A Lipid Signature with Perturbed Triacylglycerol Co-Regulation, Identified from Targeted Lipidomics, Predicts Risk for Type 2 Diabetes and Mediates the Risk from Adiposity in Two Prospective Cohorts of Chinese Adults.

BACKGROUND: The roles of individual and co-regulated lipid molecular species in the development of type 2 diabetes (T2D) and mediation from metabolic risk factors remain unknown. METHODS: We conducted profiling of 166 plasma lipid species in 2 nested case-control studies within 2 independent cohorts of Chinese adults, the Dongfeng-Tongji and the Jiangsu non-communicable disease cohorts. After 4.61 (0.15) and 7.57 (1.13) years' follow-up, 1039 and 520 eligible participants developed T2D in these 2 cohorts, respectively, and controls were 1:1 matched to cases by age and sex. RESULTS: We found 27 lipid species, including 10 novel ones, consistently associated with T2D risk in the 2 cohorts. Differential correlation network analysis revealed significant correlations of triacylglycerol (TAG) 50:3, containing at least one oleyl chain, with 6 TAGs, at least 3 of which contain the palmitoyl chain, all downregulated within cases relative to controls among the 27 lipids in both cohorts, while the networks also both identified the oleyl chain-containing TAG 50:3 as the central hub. We further found that 13 of the 27 lipids consistently mediated the association between adiposity indicators (body mass index, waist circumference, and waist-to-height ratio) and diabetes risk in both cohorts (all P < 0.05; proportion mediated: 20.00%, 17.70%, and 17.71%, and 32.50%, 28.73%, and 33.86%, respectively). CONCLUSIONS: Our findings suggested notable perturbed co-regulation, inferred from differential correlation networks, between oleyl chain- and palmitoyl chain-containing TAGs before diabetes onset, with the oleyl chain-containing TAG 50:3 at the center, and provided novel etiological insight regarding lipid dysregulation in the progression from adiposity to overt T2D.

Metabolome-Wide Association Study of Multiple Plasma Metals with Serum Metabolomic Profile among Middle-to-Older-Aged Chinese Adults.

Metal exposure has been associated with risk of various cardio-metabolic disorders, and investigation on the association between exposure to multiple metals and metabolic responses may reveal novel clues to the underlying mechanisms. Based on a metabolome-wide association study of 17 plasma metals with untargeted metabolomic profiling of 189 serum metabolites among 1992 participants within the Dongfeng-Tongji cohort, we replicated two metal-associated pathways, linoleic acid metabolism and aminoacyl-tRNA biosynthesis, with novel metal associations (false discovery rate, FDR < 0.05), and we also identified two novel pathways, including biosynthesis of unsaturated fatty acids and alpha-linolenic acid metabolism, as associated with metal exposure (FDR < 0.05). Moreover, two-way orthogonal partial least-squares analysis showed that five metabolites, including aspartylphenylalanine, free fatty acid 14:1, uridine, carnitine C14:2, and LPC 18:2, contributed most to the joint covariation between the two data matrices (12.3%, 8.3%, 8.0%, 7.4%, and 7.3%, respectively). Further BKMR analysis showed significant positive joint associations of plasma Al, As, Ba, and Zn with aspartylphenylalanine and of plasma Ba, Co, Mn, and Pb with carnitine C14:2, when all the metals were at the 55th percentiles or above, compared with the median. We also found significant interactions between As and Ba in the association with aspartylphenylalanine (P for interaction = 0.048) and between Ba and Pb in the association with carnitine C14:2 (P for interaction < 0.001). Together, these findings may provide new insights into the mechanisms underlying the adverse health effects induced by metal exposure.

Metabolite Triplet in Serum Improves the Diagnostic Accuracy of Prediabetes and Diabetes Screening.

