The associations of peripheral interleukin alterations and hippocampal subfield volume deficits in schizophrenia.

The hippocampus is one of the brain regions most vulnerable to inflammatory insults, and the relationships between peripheral inflammation and hippocampal subfields in patients with schizophrenia remain unclear. In this study, forty-six stably medicated patients with schizophrenia and 48 demographically matched healthy controls (HCs) were recruited. The serum levels of IL - 1ß, IL-6, IL-10, and IL-12p70 were measured, and 3D high-resolution T1-weighted magnetic resonance imaging was performed. The IL levels and hippocampal subfield volumes were both compared between patients and HCs. The associations of altered IL levels with hippocampal subfield volumes were assessed in patients. Patients with schizophrenia demonstrated higher serum levels of IL-6 and IL-10 but lower levels of IL-12p70 than HCs. In patients, the levels of IL-6 were positively correlated with the volumes of the left granule cell layer of the dentate gyrus (GCL) and cornu Ammonis (CA) 4, while the levels of IL-10 were negatively correlated with the volumes of those subfields. IL-6 and IL-10 might have antagonistic roles in atrophy of the left GCL and CA4. This suggests a complexity of peripheral cytokine dysregulation and the potential for its selective effects on hippocampal substructures, which might be related to the pathophysiology of schizophrenia.

A subtype of schizophrenia patients with altered methylation level of genes related to immune cell activity.

BACKGROUND: Epigenetic changes are plausible molecular sources of clinical heterogeneity in schizophrenia. A subgroup of schizophrenia patients with elevated inflammatory or immune-dysregulation has been reported by previous studies. However, little is known about epigenetic changes in genes related to immune activation in never-treated first-episode patients with schizophrenia (FES) and its consistency with that in treated long-term ill (LTS) patients. METHODS: In this study, epigenome-wide profiling with a DNA methylation array was applied using blood samples of both FES and LTS patients, as well as their corresponding healthy controls. Non-negative matrix factorization (NMF) and k -means clustering were performed to parse heterogeneity of schizophrenia, and the consistency of subtyping results from two cohorts. was tested. RESULTS: This study identified a subtype of patients in FES participants (47.5%) that exhibited widespread methylation level alterations of genes enriched in immune cell activity and a significantly higher proportion of neutrophils. This clustering of FES patients was validated in LTS patients, with high correspondence in epigenetic and clinical features across two cohorts. CONCLUSIONS: In summary, this study demonstrated a subtype of schizophrenia patients across both FES and LTS cohorts, defined by widespread alterations in methylation profile of genes related to immune function and distinguishing clinical features. This finding illustrates the promise of novel treatment strategies targeting immune dysregulation for a subpopulation of schizophrenia patients.

Longitudinal patient-reported outcomes after minimally invasive McKeown esophagectomy for patients with esophageal squamous cell carcinoma.

PURPOSE: Surgery for esophageal squamous cell carcinoma (ESCC) is characterized by a poor prognosis and high complication rate, resulting in a heavy symptom burden and poor health-related quality of life (QOL). We evaluated longitudinal patient-reported outcomes (PROs) to analyze the correlations between symptoms and QOL and their changing characteristics during postoperative rehabilitation. METHODS: We investigated patients with ESCC who underwent minimally invasive McKeown esophagectomy at Sichuan Cancer Hospital between April 2019 and December 2019. Longitudinal data of the clinical characteristics and PROs were collected. The MD Anderson Symptom Inventory and European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires were used to assess symptoms and QOL and compare the trajectories of PROs during the investigation. RESULTS: A total of 244 patients with ESCC were enrolled in this study. Regarding QOL, role and emotional functions returned to baseline at 1 month after surgery, and cognitive and social functions returned to baseline at 3 months after surgery. However, physical function and global QOL did not return to baseline at 1 year after surgery. At 7 days and 1, 3, 6, and 12 months after surgery, the main symptoms of the patients were negatively correlated with physical, role, emotional, cognitive, and social functions and the overall health status (P < 0.05). CONCLUSION: Patients with ESCC experience reduced health-related QOL and persisting symptoms after minimally invasive McKeown esophagectomy, but a recovery trend was observed within 1 month. The long-term QOL after esophagectomy is acceptable.

Trust as a catalyst: revealing the impact of government trust and professional trust on public health policy compliance during a pandemic.

