.5-related inflammatory respiratory diseases.

Association of long-term ozone air pollution and age-related macular degeneration in older Chinese population.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of legal blindness. It remains unclear whether and to what extent the ambient ozone pollution could increase the risk of AMD. METHODS: A nationwide cross-sectional survey was conducted in 129 major cities in 27 of 31 provincial regions across China from 2018 to 2021. Data in relation to demographics, residential address, and medical histories were collected. The exposure-response relationship between ozone exposure and AMD was explored using the restricted cubic splines. A piecewise logistic regression model was used to examine the magnitudes of the association, after adjusting demographic, social-economic and co-pollutants. Residential ozone exposures were estimated using a satellite-based model. RESULTS: A total of 624,167 middle-aged and older participants were included in the final analyses, the overall prevalence of AMD was 16.76 %. The risk of AMD was consistently increasing with higher warm-season ozone concentration, and the risk became much larger after the cut-off of 110 µg/m3 (approximately 50 ppb). Every 10 µg/m3 increment in warm-season ozone concentration, the adjusted odds ratio (OR) for AMD were 1.15 (1.13, 1.16) and 1.66 (1.63, 1.69) when the warm-season ozone concentration was below or above 110 µg/m3, respectively. CONCLUSION: This large-scale nationwide study provides the first epidemiological evidence demonstrating significant associations between long-term residential ozone exposure and AMD prevalence. Based on our findings, in conjunction with WHO global air quality guidelines, we suggest that a warm-season ozone of 110 µg/m3 should be adopted for middle-aged and older populations to reduce the risk of AMD. Ongoing efforts to reduce ozone exposure in communities through improved air quality regulations and public education are essential for the improvement of public health.

Criteria air pollutants and diabetes mortality classified by different subtypes and complications: A nationwide, case-crossover study.

The associations between air pollution and diabetes mortality of different subtypes and complications were largely unclear. We performed an individual-level, time-stratified case-crossover study among over 0.9 million diabetes deaths from all administrative regions of Chinese mainland during 2013-2019. Daily concentrations of fine particles (PM2.5), coarse particles (PM2.5-10), nitrogen dioxide (NO2) and ozone (O3) were obtained for each decedent using high-resolution prediction models. Conditional logistic regression models were utilized to analyze the data. Each interquartile range increment in PM2.5, PM2.5-10, NO2 and O3 concentrations on lag 0-2 d increased the risks of overall diabetes mortality by 2.81 %, 1.92 %, 3.96 % and 2.15 %, respectively. Type 2 diabetes had stronger associations with air pollution than type 1 diabetes. Air pollutants were associated with diabetic ketoacidosis and diabetic nephropathy, but not other complications. The exposure-response curves were approximately linear with a plateau at higher concentrations of PM2.5, PM2.5-10, and NO2, while the associations for O3 appear to be statistically significant beyond 60 µg/m3. This nationwide study reinforces the evidence of higher risks of acute diabetic events following short-term air pollution exposure. We identified differential effects of air pollutants on various subtypes and complications of diabetes, which require further mechanistic investigations.

Association of Fine Particulate Matter and Its Components with Macrosomia: A Nationwide Birth Cohort Study of 336 Chinese Cities.

To examine the associations between macrosomia risk and exposure to fine particulate matter (PM2.5) and its chemical components during pregnancy, we collected birth records between 2010 and 2015 in mainland China from the National Free Preconception Health Examination Project and used satellite-based models to estimate concentrations of PM2.5 mass and five main components, namely, black carbon (BC), organic carbon (OC), nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+). Associations between macrosomia risk and prenatal exposure to PM2.5 were examined by logistic regression analysis, and the sensitive subgroups were explored by stratified analyses. Of the 3,248,263 singleton newborns from 336 cities, 165,119 (5.1%) had macrosomia. Each interquartile range increase in concentration of PM2.5 during the entire pregnancy was associated with increased risk of macrosomia (odds ratio (OR) = 1.18; 95% confidence interval (CI), 1.17-1.20). Among specific components, the largest effect estimates were found on NO3- (OR = 1.36; 95% CI, 1.35-1.38) followed by OC (OR = 1.23; 95% CI, 1.22-1.24), NH4+ (OR = 1.22; 95% CI, 1.21-1.23), and BC (OR = 1.21; 95% CI, 1.20-1.22). We also that found boys, women with a normal or lower prepregnancy body mass index, and women with irregular or no folic acid supplementation experienced higher risk of macrosomia associated with PM2.5 exposure.