Large-scale population screenings are not feasible by applying laborious oral glucose tolerance tests, but using fasting blood glucose (FPG) and glycated hemoglobin (HbA1c), a considerable number of diagnoses are missed. A novel marker is urgently needed to improve the diagnostic accuracy of broad-scale diabetes screening in easy-to-collect blood samples. In this study, by applying a novel knowledge-based, multistage discovery and validation strategy, we scaled down from 108 diabetes-associated metabolites to a diagnostic metabolite triplet (Met-T), namely hexose, 2-hydroxybutyric/2-hydroxyisobutyric acid, and phenylalanine. Met-T showed in two independent cohorts, each comprising healthy controls, prediabetic, and diabetic individuals, distinctly higher diagnostic sensitivities for diabetes screening than FPG alone (>79.6 vs <68%). Missed diagnoses decreased from >32% using fasting plasma glucose down to <20.4%. Combining Met-T and fasting plasma glucose further improved the diagnostic accuracy. Additionally, a positive association of Met-T with future diabetes risk was found (odds ratio: 1.41; p = 1.03 × 10-6). The results reveal that missed prediabetes and diabetes diagnoses can be markedly reduced by applying Met-T alone or in combination with FPG and it opens perspectives for higher diagnostic accuracy in broad-scale diabetes-screening approaches using easy to collect sample materials.

Past Shift Work and Incident Coronary Heart Disease in Retired Workers: A Prospective Cohort Study.

Present shift work has been associated with coronary heart disease (CHD) among employed workers, but it remains unclear whether shift work performed in the past is still associated with CHD in retired workers. We recruited 21,802 retired workers in Shiyan, China, in 2008-2010 and 2013 and followed them for CHD events occurring up to December 31, 2018. Retired workers with longer durations of past shift work (rounded to 0.25 years) had higher CHD risks (for those with ≤5.00, 5.25-10.00, 10.50-20.00, and >20.00 years of past shift work, hazard ratios were 1.05 (95% confidence interval (CI): 0.94, 1.16), 1.08 (95% CI: 0.94, 1.25), 1.23 (95% CI: 1.07, 1.42), and 1.28 (95% CI: 1.08, 1.51), respectively). The association was substantially higher among service or sales workers than among manufacturing or manual-labor workers (for every 5-year increase in past shift work, hazard ratio = 1.11 (95% CI: 1.05, 1.16) vs. hazard ratio = 1.02 (95% CI: 0.98, 1.06)). Moreover, the risk was lower among those who were physically active than among their inactive counterparts (P for interaction = 0.019). Longer duration of past shift work was associated with higher risk of incident CHD among these retired workers, especially those from the service or sales sectors. Physical exercise might be beneficial in reducing the excess risk.

Chemical Fingerprinting of HULIS in Particulate Matters Emitted from Residential Coal and Biomass Combustion.

Identification of humic-like substances (HULIS) structures and components is still a major challenge owing to their chemical complexity. This study first employed a complementary method with the combination of two-dimensional gas chromatography-time-of-flight mass spectrometry and liquid chromatography-quadrupole-time-of-flight mass spectrometry to address low-polarity and polar components of HULIS in PM2.5 (particulate matter with an aerodynamic diameter less than 2.5 µm), respectively. The combination method showed a significant correlation in identifying overlapping species and performed well in uncovering the chemical complexity of HULIS. A total of 1246 compound species in HULIS (65.6-81.0% for each sample), approximately 1 order of magnitude more compounds than that reported in previous studies, were addressed in PM2.5 collected in real-world household biomass and coal combustion. Aromatics were the most abundant compounds (37.4-64.1% in biomass and 34.5-70.0% in coal samples) of the total mass in all HULIS samples according to carbon skeleton determination, while the major components included phenols (2.6-21.1%), ketones (6.0-17.1%), aldehydes (1.1-6.8%), esters (2.9-20.0%), amines/amides (3.2-8.5%), alcohols (3.8-17.0%), and acids (4.7-15.1%). Among the identified HULIS species, 11-36% mass in biomass and 11-41% in coal were chromophores, while another 22-35 and 23-29% mass were chromophore precursors, respectively. The combination method shows promise for uncovering HULIS fingerprinting.

