Causal relationships between the gut microbiome, blood lipids, and heart failure: a Mendelian randomization analysis.

BACKGROUND: Studies have linked gut microbiome and heart failure (HF). However, their causal relationships and potential mediating factors have not been well defined. AIMS: To investigate the causal relationships between the gut microbiome and HF and the mediating effect of potential blood lipids by using genetics. METHOD: We performed a bidirectional and mediation Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of gut microbial taxa (Dutch Microbiome Project, n = 7,738), blood lipids (UK Biobank, n = 115,078), and a meta-analysis of HF (115,150 cases and 1,550,331 controls). We applied the inverse-variance weighted estimation method as the primary method, with several other estimators as complementary methods. The multivariable MR approach based on Bayesian model averaging (MR-BMA) was used to prioritize the most likely causal lipids. RESULTS: Six microbial taxa are suggestively associated with HF causally. The most significant taxon was the species Bacteroides dorei (odds ratio = 1.059, 95% confidence interval [CI] = 1.022 - 1.097, P value = 0.0017). The MR-BMA analysis showed that apolipoprotein B (ApoB) was the most likely causal lipid for HF (the marginal inclusion probability = 0.717, P value = 0.005). The mediation MR analysis showed that ApoB mediated the causal effects of species Bacteroides dorei on HF (proportion mediated = 10.1%, 95% CI = 0.2% - 21.6%, P value = 0.031). CONCLUSION: The study suggested a causal relationship between specific gut microbial taxa and HF and that ApoB might mediate this relationship as the primary lipid determinant of HF.

We conducted a Mendelian randomization analysis to examine the causal relationships between the gut microbiome and heart failure and the mediating role of blood lipids. Six gut microbial taxa were identified as having potentially causal effects on heart failure, with Bacteroides dorei being the most significant one. Apolipoprotein B was found to be the primary lipid determinant of heart failure among five common lipids and mediated 10.1% of the causal effect of Bacteroides dorei on heart failure.

Sex- and age-specific association between outdoor light at night and obesity in Chinese adults: A national cross-sectional study of 98,658 participants from 162 study sites.

Background: Exposure to light at night (LAN) is a potent disruptor of the circadian system. Whether LAN exposure exerts a sex- or age-specific influence on obesity needs investigation. Objectives: To estimate the sex- and age-specific associations of exposure to outdoor LAN and obesity based on a national and cross-sectional survey. Methods: The study included a nationally representative sample of 98,658 adults aged ≥ 18 years who had lived in their current residence for ≥ 6 months from 162 study sites across mainland China in 2010. Outdoor LAN exposure was estimated from satellite imaging data. General obesity was defined as body-mass index (BMI) ≥ 28 kg/m2 and central obesity was defined as waist circumference ≥ 90 cm in men and ≥ 85 cm in women. Linear and logistic regression models were used to examine the associations between LAN exposure and prevalent obesity in sex and age categories. Results: A monotonically increasing association of outdoor LAN with BMI, waist circumference was observed in all sex and age categories, except for adults aged 18-39 years. Significant associations of LAN exposure with prevalent obesity were observed in each sex and age category, especially in men and older people. Per 1-quintile increase in LAN was associated with 14% increased odds of general obesity in men (odds ratio, OR=1.14, 95% confidence interval, CI=1.07-1.23) and 24% in adults aged ≥ 60 years (OR=1.24, 95% CI=1.14-1.35). Per 1-quintile increase in LAN was associated with 19% increased odds of central obesity in men (OR=1.19, 95% CI=1.11-1.26) and 26% in adults aged ≥ 60 years (OR=1.26, 95% CI=1.17-1.35). Conclusions: Increased chronic outdoor LAN exposure was associated with increased prevalence of obesity in sex- and age- specific Chinese populations. Public health policies on reducing light pollution at night might be considered in obesity prevention.

Data-driven subgroups of prediabetes and the associations with outcomes in Chinese adults.