Impacts of physical activity and particulate air pollution on the onset, progression and mortality for the comorbidity of type 2 diabetes and mood disorders.

OBJECTIVE: The co-occurrence of type 2 diabetes (T2D) and mood disorders (depression or anxiety) is an exceedingly common comorbidity with poor prognosis. We aimed to explore the effects of physical activity (PA), fine particulate matter (PM2.5) air pollution or their interactions on the initiation, progression and subsequent mortality of this comorbidity. METHODS: The prospective analysis was based on 336,545 participants in UK Biobank. Multi-state models were applied to capture potential impacts in all transition phases simultaneously along the natural history of the comorbidity. RESULTS: PA [walking (4th vs 1st quantile), moderate (4th vs 1st quantile) and vigorous activities (yes vs no)] protected against incident T2D and comorbid mood disorders afterwards, incident mood disorders, and all-cause mortality from baseline health and T2D, with the risk reductions ranging from 9 % to 23 %. Moderate and vigorous activities further prevented T2D development or mortality among depressive/anxious population. PM2.5 was associated with higher risks of developing incident mood disorders [Hazard ratio (HR) per interquartile range increase = 1.03], as well as of developing incident T2D (HR = 1.04) and further transition to comorbid mood disorders (HR = 1.10). The impacts of PA and PM2.5 were stronger during transitions to comorbidities than the occurrence of first diseases. The benefits of PA remained across all PM2.5 levels. CONCLUSIONS: Physical inactivity and PM2.5 could accelerate the initiation and progression of the comorbidity of T2D and mood disorders. PA and reducing pollution exposure may be included in health promotion strategies to decrease the comorbidity burden.

Residential greenness exposure and decreased prevalence of diabetic retinopathy: A nationwide analysis in China.

OBJECTIVE: Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness among diabetics. We aimed to explore whether long-term exposure to residential greenness was beneficial to DR. RESEARCH DESIGN AND METHODS: We used data from a large-scale, cross-sectional screening survey conducted in 129 cities of 27 provincial regions of China from 2018 to 2021 among patients with diabetes. We measured residential greenness exposure as the 3-year average of annual maximum Normalized Difference Vegetation Index (NDVI) at a spatial resolution of 250 m. DR was assessed by ophthalmologists based on fundus photographs. The primary outcome was DR, and secondary outcome included DR severity status (i.e., nonproliferative and proliferative), hallmarks of retinal lesions and macular oedema. RESULTS: A total of 484,380 adult participants with diabetes were included in the current analysis, and 15.7% of them were diagnosed with DR. NDVI was inversely and linearly associated with DR prevalence, and an increment of 0.1 NDVI was associated with a 10% (9%-10%) decrease in DR prevalence. Significant and inverse associations were further found for nonproliferative and proliferative DR, hallmarks of lesions and macular oedema. The association between greenness and DR was stronger among participants who were older, obese, lived in the south, had longer duration of diabetes or did not take antidiabetic medications. CONCLUSIONS: This large-scale nationwide study provides the first-hand epidemiological evidence on the associations of residential greenness with DR. Our findings highlight the importance of residential greenness in alleviating DR risk especially in an era of aging and urbanization.

Fine particulate matter and cardiorespiratory health in China: A systematic review and meta-analysis of epidemiological studies.