A Large-scale, multicenter serum metabolite biomarker identification study for the early detection of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. The lack of effective biomarkers for the early detection of HCC results in unsatisfactory curative treatments. Here, metabolite biomarkers were identified and validated for HCC diagnosis. A total of 1,448 subjects, including healthy controls and patients with chronic hepatitis B virus infection, liver cirrhosis, and HCC, were recruited from multiple centers in China. Liquid chromatography-mass spectrometry-based metabolomics methods were used to characterize the subjects' serum metabolic profiles and to screen and validate the HCC biomarkers. A serum metabolite biomarker panel including phenylalanyl-tryptophan and glycocholate was defined. This panel had a higher diagnostic performance than did α-fetoprotein (AFP) in differentiating HCC from a high-risk population of cirrhosis, such as an area under the receiver-operating characteristic curve of 0.930, 0.892, and 0.807 for the panel versus 0.657, 0.725, and 0.650 for AFP in the discovery set, test set, and cohort 1 of the validation set, respectively. In the nested case-control study, this panel had high sensitivity (range 80.0%-70.3%) to detect preclinical HCC, and its combination with AFP provided better risk prediction of preclinical HCC before clinical diagnosis. Besides, this panel showed a larger area under the receiver-operating characteristic curve than did AFP (0.866 versus 0.682) to distinguish small HCC, and 80.6% of the AFP false-negative patients with HCC were correctly diagnosed using this panel in the test set, which was corroborated by the validation set. The specificity and biological relevance of the identified biomarkers were further evaluated using sera from another two cancers and HCC tissue specimens, respectively. Conclusion: The discovered and validated serum metabolite biomarker panel exhibits good diagnostic performance for the early detection of HCC from at-risk populations. (Hepatology 2018;67:662-675).

Association of Solid Fuel Use With Risk of Cardiovascular and All-Cause Mortality in Rural China.

Importance: When combusted indoors, solid fuels generate a large amount of pollutants such as fine particulate matter. Objective: To assess the associations of solid fuel use for cooking and heating with cardiovascular and all-cause mortality. Design, Setting, and Participants: This nationwide prospective cohort study recruited participants from 5 rural areas across China between June 2004 and July 2008; mortality follow-up was until January 1, 2014. A total of 271 217 adults without a self-reported history of physician-diagnosed cardiovascular disease at baseline were included, with a random subset (n = 10 892) participating in a resurvey after a mean interval of 2.7 years. Exposures: Self-reported primary cooking and heating fuels (solid: coal, wood, or charcoal; clean: gas, electricity, or central heating), switching of fuel type before baseline, and use of ventilated cookstoves. Main Outcomes and Measures: Death from cardiovascular and all causes, collected through established death registries. Results: Among the 271 217 participants, the mean (SD) age was 51.0 (10.2) years, and 59% (n = 158 914) were women. A total of 66% (n = 179 952) of the participants reported regular cooking (at least weekly) and 60% (n = 163 882) reported winter heating, of whom 84% (n = 150 992) and 90% (n = 147 272) used solid fuels, respectively. There were 15 468 deaths, including 5519 from cardiovascular causes, documented during a mean (SD) of 7.2 (1.4) years of follow-up. Use of solid fuels for cooking was associated with greater risk of cardiovascular mortality (absolute rate difference [ARD] per 100 000 person-years, 135 [95% CI, 77-193]; hazard ratio [HR], 1.20 [95% CI, 1.02-1.41]) and all-cause mortality (ARD, 338 [95% CI, 249-427]; HR, 1.11 [95% CI, 1.03-1.20]). Use of solid fuels for heating was also associated with greater risk of cardiovascular mortality (ARD, 175 [95% CI, 118-231]; HR, 1.29 [95% CI, 1.06-1.55]) and all-cause mortality (ARD, 392 [95% CI, 297-487]; HR, 1.14 [95% CI, 1.03-1.26]). Compared with persistent solid fuel users, participants who reported having previously switched from solid to clean fuels for cooking had a lower risk of cardiovascular mortality (ARD, 138 [95% CI, 71-205]; HR, 0.83 [95% CI, 0.69-0.99]) and all-cause mortality (ARD, 407 [95% CI, 317-497]; HR, 0.87 [95% CI, 0.79-0.95]), while for heating, the ARDs were 193 (95% CI, 128-258) and 492 (95% CI, 383-601), and the HRs were 0.57 (95% CI, 0.42-0.77) and 0.67 (95% CI, 0.57-0.79), respectively. Among solid fuel users, use of ventilated cookstoves was also associated with lower risk of cardiovascular mortality (ARD, 33 [95% CI, -9 to 75]; HR, 0.89 [95% CI, 0.80-0.99]) and all-cause mortality (ARD, 87 [95% CI, 20-153]; HR, 0.91 [95% CI, 0.85-0.96]). Conclusions and Relevance: In rural China, solid fuel use for cooking and heating was associated with higher risks of cardiovascular and all-cause mortality. These risks may be lower among those who had previously switched to clean fuels and those who used ventilation.