Prediabetes and its pathophysiology remain important issues. We aimed to examine the cluster characteristics of prediabetes and explore their associations with developing diabetes and its complications based on 12 variables representing body fat, glycemic measures, pancreatic ß cell function, insulin resistance, blood lipids, and liver enzymes. A total of 55,777 individuals with prediabetes from the China Cardiometabolic Disease and Cancer Cohort (4C) were classified at baseline into six clusters. During a median of 3.1 years of follow-up, significant differences in the risks of diabetes and its complications between clusters were observed. The odds ratios of diabetes stepwisely increase from cluster 1 to cluster 6. Clusters 1, 4, and 6 have increased chronic kidney diseases risks, while the prediabetes in cluster 4, characterized by obesity and insulin resistance, confers higher risks of cardiovascular diseases compared with others. This subcategorization has potential value in developing more precise strategies for targeted prediabetes prevention and treatment.

Sex differences in the risk of arterial stiffness among adults with different glycemic status and modifications by age.

BACKGROUND: Studies indicate lower, comparable, and higher cardiovascular risks in women vs men in normal glucose regulation (NGR), prediabetes, and diabetes, respectively. However, this sex difference is uncertain and aging might play a part. We aimed to estimate sex differences in arterial stiffness in NGR, prediabetes, or diabetes and the potential modifications by age. METHODS: We used baseline data of 9618 participants aged ≥40 years in a large community-based cohort study in Shanghai. Glycemic status was determined by history of diabetes, fasting and 2-h post-load glucose levels, and hemoglobin A1c levels. Arterial stiffness was examined by brachial-ankle pulse wave velocity (ba-PWV). Multivariable linear regression analysis was conducted to examine the associations between sex and ba-PWV levels in glycemic and age categories. RESULTS: Before adjustment for age, women had lower, comparable, and higher ba-PWV vs men in the NGR, prediabetes, and diabetes groups, respectively. In participants aged 40-59 years, women were associated with lower ba-PWV levels in generally all glycemic strata after adjustment for age and other confounders. In participants aged ≥60 years, women were associated with significantly higher ba-PWV levels (ß coefficient = 71.5; 95% confidence interval = 23.4, 119.7) and the sex difference was attenuated in the groups of prediabetes and diabetes with a borderline significant interaction between sex and glycemic status (p for interaction = .068). CONCLUSIONS: The sex difference in cardiovascular risks in adults with NGR, prediabetes, or diabetes was dependent on age. Our findings provide new evidence for prioritizing preventive treatment against atherosclerosis in men vs women with different glycemic status.

Blood Pressure Levels, Cardiovascular Events, and Renal Outcomes in Chronic Kidney Disease Without Antihypertensive Therapy: A Nationwide Population-Based Cohort Study.

BACKGROUND: High blood pressure (BP) is highly prevalent in patients with chronic kidney disease. However, the thresholds to initiate BP-lowering treatment in this population are unclear. We aimed to examine the associations between BP levels and clinical outcomes and provide evidence on potential thresholds to initiate BP-lowering therapy in people with chronic kidney disease. METHODS: This nationwide, multicenter, prospective cohort study included 12 523 chronic kidney disease participants without antihypertensive therapy in mainland China. Participants were followed up during 2011 to 2016 for cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, hospitalized or treated heart failure, and cardiovascular death) and renal events (≥20% decline in the estimated glomerular filtration rate, end-stage kidney disease, and renal death). RESULTS: Overall, 652 cardiovascular events and 1268 renal events occurred during 43 970 person-years of follow-up. We observed a positive and linear relationship between systolic BP and risks of cardiovascular and renal events down to 90 mm Hg, as well as between diastolic BP and risks of renal events down to 50 mm Hg. A J-shaped trend was noted between diastolic BP and risks of cardiovascular events, but a linear relationship was revealed in participants <60 years (P for interaction <0.001). A significant increase in the risk of cardiovascular and renal outcomes was observed at systolic BP ≥130 mm Hg (versus 90-119 mm Hg) and at diastolic BP ≥90 mm Hg (versus 50-69 mm Hg). CONCLUSIONS: In people with chronic kidney disease, a higher systolic BP/diastolic BP level (≥130/90 mm Hg) is significantly associated with a greater risk of cardiovascular and renal events, indicating potential thresholds to initiate BP-lowering treatment.

