Circulating metabolic biomarkers and risk of new-onset hypertension: findings from the UK Biobank.

OBJECTIVE: The evidence regarding the associations of circulating metabolic biomarkers with hypertension risk is scarce. We aimed to examine the associations between circulating metabolites and risk of hypertension. METHODS: We included 49 422 individuals free of hypertension at baseline with a mean (SD) age of 53.5 (8.0) years from the UK Biobank. Nuclear magnetic resonance spectroscopy was used to quantify 143 individual metabolites. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% confidence intervals (CIs). RESULTS: During a mean (SD) follow-up of 11.2 (1.8) years, 2686 incident hypertension cases occurred. Out of 143 metabolites, 76 were associated with incident hypertension, among which phenylalanine (hazard ratio: 1.40; 95% CI: 1.24-1.58) and apolipoprotein A1 (hazard ratio: 0.76; 95% CI: 0.66-0.87) had the strongest association when comparing the highest to the lowest quintile. In general, very-low-density lipoprotein (VLDL) particles were positively, whereas high-density lipoprotein (HDL) particles were inversely associated with risk of hypertension. Similar patterns of cholesterol, phospholipids, and total lipids within VLDL and HDL particles were observed. Triglycerides within all lipoproteins were positively associated with hypertension risk. Other metabolites showed significant associations with risk of hypertension included amino acids, fatty acids, ketone bodies, fluid balance and inflammation markers. Adding 10 selected metabolic biomarkers to the traditional hypertension risk model modestly improved discrimination (C-statistic from 0.745 to 0.752, P < 0.001) for prediction of 10-year hypertension incidence. CONCLUSION: Among UK adults, disturbances in metabolic biomarkers are associated with incident hypertension. Comprehensive metabolomic profiling may provide potential novel biomarkers to identify high-risk individuals.

Integrated analysis of single-cell and bulk RNA-sequencing reveals a novel signature based on NK cell marker genes to predict prognosis and immunotherapy response in gastric cancer.

Natural killer (NK) cells play essential roles in the tumor development, diagnosis, and prognosis of tumors. In this study, we aimed to establish a reliable signature based on marker genes in NK cells, thus providing a new perspective for assessing immunotherapy and the prognosis of patients with gastric cancer (GC). We analyzed a total of 1560 samples retrieved from the public database. We performed a comprehensive analysis of single-cell RNA-sequencing (scRNA-seq) data of gastric cancer and identified 377 marker genes for NK cells. By performing Cox regression analysis, we established a 12-gene NK cell-associated signature (NKCAS) for the Cancer Genome Atlas (TCGA) cohort, that assigned GC patients into a low-risk group (LRG) or a high-risk group (HRG). In the TCGA cohort, the areas under curve (AUC) value were 0.73, 0.81, and 0.80 at 1, 3, and 5 years. External validation of the predictive ability for the signature was then validated in the Gene Expression Omnibus (GEO) cohorts (GSE84437). The expression levels of signature genes were measured and validated in GC cell lines by real-time PCR. Moreover, NKCAS was identified as an independent prognostic factor by multivariate analysis. We combined this with a variety of clinicopathological characteristics (age, M stage, and tumor grade) to construct a nomogram to predict the survival outcomes of patients. Moreover, the LRG showed higher immune cell infiltration, especially CD8+ T cells and NK cells. The risk score was negatively associated with inflammatory activities. Importantly, analysis of the independent immunotherapy cohort showed that the LRG had a better prognosis and immunotherapy response when compared with the HRG. The identification of NK cell marker genes in this study suggests potential therapeutic targets. Additionally, the developed predictive signatures and nomograms may aid in the clinical management of GC.

Association between nighttime sleep duration, midday napping, and sleep quality during early pregnancy and risk of gestational diabetes mellitus: A prospective cohort study in China.