Associations of the uric acid related genetic variants in SLC2A9 and ABCG2 loci with coronary heart disease risk.

BACKGROUND: Multiple studies investigated the associations between serum uric acid and coronary heart disease (CHD) risk. However, further investigations still remain to be carried out to determine whether there exists a causal relationship between them. We aim to explore the associations between genetic variants in uric acid related loci of SLC2A9 and ABCG2 and CHD risk in a Chinese population. RESULTS: A case-control study including 1,146 CHD cases and 1,146 controls was conducted. Association analysis between two uric acid related variants (SNP rs11722228 in SLC2A9 and rs4148152 in ABCG2) and CHD risk was performed by logistic regression model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Compared with subjects with A allele of rs4148152, those with G allele had a decreased CHD risk and the association remained significant in a multivariate model. However, it altered to null when BMI was added into the model. No significant association was observed between rs11722228 and CHD risk. The distribution of CHD risk factors was not significantly different among different genotypes of both SNPs. Among subjects who did not consume alcohol, the G allele of rs4148152 showed a moderate protective effect. However, no significant interactions were observed between SNP by CHD risk factors on CHD risk. CONCLUSIONS: There might be no association between the two uric acid related SNPs with CHD risk. Further studies were warranted to validate these results.

[Analysis on the association of single nucleotide polymorphism in the promoter region of pre-miR-320b-2 with coronary heart disease risk and factors influencing circulating microRNA-320b level].