BACKGROUND: Existing research has extensively explored the relationship between government trust and compliance behaviour, but significant controversies exist. Some studies suggest a strong positive correlation between the two. Other studies have found that government trust hinders compliance behaviour. However, during the pandemic, the effectiveness of public health policies largely depends on the public's compliance with these policies. To examine the aforementioned controversies, this study utilizes survey data on the Chinese population during the COVID-19 period to explore the relationship between compliance with public health policies and government trust. METHODS: The study conducted a questionnaire survey of 1,395 individuals from 25 provinces in China from mid-November to mid-December 2022. Firstly, we categorized the public's compliance behaviour with public health policies based on the results of factor analysis. Subsequently, we examined the impact of government trust and professional trust on compliance behaviour with public health policies by constructing a structural equation model. RESULTS: Based on the results of factor analysis, we classified public adherence to public health policies into protective compliance and restrictive compliance. Results from the structural equation model show a positive correlation between the public's trust in the government and both protective and restrictive compliance, with a stronger influence on protective compliance. Government trust also exerts a positive impact on restrictive compliance behaviour through professional trust. Additionally, the study indicates a significant positive correlation between the public's professional trust and restrictive compliance, while it does not significantly affect protective compliance. Moreover, the public from rural areas demonstrates a greater willingness to adhere to both types of public health policies. Married individuals exhibit a stronger inclination toward protective compliance, while females show a stronger tendency toward restrictive compliance. CONCLUSION: The study revealed a significant positive impact of government trust and professional trust on compliance behaviour with public health policies during the COVID-19 pandemic, refuting any negative correlation between government trust and compliance behaviour. Normative motivations for compliance behaviour had a substantial impact on adherence. These findings offer valuable insights for future public health crisis management and public policy formulation.

Altered cerebellar effective connectivity in first-episode schizophrenia and long-term changes after treatment.

AIM: Cerebello-cortical functional dysconnectivity plays a key role in the pathology of schizophrenia (SZ). We aimed to investigate the changes in cerebello-cortical directional connectivity in patients with SZ. METHODS: A total of 180 drug-naïve patients with first-episode SZ (54 reassessed after 1 year of treatment) and 166 healthy controls (HCs) were included. Resting-state functional magnetic resonance imaging was used to perform Granger causal analysis, in which each of the nine cerebellar functional systems was defined as a seed. The observed effective connectivity (EC) alterations at baseline were further assessed at follow-up and were associated with changes in psychotic symptom. RESULTS: We observed increased bottom-up EC in first-episode SZ from the cerebellum to the cerebrum (e.g. from the cerebellar attention and cingulo-opercular systems to the bilateral angular gyri, and from the cerebellar cingulo-opercular system to the right inferior frontal gyrus). In contrast, decreased top-down EC in the first-episode SZ was mainly from the cerebrum to the cerebellum (e.g. from the right inferior temporal gyrus, left middle temporal gyrus, left putamen, and right angular gyrus to the cerebellar language system). After 1 year of antipsychotic treatment, information projections from the cerebrum to the cerebellum were partly restored and positively related to symptom remission. CONCLUSION: These findings suggest that decreased top-down EC during the acute phase of SZ may be a state-dependent alteration related to symptoms and medication. However, increased bottom-up EC may reflect a persistent pathological trait.

Hippocampal subfield alterations in schizophrenia and major depressive disorder: a systematic review and network meta-analysis of anatomic MRI studies.

BACKGROUND: Hippocampal disturbances are important in the pathophysiology of both schizophrenia and major depressive disorder (MDD). Imaging studies have shown selective volume deficits across hippocampal subfields in both disorders. We aimed to investigate whether these volumetric alterations in hippocampal subfields are shared or divergent across disorders. METHODS: We searched PubMed and Embase from database inception to May 8, 2021. We identified MRI studies in patients with schizophrenia, MDD or both, in which hippocampal subfield volumes were measured. We excluded nonoriginal, animal or postmortem studies, and studies that used other imaging modalities or overlapping data. We conducted a network meta-analysis to estimate and contrast alterations in subfield volumes in the 2 disorders. RESULTS: We identified 45 studies that met the initial criteria for systematic review, of which 15 were eligible for network metaanalysis. Compared to healthy controls, patients with schizophrenia had reduced volumes in the bilateral cornu ammonis (CA) 1, granule cell layer of the dentate gyrus, subiculum, parasubiculum, molecular layer, hippocampal tail and hippocampus-amygdala transition area (HATA); in the left CA4 and presubiculum; and in the right fimbria. Patients with MDD had decreased volumes in the left CA3 and CA4 and increased volumes in the right HATA compared to healthy controls. The bilateral parasubiculum and right HATA were smaller in patients with schizophrenia than in patients with MDD. LIMITATIONS: We did not investigate medication effects because of limited information. Study heterogeneity was noteworthy in direct comparisons between patients with MDD and healthy controls. CONCLUSION: The volumes of multiple hippocampal subfields are selectively altered in patients with schizophrenia and MDD, with overlap and differentiation in subfield alterations across disorders. Rigorous head-to-head studies are needed to validate our findings.