AIM: To evaluate the prospective associations of nighttime sleep duration, midday napping, and sleep quality during early pregnancy with gestational diabetes mellitus (GDM) risk among Chinese pregnant women. METHODS: Sleep-related information was assessed by the Pittsburgh Sleep Quality Index in baseline surveys during the 6-15 (mean 10.3) gestational weeks. GDM was diagnosed during 24-28 gestational weeks according to the Chinese Guidelines on Diagnosis and Management of Hyperglycemia in Pregnancy (2022). Multivariable logistic regression models with adjustments for socio-demographic and lifestyle factors were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations of sleep traits with GDM risk. RESULTS: We identified 503 incident GDM cases among 6993 participants. Compared with women who slept for 7-9 hours/night in early pregnancy, those who slept <7 hours/night showed a higher risk of GDM (OR, 1.75; 95 % CI: 1.20-2.54), whereas those who slept >9 hours/night showed no significant association for GDM risk (OR, 1.01; 95 % CI: 0.78-1.30). Compared with women with absolutely no napping, those with ≤60 and > 60 min/day midday napping showed no significant association for GDM risk (OR, 0.82; 95 % CI: 0.64-1.05 for ≤60 min/day midday napping; OR, 0.87; 95 % CI: 0.66-1.15 for >60 min/day midday napping). Poor sleep quality was not associated with GDM risk compared with good quality (OR, 0.90; 95 % CI: 0.72-1.12). CONCLUSION: A short nighttime sleep duration during early pregnancy was associated with a higher risk of GDM, which was independent of midday napping, sleep quality and lifestyle factors.

APOE Genotype Modifies the Association between Midlife Adherence to the Planetary Healthy Diet and Cognitive Function in Later Life among Chinese Adults in Singapore.

BACKGROUND: It remains unclear if adherence to the planetary healthy diet (PHD), designed to improve human and environmental health, is associated with better cognitive function in aging, and if this association differs by apolipoprotein E (APOE) genotype. OBJECTIVES: We aimed to examine the association between the PHD pattern and risk of poor cognitive function, and to further assess whether the APOE ε4 allele could modify this association. METHODS: The study included 16,736 participants from the Singapore Chinese Health Study. The PHD score was calculated using data from a validated 165-item food frequency questionnaire at baseline (1993-1998), with higher scores indicating greater adherence to the PHD. Cognitive function was assessed by the Singapore-modified Mini-Mental State Examination at follow-up 3 visits (2014-2016). A subset of 9313 participants had APOE genotype data. Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders. RESULTS: We identified 2397 (14.3%) cases of poor cognitive function. In the total population, OR (95% CI) of poor cognitive function for each one-SD increment in the PHD score was 0.89 (0.85, 0.93). Carriers of APOE ε4 allele had increased risk of poor cognitive function (OR: 1.36, 95% CI: 1.15, 1.61). There was a significant interaction between the PHD score and the APOE ε4 allele (P-interaction = 0.042). Each one-SD increment in the PHD score was significantly associated with lower risk of poor cognitive function (OR: 0.89; 95% CI: 0.83, 0.96) in non-carriers of APOE ε4 allele, but not in APOE ε4 allele carriers (OR: 1.04, 95% CI: 0.89, 1.23). CONCLUSIONS: Midlife adherence to the PHD was associated with reduced risk of poor cognitive function in later life. However, this was not observed in carriers of APOE ε4 allele who had higher risk of poor cognitive function.

Adherence to a Planetary Health Diet, Environmental Impacts, and Mortality in Chinese Adults.

Importance: Although the EAT-Lancet Commission has recently proposed a planetary health diet (PHD) to promote human and environmental health, little is known about how PHD affects environment and mortality risk among an Asian population. Objective: To investigate whether a PHD score is associated with environmental impacts and mortality outcomes in a Chinese cohort living in Singapore. Design, Setting, and Participants: This cohort study used data from the Singapore Chinese Health Study. Eligible participants were without known cardiovascular disease and cancer at baseline; they were recruited between 1993 and 1998 and followed up using record linkage data until 2020. Data were analyzed from September 2022 to April 2023. Exposures: PHD score was calculated based on the reference consumption of 14 dietary components in PHD and individual energy intake assessed using a validated food frequency questionnaire in this cohort. Main Outcomes and Measures: Diet-related environmental impacts were estimated using a food frequency questionnaire. Mortality outcomes (all-cause, cardiovascular disease, cancer, and respiratory disease) were identified via linkage with a nationwide registry. Results: A total of 57 078 participants were included in this study (mean [SD] age, 56.1 (7.9) years; 31 958 women [56.0%]). During a median (IQR) follow-up of 23.4 (18.7-26.2) years, 22 599 deaths occurred. Comparing the highest and lowest quintiles, higher PHD scores were associated with lower greenhouse gas emissions (ß = -0.13 kg CO2 equivalent; 95% CI, -0.14 to -0.12 kg CO2 equivalent), but with higher total water footprint (ß = 0.12 m3; 95% CI, 0.11-0.13 m3) and land use (ß = 0.29 m2; 95% CI, 0.28-0.31 m2). In the adjusted multivariable model, compared with the lowest quintile, participants in the highest quintile of PHD score had lower risk of all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.81-0.89), cardiovascular disease mortality (HR, 0.79; 95% CI, 0.73-0.85), cancer mortality (HR, 0.93; 95% CI, 0.86-1.00), and respiratory disease mortality (HR, 0.81; 95% CI, 0.74-0.89). Conclusions and Relevance: In this study of Singapore Chinese adults, higher adherence to PHD was associated with reduced risk of chronic disease mortality. However, environmental impacts were uncertain, as higher adherence was associated with lower greenhouse gas emissions but higher total water footprint and land use.