OBJECTIVE: To investigate the effects of rs10916581, a common single nucleotide polymorphism (SNP) located in the promoter region of pre-miR-320b-2, on coronary heart disease (CHD) risk and circulating microRNA-320b (miR-320b) level. To explore potential factors influencing circulating miR-320b level. METHODS: Rs10916581 was genotyped in a case-control study with 1 507 CHD cases and 1 379 age- and sex-frequency-matched controls. The cases were consecutively recruited from 3 hospitals (Tongji Hospital, Union Hospital, and Wugang Hospital) in Wuhan city (Hubei, China) between May 2004 and October 2009 and all the controls resided in Wuhan communities. A subgroup of 174 CHD cases and 181 non-diabetes controls without acute infection were randomly selected and their circulating miR-320b levels were detected using quantitative reverse transcriptase polymerase chain reaction assays. The association of rs10916581 with CHD susceptibility was analyzed with multivariable logistic regression model. Generalized linear regression model was used to explore the associations of rs10916581 and some other factors with circulating miR-320b level. RESULTS: In single-factor logistic regression analysis, no association was found between rs10916581 and CHD risk. After adjustment for age, sex, BMI, smoking status, hypertension, diabetes, total triglyceride, total cholesterol/high density lipoprotein (TC/HDL-C), the result did not materially alter(compared with CC genotype, the OR (95%CI) of CHR in the subjects carried CT, TT, CT+TT genotypes were 0.94 (0.76-1.15), 0.99 (0.74-1.33) and 0.95 (0.78-1.16) ). No significant interactions were observed between the conventional risk factors of CHD (age, gender, smoking status, BMI, hypertension, diabetes, CHD family history) and rs10916581 on CHD risk (P > 0.05). Rs10916581 showed no significant association with circulating miR-320b level in cases, controls or total population (ß(95%CI) was -0.028 (-0.495-0.440), 0.250 (-0.226-0.727) and 0.134 (-0.218-0.486) respectively, P > 0.05). However, circulating miR-320b level was negatively associated with BMI (ß (95%CI) was -0.140 (-0.261--0.020), P = 0.022) while positively associated with TC/HDL(ß (95%CI) was 0.620 (0.261-0.979), P = 0.001) in cases, and in total population, its circulating level tended to be lower in diabetes or hypertension patients (ß(95%CI) was -1.025 (-1.696--0.354) and -0.594 (-1.138--0.049) respectively, P = 0.003, 0.033 respectively) and was positively associated with TC/HDL-C (ß(95%CI) was 0.108 (0.027-0.190), P = 0.009). CONCLUSION: The common SNP (rs10916581) in the promoter region of pre-miR-320b-2 might have little contribution to the CHD predisposition in Chinese Han population, and it might not affect circulating miR-320b level. Conventional CHD risk factors (BMI, TC/HDL-C, hypertension and diabetes) might have effects on its circulating level.

Associations of Plasma Metabolites With Risks of Incident Stroke and Its Subtypes in Chinese Adults.

BACKGROUND: Metabolomics studies have identified various metabolic markers associated with stroke risk, yet much uncertainty persists regarding heterogeneity in these associations between different stroke subtypes. We aimed to examine metabolic profiles associated with incident stroke and its subtypes in Chinese adults. METHODS AND RESULTS: We performed a nested case-control study within the Dongfeng-Tongji cohort, including 1029 and 266 incident cases of ischemic stroke (IS) and hemorrhagic stroke (HS), respectively, with a mean follow-up period of 6.1±2.3 years. Fifty-five metabolites in fasting plasma were measured by ultra-high-performance liquid chromatography-mass spectrometry. We examined the associations of metabolites with the risks of total stroke, IS, and HS, with a focus on the comparison of associations of plasma metabolite with IS and HS, using conditional logistic regression. We found that increased levels of asymmetrical/symmetrical dimethylarginine and glutamate were significantly associated with elevated risk of total stroke (odds ratios and 95%, 1.20 [1.08-1.34] and 1.22 [1.09-1.36], respectively; both Benjamini-Hochberg-adjusted P <0.05). When examining stroke subtypes, asymmetrical/symmetrical dimethylarginine was nominally associated with both IS and HS (odds ratios [95% CIs]: 1.16 [1.03-1.31] and 1.39 [1.07-1.81], respectively), while glutamate was associated with only IS (odds ratios [95% CI]: 1.26 [1.11-1.43]). The associations of glutamate with IS risk were significantly stronger among participants with hypertension and diabetes than among those without these diseases (both P for interaction <0.05). CONCLUSIONS: This study validated the positive associations of asymmetrical/symmetrical dimethylarginine and glutamate with stroke risk, mainly that of IS, in a Chinese population, and revealed a novel unanimous association of with both IS and HS. Our findings provided potential intervention targets for stroke prevention.

Lipidomics identified novel cholesterol-independent predictors for risk of incident coronary heart disease: Mediation of risk from diabetes and aggravation of risk by ambient air pollution.