Neurofilament Light Chain Predicts Disease Severity and Progression in Multiple System Atrophy.

BACKGROUND: Neurofilament light chain (NFL), a potential biomarker of multiple system atrophy (MSA), has been reported in several studies. OBJECTIVES: The objective of this study was to investigate whether plasma NFL levels are correlated with the progression of motor and cognition function in MSA. METHODS: Patients with MSA were part of a prospective cohort study with assessments at baseline and after 1 year. Plasma NFL was quantified using ultrasensitive Simoa technology. RESULTS: A total of 91 patients with MSA and 60 healthy controls (HCs) were enrolled. NFL levels increased from baseline to 1-year follow-up (P = 0.010). Baseline plasma NFL levels were significantly associated with motor severity and progression in patients with MSA (P < 0.05) but not with cognitive progression (P > 0.05). CONCLUSIONS: Plasma NFL is a reliable biomarker for the disease severity of MSA and monitoring the progression of MSA, but not the progression of cognition. © 2021 International Parkinson and Movement Disorder Society.

Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function.

Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.

GATA2 regulates the CAD susceptibility gene ADTRP rs6903956 through preferential interaction with the G allele.

Myocardial infarction (MI) is a frequent outcome of coronary artery disease (CAD) and the key factor contributing to worldwide disability and death. Genetic factors contribute to the pathogenesis of CAD/MI, and SNP rs6903956 in the ADTRP gene was first found associated with CAD/MI in the Chinese Han population, which was successfully replicated in other cohorts. However, whether rs6903956 is a functional SNP and its risk mechanism to CAD/MI remains unknown. The ADTRP gene-encoded androgen-dependent TFPI regulating protein regulates vascular endothelial cell function, endothelial-monocyte adhesion, and thrombosis. The allele A of rs6903956, in particular, is associated with lower ADTRP mRNA levels in lymphocytes. In the current study, we found that SNP rs6903956 exhibits allelic differences in transcriptional activity by interacting with GATA2. Also, the A allele conferred a greater risk of CAD and MI, lowered transcriptional activity, and GATA2 binding ability as compared to the G allele. Our findings provide details on how rs6903956 regulates the expression of ADTRP and may provide novel insights into CAD pathology and susceptibility.

Greenness surrounding schools and adiposity in children and adolescents: Findings from a national population-based study in China.

BACKGROUND: Previous studies have indicated that exposure to green space may benefit human health. However, the available evidence concerning the effects of greenness, especially school-based greenness, on pediatric obesity is scarce. OBJECTIVE: To explore the association between school-based greenness and adiposity in children and adolescents in China. METHOD: We conducted a nationwide cross-sectional study of 56,620 children and adolescents (aged 6-18 years) in seven provinces/municipalities across China. School-based greenness was assessed using satellite-derived Normalized Difference Vegetation Index (NDVI) and Soil Adjusted Vegetation Index (SAVI) within 100-, 500-, and 1000-m circular buffers around each school's address. Generalized linear mixed regression models were used to estimate associations of greenness with BMI z-scores (zBMI), waist circumference, and prevalent overweight/obesity. We also explored the potential mediating role of ambient air pollution and physical activity in the greenness-adiposity associations. RESULT: In the adjusted model, an IQR increase in NDVI-1000m was associated with lower zBMI (ß: -0.11, 95% confidence interval[CI]: -0.13,-0.09) and waist circumference (ß: -0.64, 95%CI: -0.78,-0.50). Consistently, an IQR increase in NDVI-100m, NDVI-500m, NDVI-1000m was associated with 7-20% lower odds of overweight/obesity in the adjusted models. Air pollutants mediated 6.5-29.1% of the association between greenness and zBMI. No significant mediation effect was observed for physical activity. CONCLUSION: Higher school-based greenness levels were associated with lower zBMI, waist circumference, and lower odds of overweight and obesity in children and adolescents. Ambient air pollutants may partially mediate the greenness-adiposity associations.