A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disease with hypogonadism and infertility caused by the defects in embryonic migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, hypothalamic GnRH secretion or GnRH signal transduction. PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the Gαq, Gαs and ERK1/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of Gαq, instead of MAPK/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to Gαq signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according Gαq pathway functionality: (i) neutral (N, >80% activity); (ii) low pathogenicity (L, 50-80% activity); (iii) medium pathogenicity (M, 20-50% activity) and (iv) high pathogenicity (H, <20% activity). We further compared the cell-based functional results with in silico mutational prediction programs. Our results indicated that while Sorting Intolerant from Tolerant predictions were accurate for transmembrane region mutations, mutations localized in the intracellular and extracellular domains were accurately predicted by the Combined Annotation Dependent Depletion prediction tool. Our results thus provide a functional database that can be used to guide diagnosis and appropriate genetic counseling in IHH patients with PROKR2 mutations.

Risk of cardiovascular disease, death, and renal progression in diabetes according to albuminuria and estimated glomerular filtration rate.

AIM: We aimed to examine risks of major cardiovascular events (MACEs), renal outcomes, and all-cause mortality in type 2 diabetes mellitus (T2DM) patients with different diabetic kidney disease (DKD) subtypes. METHODS: A total of 36,509 participants with T2DM recruited from 20 community sites across mainland China were followed up during 2011-2016. DKD subtypes were categorized based on albuminuria (urinary albumin-to-creatinine ratio, UACR ≥ 30 mg/g) and reduced estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m2) as Alb-/eGFR-, Alb+/eGFR-, Alb-/eGFR+, and Alb+/eGFR+. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of developing clinical outcomes in DKD subtypes. RESULTS: More than half (53.5%) of participants with diabetes and reduced eGFR had normal UACR levels (Alb-/eGFR+), termed as non-albuminuria DKD. These patients had a modest increase in the risks of MACEs (hazard ratio, HR 1.42 [95% CI 1.08;1.88]) and mortality (HR 1.42 [1.04;1.92]) compared with patients without DKD, whereas CKD progression was not significantly increased (HR 0.97 [0.60;1.57]). Participants with albuminuria (Alb+/eGFR- or Alb+/eGFR+) had higher risks of clinical outcomes. Subgroup analysis revealed that the associations between non-albuminuria DKD and risks of MACEs and mortality were more evident in those aged <65 years. CONCLUSION: Non-albuminuria DKD accounts for more than half of DKD cases with low eGFR in Chinese diabetes patients. Diabetes patients with albuminuria are at higher risks of developing clinical outcomes and warrant early intervention, as well as patients with non-albuminuria DKD with age < 65 years.

Comorbidities prolonged viral shedding of patients infected with SARS-CoV-2 omicron variant in Shanghai: A multi-center, retrospective, observational study.

BACKGROUND: As the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surges amid the coronavirus disease 2019 (COVID-19) pandemic, there is limited comorbidities data associated with viral shedding time (VST). We aimed to investigate the effect of comorbidities on VST in asymptomatic and mild patients with omicron. METHODS: A multi-center, retrospective, observational study was conducted from March 12, 2022 to May 24, 2022 in Shanghai. The analysis was adjusted for patients' baseline demographic, using log-rank test and logistic regression model. RESULTS: The study enrolled 198,262 subjects. The median duration of viral shedding time (VST) was 8.29 days. The number of cumulative viral shedding events was significantly lower in the chronic obstructive pulmonary disease (COPD), hyperlipidemia, diabetes, urinary system disease, and cardiocerebrovascular disease than in the no corresponding comorbidities group. Patients with comorbidities had a lower incidence of viral shedding, and the most significant independent risk factor is COPD (aOR 1.78, 95% CI: 1.53-2.08, p < 0.001). Across different age ranges, the comorbidities affecting viral shedding also differ, with the greatest risk factors for viral shedding being hyperlipidemia (aOR 2.23, 95% CI: 1.50-3.31, p < 0.001) and COPD (aOR 1.85, 95% CI: 1.50-2.28, p < 0.001) between ages of 18-39 and 40-64, and thyroid dysfunction (aOR 2.36, 95% CI: 1.60-3.47, p < 0.001) above age 64. CONCLUSIONS: Omicron-infected patients with comorbidities might prolong the VST. The independent risk factors also differ across age ranges, suggesting that providing targeted effective prevention and control guidance and allocating appropriate resources to different populations should be a crucial strategy.