INTRODUCTION: Previous lipidomics studies have identified various lipid predictors for cardiovascular risk, however, with limited predictive increment, sometimes using too many predictor variables at the expense of practical efficiency. OBJECTIVES: To search for lipid predictors of future coronary heart disease (CHD) with stronger predictive power and efficiency to guide primary intervention. METHODS: We conducted a prospective nested case-control study involving 1,621 incident CHD cases and 1:1 matched controls. Lipid profiling of 161 lipid species for baseline fasting plasma was performed by liquid chromatography-mass spectrometry. RESULTS: In search of CHD predictors, seven lipids were selected by elastic-net regression during over 90% of 1000 cross-validation repetitions, and the derived composite lipid score showed an adjusted odds ratio of 3.75 (95% confidence interval: 3.15, 4.46) per standard deviation increase. Addition of the lipid score into traditional risk model increased c-statistic to 0.736 by an increment of 0.077 (0.063, 0.092). From the seven lipids, we found mediation of CHD risk from baseline diabetes through sphingomyelin (SM) 41:1b with a considerable mediation proportion of 36.97% (P < 0.05). We further found that the positive associations of phosphatidylcholine (PC) 36:0a, SM 41:1b, lysophosphatidylcholine (LPC) 18:0 and LPC 20:3 were more pronounced among participants with higher exposure to fine particulate matter or its certain components, also to ozone for LPC 18:0 and LPC 20:3, while the negative association of cholesteryl ester (CE) 18:2 was attenuated with higher black carbon exposure (P < 0.05). CONCLUSION: We identified seven lipid species with greatest predictive increment so-far achieved for incident CHD, and also found novel biomarkers for CHD risk stratification among individuals with diabetes or heavy air pollution exposure.

Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design.

Emerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.

Nontargeted Metabolomics Revealed Novel Association Between Serum Metabolites and Incident Acute Coronary Syndrome: A Mendelian Randomization Study.

Background This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.

Alternations in the gut microbiota and metabolome with newly diagnosed unstable angina.

Gut microbiota plays an important role in coronary heart disease, but its compositional and functional changes in unstable angina (UA) remain unexplored. We performed metagenomic sequencing of 133 newly diagnosed UA patients and 133 sex- and age-matched controls, and profiled the fecal and plasma metabolomes in 30 case-control pairs. The alpha diversity of gut microbiota was increased in UA patients: the adjusted odds ratios (ORs) per standard deviation increase in Shannon and Simpson indices were 1.30 (95% confidence interval, 1.01-1.70) and 1.36 (1.05-1.81), respectively. Two common species (depleted Klebsiella pneumoniae and enriched Streptococcus parasanguinis; P ≤ 0.002) and three rare species (depleted Weissella confusa, enriched Granulicatella adiacens and Erysipelotrichaceae bacterium 6_1_45; P ≤ 0.005) were associated with UA. The UA-associated gut microbiota was depleted in the pathway of L-phenylalanine degradation (P = 0.001), primarily contributed by Klebsiella pneumoniae. Consistently, we found increased circulating phenylalanine in UA patients (OR = 2.76 [1.17-8.16]). Moreover, Streptococcusparasanguinis was negatively correlated with fecal citrulline (Spearman's rs = -0.470, P = 0.009), a metabolite depleted in UA patients (OR = 0.26 [0.08-0.63]). These findings are informative to help understand the metabolic connection between gut microbiota and UA.

Associations between urinary bisphenol A and its analogues and semen quality: A cross-sectional study among Chinese men from an infertility clinic.

Human studies on association between bisphenol A (BPA) exposure and semen quality, mostly based on single urinary measurement, are inconsistent. There is limited human evidence on BPA analogues such as bisphenol F (BPF) and bisphenol S (BPS), and little is known on potential effects of bisphenol mixtures. We aimed to explore whether individual or mixtures of BPA, BPS and BPF assessed in repeated urinary measurements were associated with semen quality among 984 Chinese men from an infertility clinic. We found that higher BPA exposure was associated with increased odds ratios (ORs) of having below-reference sperm concentration, total sperm count, progressive motility and total motility (all P for trends < 0.05). Higher BPS exposure was associated with increased ORs of having below-reference progressive motility and total motility (both P for trends = 0.02); the ORs comparing extreme quartiles were 1.62 (95% CI: 1.07, 2.43) and 1.57 (95% CI: 1.06, 2.33), respectively. Elevated risks for each outcome were also observed when bisphenol mixtures were at ≥ 55th percentiles. For semen quality parameters modeled as continuous outcomes, inverse associations with individual BPA and BPS and bisphenol mixtures were still estimated. Our results suggested that higher exposure to individual BPA and BPS and bisphenol mixtures were associated with impaired semen quality.