Characteristics of White Matter Structural Networks in Chronic Schizophrenia Treated With Clozapine or Risperidone and Those Never Treated.

BACKGROUND: Despite its benefits, a major concern regarding antipsychotic treatment is its possible impact on the brain's structure and function. This study sought to explore the characteristics of white matter structural networks in chronic never-treated schizophrenia and those treated with clozapine or risperidone, and its potential association with cognitive function. METHODS: Diffusion tensor imaging was performed on a unique sample of 34 schizophrenia patients treated with antipsychotic monotherapy for over 5 years (17 treated with clozapine and 17 treated with risperidone), 17 never-treated schizophrenia patients with illness duration over 5 years, and 27 healthy control participants. Graph theory and network-based statistic approaches were employed. RESULTS: We observed a disrupted organization of white matter structural networks as well as decreased nodal and connectivity characteristics across the schizophrenia groups, mainly involving thalamus, prefrontal, and occipital regions. Alterations in nodal and connectivity characteristics were relatively milder in risperidone-treated patients than clozapine-treated patients and never-treated patients. Altered global network measures were significantly associated with cognitive performance levels. Structural connectivity as reflected by network-based statistic mediated the difference in cognitive performance levels between clozapine-treated and risperidone-treated patients. LIMITATIONS: These results are constrained by the lack of random assignment to different types of antipsychotic treatment. CONCLUSION: These findings provide insight into the white matter structural network deficits in patients with chronic schizophrenia, either being treated or untreated, and suggest white matter structural networks supporting cognitive function may benefit from antipsychotic treatment, especially in those treated with risperidone.

Surveillance of the 'bud event of norovirus-associated gastroenteritis' in schools: does it work in the prevention of norovirus infection outbreaks in Shanghai?

Outbreaks of norovirus-associated gastroenteritis have been reported in schools in recent decades in China. For early warning and response to infectious disease outbreaks, the Shanghai Infectious Diseases Bud Event Surveillance System (IDBESS) was established in 2016. Bud event is a term used for the early sign of a potential infectious disease outbreak in public settings when the first few cases appear. This study aimed to describe the epidemiological characteristics of Norovirus-associated gastroenteritis bud events from June 2016 to December 2017 and to understand factors influencing the severity of events. Data were extracted from the IDBESS, supplemented by field investigations and school absence surveillance. In total, 189 bud events of Norovirus-associated gastroenteritis were reported in schools and kindergartens, affecting 3827 individuals and 52.38% happened in primary schools. The attack rate of Norovirus-associated gastroenteritis was 3.82% on average in students in the affected schools. In each event, case numbers varied between 5 and 148, with a median of 16. The duration of bud events lasted for 2 days on average. School absence happened in 47.93% (1797/3749) of affected students and the average duration of absence was 3.07 days. It was found that a longer delay before reporting was associated with a longer-lasting duration of bud event (OR = 2.25, 95% CI: 1.65, 3.07). In conclusion, ascribed to the sensitive threshold for alerting and the timely field investigation, the surveillance of bud events of Norovirus-associated gastroenteritis is effective in the control of Norovirus infection among preschool children and students in Shanghai.

Risk factors associated with progression and persistence of small- and medium-sized coronary artery aneurysms in Kawasaki disease: a prospective cohort study.