Comorbidities prolonged viral shedding of patients infected with SARS-CoV-2 omicron variant in Shanghai: A multi-center, retrospective, observational study.

BACKGROUND: As the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surges amid the coronavirus disease 2019 (COVID-19) pandemic, there is limited comorbidities data associated with viral shedding time (VST). We aimed to investigate the effect of comorbidities on VST in asymptomatic and mild patients with omicron. METHODS: A multi-center, retrospective, observational study was conducted from March 12, 2022 to May 24, 2022 in Shanghai. The analysis was adjusted for patients' baseline demographic, using log-rank test and logistic regression model. RESULTS: The study enrolled 198,262 subjects. The median duration of viral shedding time (VST) was 8.29 days. The number of cumulative viral shedding events was significantly lower in the chronic obstructive pulmonary disease (COPD), hyperlipidemia, diabetes, urinary system disease, and cardiocerebrovascular disease than in the no corresponding comorbidities group. Patients with comorbidities had a lower incidence of viral shedding, and the most significant independent risk factor is COPD (aOR 1.78, 95% CI: 1.53-2.08, p < 0.001). Across different age ranges, the comorbidities affecting viral shedding also differ, with the greatest risk factors for viral shedding being hyperlipidemia (aOR 2.23, 95% CI: 1.50-3.31, p < 0.001) and COPD (aOR 1.85, 95% CI: 1.50-2.28, p < 0.001) between ages of 18-39 and 40-64, and thyroid dysfunction (aOR 2.36, 95% CI: 1.60-3.47, p < 0.001) above age 64. CONCLUSIONS: Omicron-infected patients with comorbidities might prolong the VST. The independent risk factors also differ across age ranges, suggesting that providing targeted effective prevention and control guidance and allocating appropriate resources to different populations should be a crucial strategy.

Causal Association Between Obesity, Circulating Glutamine Levels, and Depression: A Mendelian Randomization Study.

CONTEXT: Observational studies indicated obesity and glutamatergic dysfunction as potential risk factors of depression, and reported disturbance of glutamine metabolism in obese state. However, it remains unclear whether the interrelationships between obesity, glutamine, and depression are causal. OBJECTIVE: We conducted 2-sample bidirectional mendelian randomization (MR) analyses to explore the causalities between circulating glutamine levels, specific depressive symptoms, major depressive disorder (MDD), and body mass index (BMI). METHODS: Univariable MR, multivariable MR (MVMR), and linkage disequilibrium score regression (LDSR) analyses were performed. RESULTS: Genetic downregulation of glutamine was causally associated with MDD, anhedonia, tiredness, and depressed mood at the false discovery rate (FDR)-controlled significance level (estimate, -0.036 ∼ -0.013; P = .005 to P = .050). Elevated BMI was causally linked to lower glutamine level (estimate, -0.103; P = .037), as well as more severe depressed mood, tiredness, and anhedonia (estimate, 0.017 ∼ 0.050; P < .001 to P = .040). In MVMR analysis, BMI was causally related to depressed mood dependently of glutamine levels. Conversely, it showed limited evidence supporting causal effects of depression on glutamine levels or BMI, except a causal association of tiredness with elevated BMI (estimate, 0.309; P = .003). LDSR estimates were directionally consistent with MR results. CONCLUSION: The present study reported that higher BMI was causally associated with lower glutamine levels. Both obesity and downregulation of glutamine were causally linked to depression.

Galectin-9 expression clinically associated with mature dendritic cells infiltration and T cell immune response in colorectal cancer.