Metabolome-Genome-Wide Association Study (mGWAS) Reveals Novel Metabolites Associated with Future Type 2 Diabetes Risk and Susceptibility Loci in a Case-Control Study in a Chinese Prospective Cohort.

In a Chinese prospective cohort, 500 patients with new-onset type 2 diabetes (T2D) within 4.61 years and 500 matched healthy participants are selected as case and control groups, and randomized into discovery and validation sets to discover the metabolite changes before T2D onset and the related diabetogenic loci. A serum metabolomics analysis reveals that 81 metabolites changed significantly before T2D onset. Based on binary logistic regression, eight metabolites are defined as a biomarker panel for T2D prediction. Pipecolinic acid, carnitine C14:0, epinephrine and phosphatidylethanolamine 34:2 are first found associated with future T2D. The addition of the biomarker panel to the clinical markers (BMI, triglycerides, and fasting glucose) significantly improves the predictive ability in the discovery and validation sets, respectively. By associating metabolomics with genomics, a significant correlation (p < 5.0 × 10-8) between eicosatetraenoic acid and the FADS1 (rs174559) gene is observed, and suggestive correlations (p < 5.0 × 10-6) between pipecolinic acid and CHRM3 (rs535514), and leucine/isoleucine and WWOX (rs72487966) are discovered. Elevated leucine/isoleucine levels increased the risk of T2D. In conclusion, multiple metabolic dysregulations are observed to occur before T2D onset, and the new biomarker panel can help to predict T2D risk.

Trans-ethnic genome-wide association study of severe COVID-19.

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10-10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10-9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10-8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.

[Effect of fructus corni polysaccharides on damaged sexual function of male rats].

OBJECTIVE: To observe the effects of Fructus Corni polysaccharides (FCP) on sexual function of hemicastrated rats. METHOD: 70 male SD rats are randomly divided into 7 groups with their right testis extirpated except for normal control group. Normal control group and negative control group are given saline (ig) while positive control group are injected hypodermically testosterone propionate at dose of 2 mg x kg(-1) x d(-1). FCP control groups are given FCP separately at dose of 10, 50, 100, 150 mg x kg(-1) x d(-1) (ig). Mating test and erective test are observed. The levels of serum sex hormone T, LSH, FSH, E2 are detected with the Radioimmunoassay (RIA). RESULT: Incubation period of penis erection and mounting are shortened in FCP control groups and positive control group, and the percentage of mounting rats is increased. The level of serum sex hormone T is increased, but estradiol level is reduced. The organ coefficient of foreskin gland and seminal vesicle-prostate gland as well as sperm count and vigor are increased significantly (P < 0.01 or P < 0.05). CONCLUSION: FCP can increase the sexual function of hemicastrated rats. The mechanism is probably through adjustment of the hypothalamus-pituitary-gonadal axis.

Association of exhaled carbon monoxide with risk of cardio-cerebral-vascular disease in the China Kadoorie Biobank cohort study.