Metal Exposure during Early Pregnancy and Risk of Gestational Diabetes Mellitus: Mixture Effect and Mediation by Phospholipid Fatty Acids.

Despite existing studies exploring the association between metal exposure and gestational diabetes mellitus (GDM), most of them have focused on a single metal or a small mixture of metals. Our prospective work investigated the joint and independent effects of early gestational exposure to 17 essential and nonessential metals on the GDM risk and potential mediation by plasma phospholipid fatty acids (PLFAs) based on a nested case-control study established with 335 GDM cases and 670 randomly matched healthy controls. The Bayesian kernel machine regression (BKMR) and quantile g-computation analyses demonstrated a joint effect from metal co-exposure on GDM risk. BKMR with hierarchical variable selection indicated that the group of essential metals was more strongly associated with GDM than the group of nonessential metals with group posterior inclusion probabilities (PIPs) of 0.979 and 0.672, respectively. Cu (0.988) and Ga (0.570) had the largest conditional PIPs within each group. We also observed significant mediation effects of selected unsaturated PLFAs on Cu-GDM and Ga-GDM associations. KEGG enrichment analysis further revealed significant enrichment in the biosynthesis of unsaturated PLFAs. C18:1 n-7 exhibited the largest proportion of mediation in both associations (23.8 and 22.9%). Collectively, our work demonstrated the joint effect of early gestational metal exposure on GDM risk and identified Cu and Ga as the key species to the joint effect. The findings lay a solid ground for further validation through multicenter investigations and mechanism exploration via laboratory studies.

Blood Cell Parameters From Early to Middle Pregnancy and Risk of Gestational Diabetes Mellitus.

CONTEXT: Chronic low-grade inflammation may play a crucial role in the pathogenesis of gestational diabetes mellitus (GDM). However, prospective studies on the relations of inflammatory blood cell parameters during pregnancy with GDM are lacking. OBJECTIVE: To prospectively investigate the associations of inflammatory blood cell parameters in both early and middle pregnancy, and their change patterns from early to middle pregnancy, with GDM risk. METHODS: We used data from the Tongji-Shuangliu Birth Cohort. Inflammatory blood cell parameters (white blood cells [WBC], neutrophils, lymphocytes, monocytes, neutrophil to lymphocyte ratio [NLR], and platelets) were assayed before 15 weeks and between 16 and 28 weeks of gestational age. Logistic regression was used to evaluate the associations between inflammatory blood cell parameters and GDM. RESULTS: Of the 6354 pregnant women, 445 were diagnosed with GDM. After adjustment for potential confounders, WBC, neutrophils, lymphocytes, monocytes, and NLR in early pregnancy were positively associated with GDM risk (odds ratios [95% CI] for extreme-quartile comparison were 2.38 [1.76-3.20], 2.47 [1.82-3.36], 1.40 [1.06-1.85], 1.69 [1.27-2.24], and 1.51 [1.12-2.02], respectively, all P for trend ≤ .010). Similarly, higher levels of WBC, neutrophils, monocytes, and NLR in middle pregnancy were associated with increased risk of GDM (all P for trend ≤ .014). Stable high levels (≥ median in both early and middle pregnancy) of WBC, neutrophils, monocytes, and NLR were positively associated with GDM risk (all P ≤ .001). CONCLUSION: Increased WBC, neutrophils, monocytes, and NLR in both early and middle pregnancy and their stable high levels from early to middle pregnancy were associated with higher GDM risk, highlighting that they might be clinically relevant for identifying individuals at high risk for GDM.