BACKGROUND: Galectin-9 is a member of the galectin family and has been reported to have a tumor-promoting or antitumor effect in response to the immune microenvironment. However, the immunomodulatory effect of galectin-9 in colorectal cancer (CRC) remains unclear. The antigen presentation and antitumor immune effects of galectin-9 in CRC were examined in this study. METHODS: The expression of galectin-9, dendritic cell markers (CD208 and CD1a), T-cell markers (CD3 and CD8) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was assessed using immunohistochemistry in CRC samples. The correlation between galectin-9 and immune cells or immunomodulatory factors was also evaluated via multiple gene expression databases. RESULTS: The level of galectin-9 was decreased in mismatch repair-proficient patients compared with mismatch repair-deficient patients (p = 0.0335). GSEA showed that the regulatory mechanism of galectin-9 in CRC was related to a variety of immune pathways. Galectin-9 expression was strongly correlated with immune cell infiltration and immunomodulators (all p < 0.0001). In the relationship between galectin-9 expression and the infiltration of DCs, there was a negative correlation in CD1a + immature DCs (R = -0.263, p = 0.042). A strong positive correlation was observed in CD208 + mature DCs (R = 0.391, p < 0.01). Patients with high galectin-9 expression also exhibited abundant CD8 + T-cell and CD3 + T-cell infiltration. CONCLUSION: Collectively, our findings provide evidence that galectin-9 may increase the antitumor immune response of patients with CRC. DCs play an important role in galectin-9-mediated antitumor immune responses, which provides further insight into the development of immunotherapy.

Outdoor light at night in relation to glucose homoeostasis and diabetes in Chinese adults: a national and cross-sectional study of 98,658 participants from 162 study sites.

AIMS/HYPOTHESIS: Exposure to artificial light at night (LAN) disrupts the circadian timing system and might be a risk factor for diabetes. Our aim was to estimate the associations of chronic exposure to outdoor LAN with glucose homoeostasis markers and diabetes prevalence based on a national and cross-sectional survey of the general population in China. METHODS: The China Noncommunicable Disease Surveillance Study was a nationally representative study of 98,658 participants aged ≥18 years who had been living in their current residence for at least 6 months recruited from 162 study sites across mainland China in 2010. Diabetes was defined according to ADA criteria. Outdoor LAN exposure in 2010 was estimated from satellite data and the participants attending each study site were assigned the same mean radiance of the outdoor LAN at the study site. The linear regression incorporating a restricted cubic spline function was used to explore the relationships between LAN exposure and markers of glucose homoeostasis. Cox regression with a constant for the time variable assigned to all individuals and with robust variance estimates was used to assess the associations between the levels of outdoor LAN exposure and the presence of diabetes by calculating the prevalence ratios (PRs) with adjustment for age, sex, education, smoking status, drinking status, physical activity, family history of diabetes, household income, urban/rural areas, taking antihypertensive medications, taking lipid-lowering medications, and BMI. RESULTS: The mean age of the study population was 42.7 years and 53,515 (weighted proportion 49.2%) participants were women. Outdoor LAN exposure levels were positively associated with HbA1c, fasting and 2 h glucose concentrations and HOMA-IR and negatively associated with HOMA-B. Diabetes prevalence was significantly associated with per-quintile LAN exposure (PR 1.07 [95% CI 1.02, 1.12]). The highest quintile of LAN exposure (median 69.1 nW cm-2 sr-1) was significantly associated with an increased prevalence of diabetes (PR 1.28 [95% CI 1.03, 1.60]) compared with the lowest quintile of exposure (median 1.0 nW cm-2 sr-1). CONCLUSIONS/INTERPRETATION: There were significant associations between chronic exposure to higher intensity of outdoor LAN with increased risk of impaired glucose homoeostasis and diabetes prevalence. Our findings contribute to the growing evidence that LAN is detrimental to health and point to outdoor LAN as a potential novel risk factor for diabetes.

Age-specific prevalence, subtypes and risk factors of metabolic diseases in Chinese adults and the different patterns from other racial/ethnic populations.