This review aimed to systematically summarize the epidemiological literature on the cardiorespiratory effects of PM2.5 published during the 13th Five-Year Plan period (2016-2020) in China. Original articles published between January 1, 2016 and June 30, 2021 were searched in PubMed, Web of Science, the China National Knowledge Internet Database and Wanfang Database. Random- or fixed-effects models were used to pool effect estimates where appropriate. Of 8558 records identified, 145 met the full eligibility criteria. A 10 µg/m³ increase in short-term PM2.5 exposure was significantly associated with increases of 0.70%, 0.86%, 0.38% and 0.96% in cardiovascular mortality, respiratory mortality, cardiovascular morbidity, and respiratory morbidity, respectively. The specific diseases with significant associations included stroke, ischemic heart disease, heart failure, arrhythmia, chronic obstructive pulmonary disease, pneumonia and allergic rhinitis. The pooled estimates per 10 µg/m³ increase in long-term PM2.5 exposure were 15.1%, 11.9% and 21.0% increases in cardiovascular, stroke and lung cancer mortality, and 17.4%, 11.0% and 4.88% increases in cardiovascular, hypertension and lung cancer incidence respectively. Adverse changes in blood pressure, heart rate variability, systemic inflammation, blood lipids, lung function and airway inflammation were observed for either short-term or long-term PM2.5 exposure, or both. Collectively, we summarized representative exposure-response relationships between short- and long-term PM2.5 exposure and a wide range of cardiorespiratory outcomes applicable to China. The magnitudes of estimates were generally smaller in short-term associations and comparable in long-term associations compared with those in developed countries. Our findings are helpful for future standard revisions and policy formulation. There are still some notable gaps that merit further investigation in China.

Ambient air pollution and hospitalization for type 2 diabetes in China: A nationwide, individual-level case-crossover study.

Scarce evidence is available on the short-term association between air pollution and type 2 diabetes (T2D). We aimed to evaluate the associations between short-term exposure to six criteria air pollutants and hospitalization for T2D based on a national registry. We conducted an individual-level, time-stratified case-crossover study among inpatients with a primary diagnosis of T2D from 153 hospitals across 20 provincial regions in China (2013-2021). Daily concentrations of fine particulate matter (PM2.5), inhalable particle (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO), and ozone were collected from the nearest monitoring stations. T2D patients were separated into those admission for T2D with and without complications. Distributed lag non-linear models combined with conditional logistic regressions were used to estimate the associations. A total of 88,904 patients were hospitalized for T2D. Short-term exposures to all six air pollutants above except for ozone were significantly associated with the risk of hospitalization for T2D and both subclasses. An interquartile range increase in the concentrations of PM2.5, PM10, NO2, SO2, and CO at lag 0-2 d was associated with higher hospitalization risk of T2D by 1.71% (95%CI: 0.56%, 2.87%), 2.08% (0.88%, 3.29%), 4.85% (3.29%, 6.44%), 2.44% (1.22%, 3.67%) and 2.55% (1.24%, 3.88%), respectively. The associations of T2D hospitalizations were stronger in cold season than in warm season. Air pollutants had more acute and stronger associations with T2D with complications. The exposure-response relationship curves showed no thresholds, and the slopes were larger for T2D with complications. This nationwide individual-level, case-crossover study provides the first comprehensive evidence that short-term exposure to multiple criteria air pollutants may increase the risk of hospitalizations for T2D, especially for T2D with complications.

Long-term exposure to ambient air pollution is a risk factor for trajectory of cardiometabolic multimorbidity: A prospective study in the UK Biobank.

BACKGROUND: Although air pollution has been frequently linked to a range of cardiometabolic diseases, its association with the onset, progression, and prognosis of cardiometabolic multimorbidity (CMM) has never been studied. METHODS: We conducted this prospective analysis based on the UK Biobank cohort. CMM was defined as the coexistence of at least two cardiometabolic diseases, including type 2 diabetes, ischemic heart disease and stroke. Multi-state model was used to analyze the association between air pollution and the trajectory of CMM. FINDINGS: 410,494 middle- and old-age participants were included. During a median follow-up of 12.0 years, 56,877 participants developed first cardiometabolic disease (FCMD), 8616 developed CMM, and 22,423 died. The risks of transitions from baseline to FCMD, from FCMD to CMM, and transitions from baseline and FCMD to all-cause mortality increased by 3% (2%, 5%), 3% (1%, 6%), 5% (2%, 7%) and 2% (-1%, 6%), respectively, per interquartile range increase of fine particulate matter. The corresponding increases were 3% (2%, 5%), 6% (3%, 9%), 4% (2%, 7%) and 6% (2%, 10%), respectively, for nitrogen dioxide. Older participants, males, and individuals with excessive alcohol drinking and lower economic levels were more likely to experience these risks. INTERPRETATION: Air pollution exposures could play important roles in almost all transition phases of CMM development. Our results highlight clean air as an upstream approach to mitigate both initiation and progression of CMM, especially in vulnerable populations. FUNDING: Shanghai Municipal Science and Technology Commission (21TQ015); The National Natural Science Foundation of China (92143301 and 92043301).