The relationship between physical activity in early pregnancy and hypertensive disorders of pregnancy: a cohort study in Chinese women.

BACKGROUND: We aimed to examine prospective associations between different intensities and different types of physical activity (PA) in early pregnancy and hypertensive disorders of pregnancy (HDP) among Chinese women. METHODS: A total of 6,820 pregnant women from the Tongji-Shuangliu Birth Cohort were included in this study. The pregnancy physical activity questionnaire (PPAQ) was used to assess PA, including household/caregiving, occupational, sports/exercise, and transportation activities in the first trimester of pregnancy. The diagnosis of HDP was collected, including gestational hypertension (GH) and preeclampsia (PE). Data were analyzed by unconditional multivariate logistic regression, and the odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: A total of 178 (2.6%) of the 6,820 women were diagnosed with HDP, of which 126 (1.8%) were GH and 52 (0.8%) were PE. Overall, we found no association between PA in early pregnancy and PE. A trend toward lower risk was found only among women with GH and among those with higher levels of moderate-to-vigorous intensity physical activity (MVPA) (adjusted OR 0.54, 95% CI 0.31-0.96). No association was observed between PA and HDP in early pregnancy, regardless of different intensities or types of PA. CONCLUSION: MVPA in the first trimester is an influencing factor of HDP. Encouraging pregnant women to engage in MVPA in the first trimester may help to prevent GH.

Association between Prepregnancy Weight Change and Risk of Gestational Diabetes Mellitus in Chinese Pregnant Women.

BACKGROUND: Evidence regarding prepregnancy weight change and gestational diabetes mellitus (GDM) is lacking among East Asian women. OBJECTIVES: Our study aimed to investigate the association between weight change from age 18 y to pregnancy and GDM in Chinese pregnant women. METHODS: Our analyses included 6972 pregnant women from the Tongji-Shuangliu Birth Cohort. Body weights were recalled for age 18 y and the time point immediately before pregnancy, whereas height was measured during early pregnancy. Prepregnancy weight change was calculated as the difference between weight immediately before pregnancy and weight at age 18 y. GDM outcomes were ascertained by 75-g oral-glucose-tolerance test. Multivariable logistic regression models were used to examine the association between prepregnancy weight change and risk of GDM. RESULTS: In total, 501 (7.2%) developed GDM in the cohort. After multivariable adjustments, prepregnancy weight change was linearly associated with a higher risk of GDM (P < 0.001). Compared with participants with stable weight (weight change within 5.0 kg) before pregnancy, multivariable-adjusted odds ratios and 95% confidence intervals were 1.55 (1.22, 1.98) and 2.24 (1.78, 2.83) for participants with moderate (5-9.9 kg) and high (≥10 kg) weight gain, respectively. In addition, overweight/obesity immediately before pregnancy mediated 17.6% and 31.7% of the associations of moderate and high-weight gain with GDM risk, whereas weekly weight gain during pregnancy mediated 21.1% and 22.7% of the associations. CONCLUSIONS: Weight gain from age 18 y to pregnancy was significantly associated with a higher risk of GDM. Maintaining weight stability, especially prevention of excessive weight gain from early adulthood to pregnancy, could be a potential strategy to reduce GDM risk.

BMI and lipidomic biomarkers with risk of gestational diabetes in pregnant women.

OBJECTIVE: The study aimed to identify BMI-related lipids and to explore the role of lipids linking BMI and gestational diabetes mellitus (GDM). METHODS: Plasma lipidome, height, and weight were measured in early pregnancy among 1008 women. Pearson correlation analyses and least absolute shrinkage and selection operator regression (LASSO) were performed to identify BMI-associated lipids. Based on these lipids, a lipid score was created using LASSO, and its association with GDM risk was evaluated by conditional logistic regression. The causal relationships between BMI and lipids were tested by Mendelian randomization analysis with genotyping data. Mediation analysis was conducted to evaluate the mediating effect of lipids on the association of BMI with GDM. RESULTS: Of 366 measured lipids, BMI was correlated with 28 lipids, which mainly belong to glycerophospholipids and glycerolipids. A total of 10 lipid species were associated with BMI, and a lipid score was established. A causal relationship between BMI and lysophosphatidylcholine 14:0 was observed. The lipid score was associated with a 1.69-fold increased risk of GDM per 1-point increment (95% CI: 1.33-2.15). Furthermore, BMI-associated lipids might explain 66.4% of the relationship between BMI and GDM. CONCLUSIONS: Higher BMI in early pregnancy was associated with altered lipid metabolism that may contribute to the increased risk of GDM.