BACKGROUND: Age has substantial influence on metabolic diseases patterns. Ethnic disparities of metabolic characteristics between Chinese and other populations also exist. Large-scale investigations of age-specific prevalence, subtypes and modifiable risk factors of metabolic disorders are essential to promote individualized strategies for the control and prevention of metabolic diseases in multi-ethnic populations. The study aims to address the age-specific prevalence, subtype characteristics and risk factor profiles of metabolic diseases among different races/ethnicities. METHODS: We analyzed data from the China Noncommunicable Disease Surveillance 2010 and the National Health and Nutrition Evaluation Survey (NHANES). We examined the prevalence and subtypes of hypertension, diabetes and hyperlipidemia across age groups in four ethnic populations. We also investigated the odds ratios (ORs) of metabolic diseases associated with 11 classical risk factors in the young and the elder Mainland Chinese. RESULTS: The sex and BMI standardized prevalence of hypertension in Chinese aged 18-40 years was 18.5% and was the highest among the four populations. The main pathophysiologic subtype of diabetes was characterized by insulin resistance, instead of ß-cell dysfunction in Mainland Chinese, and this pattern was more evident in obese subjects. The major subtype of hyperlipidemia in Mainland Chinese was hypertriglyceridemia, while Non-Hispanic Whites and Blacks were more prone to high low-density lipoprotein cholesterol. For risk of hypertension, diabetes and hyperlipidemia, young Chinese adults were more prone to general and central obesity than older ones. The other factors showed similar effects on the young and the old. CONCLUSIONS: The age-specific prevalence, subtypes and risk factors of metabolic diseases were substantially different in Chinese and other ethnic/racial populations.

Association between triglyceride glucose index and carotid intima-media thickness in obese and nonobese adults.

BACKGROUND: The triglyceride glucose (TyG) index is closely associated with subclinical atherosclerosis. However, the association remains inconclusive among obese and nonobese individuals. METHODS: This prospective study was conducted in 5751 adults with normal carotid intima-media thickness (CIMT) at baseline. We divided the population into four groups based on the TyG index, which was calculated by the following formula: Ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Information on CIMT was acquired by ultrasonography. Incident elevated CIMT was defined as IMT values greater than 0.9 mm at follow-up. Odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between TyG index and elevated CIMT were estimated using multivariable logistic regression models. RESULTS: After a median follow-up of 4.3 years, 722 (12.6%) individuals had progressed to elevated CIMT. Compared with the second quartile of the TyG index, the first and fourth quartile both conferred higher risks of elevated CIMT after adjusting for potential confounders. In the total population, the ORs for the first and fourth quartile were 1.29 (95% CI, 1.00-1.66) and 1.42 (95% CI, 1.11-1.83), respectively. Restricted cubic splines demonstrated an approximately U-shaped association between TyG index and elevated CIMT among the total and nonobese adults (P for nonlinearity <.05), but not in those with general or abdominal obesity. CONCLUSIONS: A U-shaped association was observed between TyG index and elevated CIMT only among nonobese Chinese adults.

Examining the Linear Association Between Blood Pressure Levels and Cardiovascular Diseases in the Absence of Major Risk Factors in China.

BACKGROUND: Many studies demonstrate a J-shaped association between blood pressure and cardiovascular diseases (CVDs), but the findings are plagued by confounding from other traditional cardiovascular risk factors (CVRFs). Our aims were to examine the associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels with CVD in individuals without major CVRFs and whether there were thresholds for the association. METHODS: In the 4C study (China Cardiometabolic Disease and Cancer Cohort), 36 042 CVRF-free participants without CVD, diabetes, dyslipidemia, hypertension, or smoking were identified during 2011 to 2012. Among CVRF-free participants, 17 476 CVRF-preferable individuals with better glycemic (fasting glucose, <110 mg/dL; 2-hour post-load glucose, <140 mg/dL) and lipid profile (total cholesterol, <200 mg/dL; LDL [low-density lipoprotein] cholesterol, <130 mg/dL) were selected. The total person-years of follow-up for CVRF-free subjects and CVRF-preferable subjects were 130 147 and 63 573 person-years, respectively. Information on the development of major CVDs was collected during 2014 to 2016. Cox proportional hazard models were performed to estimate the risks for incident CVD by SBP and DBP groups, respectively. RESULTS: We found that both baseline SBP and DBP presented significantly linear associations with CVD risks in CVRF-free and CVRF-preferable participants. There is significant increase in the CVD risk among CVRF-free participants with baseline SBP level of 110 to 119 mm Hg (hazard ratio, 1.79 [95% CI, 1.19-2.71]), 120 to 129 mm Hg (hazard ratio, 2.03 [95% CI, 1.36-3.03]), and 130 to 139 mm Hg (hazard ratio, 2.15 [95% CI, 1.40-3.28]) compared with SBP <110 mm Hg. Significant increases were also observed for DBP level of 80 to 89 mm Hg (hazard ratio, 1.43 [95% CI, 1.03-1.97]) compared with DBP <70 mm Hg. Similar results were observed in CVRF-preferable participants. CONCLUSIONS: SBP and DBP with levels currently considered normal were significantly and linearly associated with incident CVD without thresholds above 110/70 mm Hg among Chinese adults without major CVRFs.