Association between plasma free fatty acid levels and primary angle-closure glaucoma based on a mass spectrometry metabolomics analysis.

PURPOSE: To determine the association between plasma free fatty acid (FFA) levels and primary angle-closure glaucoma (PACG). METHODS: Free fatty acid (FFA) levels in patients with PACG (n = 181) and people without glaucoma (n = 340) were compared. Twenty-two FFAs and six lipid classes were measured using metabolomics analysis. Odds ratio (OR) of these metabolites and their 95% confidence intervals (95%CI) for PACG were obtained by logistic regression. Stepwise forward selection was performed to identify FFAs that influenced PACG risk. Areas under the curve (AUC) were applied to assess the predictive performance. Spearman's rank correlation was used to assess the relationship between ocular parameters and FFAs. RESULTS: Most FFAs in the PACG group were lower than those in the non-glaucoma group. Docosahexaenoic acid (DHA; OR for fourth quartile (Q4) vs. first quartile (Q1): 0.32 (0.16-0.66); per standard deviation (SD) increase: 0.64 (0.49-0.83); p for trend: 0.0007) and total saturated fatty acids (SFAs; OR for Q4 versus Q1: 0.27 (0.13-0.56); per SD increase: 0.65 (0.50-0.87); p for trend: 0.0004) were associated with decreased PACG risk. The AUC of the model that included DHA, total SFAs, demographic and ophthalmic factors increased from 0.8230 (0.7811-0.8649) to 0.8512 (0.8133-0.8891) (increased AUC: 0.0282 (0.0112-0.0453); p for increased AUC: 0.0012). Additionally, the cup-disc ratio had a weak negative correlation with DHA and total SFAs (DHA: r = -0.12085, p = 0.0065; total SFAs: r = -0.13318, p = 0.0024). CONCLUSIONS: Decrease in FFA levels may be related to lipid peroxidation. Docosahexaenoic acid (DHA) and total SFAs may be screening indices for PACG patients.

Plasma Amino Acids and Residual Hypertriglyceridemia in Diabetic Patients Under Statins: Two Independent Cross-Sectional Hospital-Based Cohorts.

Objective: The objective of the study was to investigate the relationship of amino acid metabolism with hypertriglyceridemia in diabetic patients under statins free of prior cardiovascular diseases. Methods: Two independent cross-sectional hospital based cohorts, i.e., Liaoning Medical University First Affiliated Hospital (LMUFAH, n = 146) and the Second Affiliated Hospital of Dalian Medical University (SAHDMU, n = 294) were included in the current analysis. Hypertriglyceridemia was defined as triglyceride ≥1.7 mmol/L, and well-controlled LDL-C was defined as <2.6 mmol/L. The adjusted ORs (95% CI) of circulating metabolic measures for hypertriglyceridemia were assessed using logistic regression. Pooled results of metabolites with the same direction of association in both cohorts were combined using inverse variance-weighted fixed-effect meta-analysis. Difference of identified metabolites in patients with and without hypertriglyceridemia were also obtained in the context of LDL-C. Results: Patients, 86 and 106, were with hypertriglyceridemia in LMUFAH and SAHDMU, respectively. We observed that elevated alanine, asparagine, leucine, and valine were consistently associated with increased hypertriglyceridemia in both cohorts. In fixed-effect pooled analysis, the OR (95% CI) per SD increase was 1.71 (1.32-2.20) for alanine, 1.62 (1.20-2.19) for asparagine, 1.64 (1.22-2.20) for leucine, and 1.62 (1.22-2.13) for valine (all P values ranged from 0.0018 to <0.0001); adjusting for C-peptide attenuated effect sizes of Ala, Leu, and Val for hypertriglyceridemia. The difference were robust in groups with well- or bad-controlled LDL-C. Conclusion: Among 23 amino acids, alanine, asparagine, leucine, and valine were positively associated with increased residual risk of hypertriglyceridemia in diabetic patients with statin treatment.