Sperm mitochondrial DNA copy number in relation to semen quality: A cross-sectional study of 1164 potential sperm donors.

OBJECTIVE: To investigate the association between mitochondrial DNA copy number (mtDNAcn) and semen quality. DESIGN: A cross-sectional study. SETTING: Hubei Province Human Sperm Bank of China (from April 2017 to July 2018). POPULATION: A total of 1164 healthy male sperm donors with 5739 specimens. MAIN OUTCOME MEASURES: Real-time quantitative polymerase chain reaction (RT-PCR) was used to measure sperm mtDNAcn. We also determined semen volume, concentration and motility parameters (progressive motility, nonprogressive motility and immotility). METHODS: Mixed-effect models and general linear models were uses. RESULTS: After adjusting for relevant confounding factors, mixed-effect models revealed diminished sperm motility (progressive and total), concentration, and total count across the quartiles of mtDNAcn (all P < 0.05). Compared with men in the lowest quartile, men in the highest quartile of mtDNAcn had lower progressive sperm motility, total motility, concentration and total count of -8.9% (95% CI -12.7% to -5.0%), -8.0% (95% CI -11.6% to -4.4%), -42.8% (95% CI -47.7% to -37.4%), and - 44.3% (95% CI -50.1% to -37.7%), respectively. These inverse dose-response relationships were further confirmed in the cubic spline models, where mtDNAcn was modelled as a continuous variable. CONCLUSIONS: We found that mtDNAcn was inversely associated with semen quality in a dose-dependent manner. Our results provide novel clues that sperm mtDNAcn may serve as a useful predictor of human semen characteristics. TWEETABLE ABSTRACT: Sperm mitochondrial DNA copy number was markedly associated with diminished sperm motility (progressive and total), concentration and total count.

Associations between depression, oxidative stress, and semen quality among 1,000 healthy men screened as potential sperm donors.

OBJECTIVE: To explore the association between depression and semen quality and the mediating role of oxidative stress. DESIGN: Cross-sectional study with repeated measures of semen quality. SETTING: Human Sperm Bank of Hubei Province, People's Republic of China. PATIENT(S): From April 2017 to July 2018, we recruited 1,000 potential sperm donors who completed the Beck Depression Inventory questionnaire and had measures of oxidative stress biomarkers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Severity of depression was evaluated by the Beck Depression Inventory scores (0-4, no depression; 5-13, mild depression; 14-20, moderate depression; and 21 or greater, severe depression). The urinary concentrations of 8-hydroxy-2-deoxyguanosine, 4-hydroxy-2-nonenal-mercapturic acid, and 8-iso-prostaglandin F2α (8-isoPGF2α) were measured to reflect oxidative stress status. Repeated semen quality parameters (n = 5,880) were examined by trained professional technicians according to the World Health Organization laboratory manual. Associations between depression, oxidative stress, and repeated measures of semen quality parameters were evaluated using linear or mixed-effects models with adjustment for potential confounders. Mediation analysis was performed to test the potential mediating role of oxidative stress. RESULT(S): A total of 391 (39.1%) men were classified as mild depression, 67 (6.7%) as moderate depression, and 19 (1.9%) as severe depression. Inverse dose-response relationships between severity of depression and semen quality parameters were found. Compared with men without depression (n = 523), those with severe depression had a 25.26% (95% confidence interval, -38.65%, -8.93%) lower semen volume, 37.04% (-55.37%, -11.20%) lower total sperm count, 13.57% (-23.17%, -2.78%) lower total motility, and 15.08% (-25.09%, -3.72%) lower progressive motility; men with moderate depression also had a 12.28% (-21.16%, -2.40%) lower semen volume and 23.56% (-36.50%, -7.97%) lower total sperm count. We found a positive dose-response relationship between severity of depression and urinary 8-isoPGF2α concentrations. However, we found no evidence that the associations between depression status and semen quality were mediated by oxidative stress markers. CONCLUSION(S): In the study of Chinese male sperm donors, men with depression had worse semen quality parameters, including semen volume, sperm concentration, total sperm count, total motility, and progressive motility. Although depression was positively associated with urinary 8-isoPGF2α concentrations, depression-semen quality associations were not mediated by oxidative stress.