Amino acids, microbiota-related metabolites, and the risk of incident diabetes among normoglycemic Chinese adults: Findings from the 4C study.

Although previous studies suggest that amino acids (AAs) and microbiota-related metabolites (MRMs) are associated with type 2 diabetes mellitus (T2DM), the results remain unclear among normoglycemic populations. We test 28 serum AAs and 22 MRMs in 3,414 subjects with incident diabetes and matched normoglycemic controls from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. In fully adjusted logistic regression models, per SD increment of branched-chain AAs, aromatic AAs, asparagine, alanine, glutamic acid, homoserine, 2-aminoadipic acid, histidine, methionine, and proline are positively associated with incident T2DM. In the MRM panel, serum carnitines, N-acetyltryptophan, and uric acid are positively associated with incident T2DM. Causal mediation analyses indicate 34 significant causal mediation linkages, with 88.2% through obesity and lipids. Variances explained in the serum metabolites are modestly limited in the comprehensive catalog of risk factor-metabolite-diabetes associations. These findings reveal that systematic AAs and MRMs change profile before T2DM onset and support a potential role of metabolic alterations in the pathogenesis of diabetes.

The association between early-life famine exposure and adulthood obesity on the risk of dyslipidemia.

BACKGROUND AND AIMS: The joint effect of famine exposure and adulthood obesity on risk of dyslipidemia remains unclear. Thus, we aim to explore the joint effect of famine exposure and adulthood obesity on the risk of dyslipidemia, and the potential effect of adult general or abdominal obesity on the association between famine exposure and dyslipidemia. METHODS AND RESULTS: We conducted a community-based cohort study in 8880 subjects aged 40 years or older. Participants were divided into nonexposed, fetal-exposed, childhood-exposed, adolescent-exposed according to birth date. General obesity and abdominal obesity were defined according to body mass index (BMI: overweight≥24.0 kg/m2, obesity≥28.0 kg/m2) and waist-to-hip ratio (WHR, men/women: moderate≥0.90/0.85, high≥0.95/0.90). Dyslipidemia was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. Compared with nonexposed participants, fetal-exposed individuals had significantly increased risk of dyslipidemia (OR:1.24, 95%CI: 1.03-1.50) in the whole study. Significant increased risk of dyslipidemia related to famine exposure was observed in women [ORs (95%CIs) were 1.36 (1.05-1.76) and 1.70 (1.22-2.37) for the fetal and childhood-exposed group, respectively] but not in men. Moreover, both general and central obesity had significant multiplicative interactions with famine exposure for the risk of dyslipidemia (P for interaction = 0.0001 and < 0.0001, respectively). Significant additive interaction was found between famine exposure and WHR on risk of dyslipidemia in women, with the relative excess risk due to interaction (RERI) and 95% CI of 0.43 (0.10-0.76). CONCLUSION: Coexistence of early-life undernutrition and adulthood obesity was associated with a higher risk of dyslipidemia in later life.

[Analysis of CHD7 gene variants in 22 patients with idiopathic hypogonadotropic hypogonadism].