Decreased plasma n6 : n3 polyunsaturated fatty acids ratio interacting with high C-peptide promotes non-alcoholic fatty liver disease in type 2 diabetes patients.

AIMS/INTRODUCTION: To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression. MATERIALS AND METHODS: We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD. RESULTS: Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 µmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant. CONCLUSION: Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

Interactive effects of asparagine and aspartate homeostasis with sex and age for the risk of type 2 diabetes risk.

BACKGROUND: Asparagine and aspartate homeostasis are linked with type 2 diabetes (T2D). This study aimed to explore whether asparagine and aspartate metabolism interacted with sex and age to increase the risk of T2D. METHODS: From 27 May 2015 to 3 August 2016, we consecutively retrieved 1032 T2D patients and 1522 subjects without T2D from a tertiary care hospital in Liaoning, China. Restricted cubic spline nested in the logistic regression was used to draw odds ratio curves of plasma asparagine to aspartate ratio for T2D by sex and age. Cut-off point was selected where curves went apart, indicating possible interaction. Addictive interactions of asparagine to aspartate ratio with sex or age and secondary interaction with copresence of unfavorable sex and age were further estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RESULTS: Ratio of asparagine to aspartate > 1.5 was associated with elevated risk of T2D (OR 7.99, 95%CI 5.50 to 11.6), which was enhanced by female gender to 13.6, (95%CI 8.10-22.9) and by > 50 years of age to 28.7 (14.6-56.3), with significant additive interactions. There was a significant secondary-interaction of copresence of female sex and > 50 years of age with high asparagine to aspartate ratio for increased T2D risk with the OR being further increased to 34.4 (20.5-57.5). CONCLUSIONS: High asparagine to aspartate ratio was associated with markedly increased risk of T2D, which was further amplified by either female gender or > 50 years of age, and especially both.

Plasma phenylalanine and tyrosine and their interactions with diabetic nephropathy for risk of diabetic retinopathy in type 2 diabetes.

OBJECTIVE: Tight control of hyperglycemia reduces risk of diabetic retinopathy (DR), but the residual risk remains high. This study aimed to explore relationships between plasma phenylalanine and tyrosine with DR in type 2 diabetes (T2D) and interactions between the two amino acids, and their secondary interaction with renal dysfunction. RESEARCH DESIGN AND METHODS: We extracted data of 1032 patients with T2D from tertiary hospital consecutively from May 2015 to August 2016. Binary logistic regression models with restricted cubic spline were used to check potential non-linear associations and to obtain ORs and 95% CIs of variables under study. Addictive interaction was estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Area under the receiver operating characteristic curve was used to check increased predictive values. RESULTS: Of 1032 patients, 162 suffered from DR. Copresence of low phenylalanine and low tyrosine increased DR risk (OR 6.01, 95% CI 1.35 to 26.8), while either of them alone did not have a significant effect with significant additive interaction. Presence of diabetic nephropathy further increased the OR of copresence of low phenylalanine and low tyrosine for DR to 25.9 (95% CI 8.71 to 76.9) with a significant additive interaction. Inclusion of phenylalanine and tyrosine in a traditional risk factor model significantly increased area under the curve from 0.81 to 0.83 (95% CI 0.80 to 0.86). CONCLUSION: Plasma low phenylalanine and low tyrosine worked independently and synergistically to increase the risk of DR in T2D. Presence of renal dysfunction further amplified the effect of copresence of low phenylalanine and low tyrosine on DR risk.

Role of aromatic amino acids in pathogeneses of diabetic nephropathy in Chinese patients with type 2 diabetes.