Exhaled carbon monoxide (COex) level has been proposed as a noninvasive and easily-obtainable cardiovascular risk marker, however, with limited prospective evidence, and its association with stroke risk has been rarely explored. Measurements of COex were performed during 2004-2008 baseline examinations in the China Kadoorie Biobank study among 512,891 adults aged 30-79 years from 10 diverse study areas. After excluding participants with baseline cardiopulmonary diseases, stroke and cancer, 178,485 men and 267,202 women remained. Cox regression yielded hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of cardio-cerebral-vascular disease (CCVD) associated with COex levels, with sequential addition of adjustment for proxy variables for CO exposure, including study area indexing ambient CO variations at large, and smoking and solid fuel use, apart from adjusting for traditional cardiovascular risk factors. During 7-year follow-up, we documented 1744 and 1430 major coronary events (myocardial infarction plus fatal ischemic heart disease), 8849 and 10,922 ischemic strokes, and 2492 and 2363 hemorrhagic strokes among men and women, respectively. The HRs with 95% CIs comparing the highest with lowest COex quintile were 2.15 [1.72, 2.69] for major coronary events, 1.65 [1.50, 1.80] for ischemic stroke, and 1.35 [1.13, 1.61] for hemorrhagic stroke among men, while among women higher associated risk was only observed for major coronary events (1.64 [1.35, 2.00]) and ischemic stroke (1.87 [1.73, 2.01]). The elevated risks were consistent when COex level was over 3 ppm. However, these associations were all attenuated until null by sequential addition of stratification by study areas, and adjustments of smoking and solid fuel use. Nevertheless, the association with ischemic stroke was maintained among the subgroup of male smokers even with adjustment for the depth and amount of cigarette smoking (HR [95% CI]: 1.37 [1.06, 1.77]), while a negative association with hemorrhagic stroke also appeared within this subgroup. Higher COex level (over 3 ppm) was associated with elevated risk of ischemic CCVD, but not independently of CO exposure. Our finding suggests that, though not an independent risk factor, COex could potentially provide a cost-effective biomarker for ischemic cardio-cerebral-vascular risk, given that CO exposure is ubiquitous.

Cooking fuels and risk of all-cause and cardiopulmonary mortality in urban China: a prospective cohort study.

BACKGROUND: Cooking practice has transitioned from use of solid fuels to use of clean fuels, with addition of better ventilation facilities. However, the change in mortality risk associated with such a transition remains unclear. METHODS: The China Kadoorie Biobank (CKB) Study enrolled participants (aged 30-79 years) from ten areas across China; we chose to study participants from five urban areas where transition from use of solid fuels to clean fuels for cooking was prevalent. Participants who reported regular cooking (weekly or more frequently) at baseline were categorised as persistent clean fuel users, previous solid fuel users, or persistent solid fuel users, according to self-reported fuel use histories. All-cause and cardiopulmonary mortality were identified through linkage to China's Disease Surveillance Point system and local mortality records. FINDINGS: Between June 24, 2004, and July 15, 2008, 226 186 participants living in five urban areas of China were enrolled in the CKB Study. Among 171 677 participants who reported cooking regularly (weekly or more frequently), 75 785 (44%) were persistent clean fuel users, 80 511 (47%) were previous solid fuel users, and 15 381 (9%) were persistent solid fuel users. During a mean of 9·8 (SD 1·7) years of follow-up, 10 831 deaths were documented, including 3819 cardiovascular deaths and 761 respiratory deaths. Compared with persistent clean fuel users, persistent solid fuel users had significantly higher risks of all-cause mortality (hazard ratio [HR] 1·19, 95% CI 1·10-1·28), cardiovascular mortality (1·24, 1·10-1·39), and respiratory mortality (1·43, 1·10-1·85). The excess risk of all-cause and cardiopulmonary mortality fell by more than 60% in 5 years after cessation of solid fuel use and continued to decrease afterwards. Use of ventilation was associated with lower all-cause mortality risk, even among persistent clean fuel users (HR 0·78, 0·69-0·89). INTERPRETATION: Solid fuel use for cooking is associated with a higher risk of mortality, and cessation of solid fuel use cuts excess mortality risks swiftly and substantially within 5 years. Ventilation use also lowers the risk of mortality, even among people who persistently use clean fuels. It is of prime importance for both policy makers and the public to accelerate the transition from solid fuels to clean fuels and promote efficient ventilation to minimise further adverse health effects. FUNDING: National Natural Science Foundation of China, Wellcome Trust, and Kadoorie Charitable Foundation.