OBJECTIVE: To explore clinical evaluation and genetic analysis of patients with idiopathic hypogonadotropic hypogonadism (IHH). METHODS: The clinical data and phenotypes of 22 patients with IHH diagnosed and treated in our department were reviewed and analyzed. Whole-exome sequencing (WES) and Sanger method were used for variant analysis and verification. RESULTS: Among the 22 cases of IHH probands, 12 cases of Kalman syndrome (KS) and 10 cases of IHH (nIHH) with normal sense of smell. On physical examination, males showed short penis, small testicles, small or inconspicuous laryngeal knots, and a sharp voice. Mammary gland development, mammary gland dysplasia, primary amenorrhea, etc. in women. Sex hormone examination: Follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2) levels are reduced or at the lower limit of normal. There were nine missense variants of CHD7 gene in 8 patients. Based on the American College of Medical Genetics and Genomics guidelines, the c.307T>A(p.Ser103Thr), c.3143G>A(p.Gly1048Glu), c.6956G>T (p.Arg2319Leu) and c.3145A>T (p.Ser1049Cys) variants of CHD7 gene were predicted to be likely pathogenic (PS1+PP1+PM2, PM2+PM6+PP2+PP3, PM2+PM5+PM6+PP2+PP3 and PM2+PM6+PP2+PP3), the remaining 14 cases of IHH patients had negative genetic screening. CONCLUSION: CHD7 gene variants may be related to IHH disease.

SLIT2 Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism.

INTRODUCTION: Idiopathic hypogonadotropic hypogonadism (IHH) is a rare reproductive disorder resulting from gonadotropin-releasing hormone (GnRH) deficiency. However, in only approximately half of patients with IHH is it possible to identify a likely molecular diagnosis. Mice lacking Slit2 have a reduced number or altered patterning of GnRH neurons in the brain. In order to assess the contribution of SLIT2 to IHH, we carried out a candidate gene burden test analysis. METHODS: A total of 196 IHH probands and 2,362 ethic-matched controls were recruited for this study. The IHH probands and controls were subjected to whole-exome sequencing. In the IHH patients with SLIT2 variants and their available family members, detailed phenotyping and segregation analysis were performed. RESULTS: Nine heterozygous SLIT2 rare sequencing variants (RSVs) were identified in 13 probands, with a prevalence of 6.6%. Furthermore, we identified an increased mutational burden for SLIT2 in this cohort (odds ratio = 2.2, p = 0.021). The segregation analysis of available IHH families revealed that the majority of SLIT2 RSVs were inherited from unaffected or partially affected parents. CONCLUSION: Our study suggests SLIT2 as a new IHH-associated gene and expands the clinical and genetic spectrum of IHH. Furthermore, SLIT2 alone does not appear to be sufficient to cause the disorder, and it may interact with other IHH-associated genes to induce a clinical phenotype.

Use of the new guidelines on an earlier age threshold of 35 years for diabetes screening can identify an additional 6.3 million undiagnosed individuals with diabetes and 72.3 million individuals with prediabetes among Chinese adults: An analysis of a nationally representative survey.

BACKGROUND: Young-onset diabetes has been increasingly prevalent in China and most of the young patients with diabetes remain undiagnosed. Recently, the American Diabetes Association (ADA) updated their screening criteria and turned down the age threshold of diabetes screening from 45 years to 35 years, which highlighted the importance of identifying young individuals with diabetes. Herein, we aimed to evaluate the clinical relevance of updated ADA screening recommendations in Chinese adults and the metabolic features and risk factor profiles of these newly diagnosed individuals. STUDY DESIGN AND METHODS: Using a complex, multistage, probability sampling design, we analyzed data from a nationally representative sample of 98,658 Chinese adults in 2010. Participants without previously diagnosed diabetes were included into the present study. We calculated the proportion of individuals with diabetes eligible for screening and the number needed to screen (NNS) to identify one patient with diabetes by age groups. RESULTS: Setting an earlier age threshold of diabetes screening can identify additional 6.3 million patients with diabetes and 72.3 million individuals with prediabetes, and the proportion of identified individuals increased more in rural, underdeveloped, and central areas. The NNS in Chinese adults dropped significantly from 28 in 30-34 age group to 15 in 35-45 years of age and remained low afterwards. The undiagnosed patients with diabetes who met the new screening age threshold of ADA recommendation were characterized by younger age, lower blood pressure and blood lipids, but higher proportion of overweight and higher level of insulin resistance, and tended to have an unhealthy diet habit, including low intake of fruits and vegetables and high intake of sugar-sweetened beverages, compared to those aged over 45 years. CONCLUSIONS: The new age threshold of 35 years for diabetes screening would reduce the proportion of undiagnosed diabetes with high cost-effectiveness, given the NNS for a positive test result was much lower in 35-45 age group comparing to the lower age group in Chinese adults.