BACKGROUND: We aimed to estimate the associations between aromatic amino acids (AAAs) and diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). METHODS: We collected clinical and metabolomic data from 132 healthy subjects (HS group), 132 type 2 diabetes patients without diabetic nephropathy (T2D group) and 132 diabetic nephropathy patients (DN group) in tertiary hospital from May 2015 to August 2016. The odds ratio (OR) and 95% confidence interval (CI) were obtained by logistic regression. RESULTS: The odds ratio of tyrosine for DN increased gradually. High tyrosine was associated with an increased OR of DN (model 3, OR:0.329, 95%CI, 0.144-0.750) when comparing extreme quantiles. CONCLUSION: In Chinese patients with T2D, elevated tyrosine was associated with increased risk of DN.

The Association Between Acylcarnitine Metabolites and Cardiovascular Disease in Chinese Patients With Type 2 Diabetes Mellitus.

Objective: The association between acylcarnitine metabolites and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to investigate associations between acylcarnitines and CVD in Chinese patients with T2DM. Methods: A cross-sectional study was conducted from May 2015 to August 2016. Medical records of 741 patients with T2DM were retrieved from the main electronic database of Liaoning Medical University First Affiliated Hospital. CVD was defined as having either coronary artery disease (CAD) or heart failure (HF) or stroke. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Factor analysis was used to reduce the dimensions and extracted factors of the 25 acylcarnitine metabolites. Multivariable binary logistic regression was used to obtain odds ratios (OR) of the factors extracted from the 25 acylcarnitine metabolites and their 95% confidence intervals (CI) for CVD. Results: Of the 741 patients with T2DM, 288 had CVD. Five factors were extracted from the 25 acylcarnitines and they accounted for 65.9% of the total variance. Factor 1 consisted of acetylcarnitine, butyrylcarnitine, hydroxylbutyrylcarnitine, glutarylcarnitine, hexanoylcarnitine, octanoylcarnitine, and tetradecanoyldiacylcarnitine. Factor 2 consisted of decanoylcarnitine, lauroylcarnitine, myristoylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, tetradecenoylcarnitine, and 3-hydroxypalmitoylcarnitine. After adjusting for potential confounders, increased factor 1 and 2 were associated with increased risks of CVD in T2DM (OR of factor 1: 1.45, 95% CI: 1.03-2.03; OR of factor 2: 1.23, 95% CI: 1.02-1.50). Conclusions: Elevated plasma levels of some acylcarnitine metabolites, i.e., those extracted into factor 1 and 2, were associated with CVD risk in T2DM.

Plasma Free Amino Acids and Risk of Cardiovascular Disease in Chinese Patients With Type 2 Diabetes.

Objectives: This study aimed to explore associations between plasma free amino acids (PFAA) and risk of cardiovascular disease (CVD) in Chinese with Type 2 diabetes (T2D). Methods: We retrieved 741 inpatients with T2D consecutively from tertiary hospital. Twenty-three PFAA were measured. CVD was defined as having coronary heart disease (CHD) or stroke. Principal component analysis was used to extract factors of PFAA. Factors and their components were introduced into binary logistic regressions as continuous and tertiles to obtain OR (odds ratio) and 95% confidence interval (CI) for CVD (or its components) risk. Results: Of 741 inpatients, 282 (38.1%) had CVD (CHD alone: 122, stroke alone: 109, both: 51). Five factors were extracted, accounting for 65% of the total variance. Factor 3 composed of glutamate and tryptophan was associated with increased CVD risk (ORs, 95%CI of top vs. bottom tertiles: 1.60, 1.02-2.50 for CVD; 2.19, 1.17-4.07 for stroke, 1.51, 0.83-2.73 for CHD); the ORs (top vs. bottom tertiles) of glutamate were 2.62 (95%CI, 1.18-5.84) for stroke and 1.44 (0.80-2.61) for CHD; the ORs (top vs. bottom tertiles) of tryptophan were 1.50 (0.81-2.75) for stroke and 1.07 (0.58-1.97) for CHD. Comparable results were observed according to important confounders (all P for interaction >0.05). Conclusions: Elevated factor 3 composed of glutamate and tryptophan was associated with increased CVD, especially stroke in T2D in China.