To identify the risk factors of progression and persistence of small- and medium-sized coronary artery aneurysm (CAA) in a contemporary cohort of patients with Kawasaki disease (KD) and to determine the relationship between CAA progression and persistence. A total of 89 KD patients with small- and medium-sized CAA were prospectively enrolled. All patients were followed up at least for 2 years by serial echocardiography. Multivariate logistic regression analysis was conducted to evaluate independent risk factors for CAA progression and persistence. A total of 46 (51.7%) and 73 (82.0%) patients showed echocardiographic CAA regression by 1 month and 24 months of follow-up, respectively. CAA progression was documented in 12 (13.5%) patients during follow-up. The initial aneurysm size according to CAA classification (OR 0.089, 95% CI 0.013-0.634, P = 0.016) and CAA progression (OR 42.618, 95% CI 3.740-485.6, P = 0.003) were independently associated with CAA persistence. The number of involved coronary arteries (OR 0.223, 95% CI 0.065-0.767, P = 0.015) and lymphocyte proportion (OR 1.327, 95% CI 1.019-1.727, P = 0.040) were independently associated with CAA progression.Conclusion: Patients with KD and greater initial aneurysm size, CAA progression, more involved coronary arteries, and lower lymphocyte proportion may require intensive cardiac monitoring and adjuvant therapies.What is Known:• Long-term outcomes of patients with KD and CAA are primarily driven by the consequences of CAA regression and progression.• Regression and progression occurs more frequently in patients with small- and medium-sized CAAs, and less frequently for giant CAAs.What is New:• The CAA size at diagnosis, NCAI, and the proportion of lymphocytes are presumably associated with the small- and medium-sized CAA persistence or CAA progression.• The CAA progression was associated with CAA persistence.

Physical activity and health in Chinese children and adolescents: expert consensus statement (2020).

China is experiencing significant public health challenges related to social and demographic transitions and lifestyle transformations following unprecedented economic reforms four decades ago. Of particular public health concern is the fourfold increase in overweight and obesity rates in the nation's youth population, coupled with the low prevalence of adolescents meeting recommended levels of physical activity. Improving the overall health of China's more than 170 million children and adolescents has become a national priority. However, advancing nationwide health initiatives and physical activity promotion in this population has been hampered by the lack of a population-specific and culturally relevant consensus on recommendations for achieving these ends. To address this deficiency and inform policies to achieve Healthy China 2030 goals, a panel of Chinese experts, complemented by international professionals, developed this consensus statement. The consensus was achieved through an iterative process that began with a literature search from electronic databases; in-depth reviews, conducted by a steering committee, of the resulting articles; and panel group evaluations and discussions in the form of email correspondence, conference calls and written communications. Ultimately, the panel agreed on 10 major themes with strong scientific evidence that, in children and adolescents aged 6-17, participating in moderate to vigorous physical activities led to multiple positive health outcomes. Our consensus statement also (1) highlights major challenges in promoting physical activity, (2) identifies future research that addresses current knowledge gaps, and (3) provides recommendations for teachers, education experts, parents and policymakers for promoting physical activity among Chinese school-aged children and adolescents. This consensus statement aligns with international efforts to develop global physical activity guidelines to promote physical activity and health and prevent lifestyle-related diseases in children and adolescents. More importantly, it provides a foundation for developing culturally appropriate and effective physical activity interventions, health promotion strategies and policy initiatives to improve the health of Chinese children and adolescents.

Patterns of brain regional functional coherence in cognitive impaired ALS.

Background: The aim of the study is to reveal the brain regional functional coherence alterations in the early-stage amyotrophic lateral sclerosis (ALS) patients with cognitive impairments.Methods: Resting state functional MRI (fMRI) was performed to characterize the amplitude of regional homogeneity (ReHo). Twenty-one ALS patients with cognitive impairments (ALSci), 21 ALS patients without cognitive impairments (ALSnci) and 21 healthy controls (HCs) were enrolled.Result: Compared with HCs, the ALSci subgroup showed increased ReHo in bilateral inferior parietal lobules (IPLs), precuneus and inferior cerebellar areas, and the ALSnci subgroup had increased ReHo in the left IPL and left inferior cerebellar area. The ALSci subgroup also had increased ReHo in the right IPL and right inferior cerebellar area relative to the ALSnci subgroup. Meantime, compared with HCs, both ALS subgroups showed decreased ReHo in bilateral sensorimotor cortices. The ReHo values in the right cerebellar area were negatively correlated with the Chinese version of Addenbrooke Cognitive Examination-revised (ACE-R) total scores in all ALS patients. In addition, the grey matter (GM) volume revealed no significant difference among three groups, which indicated that the altered ReHo was not caused by the anatomic change.Conclusion: The altered regional functional coherence might indicate the underlying deficits of ALS with and without cognitive impairments. Our findings support that ALS is a multisystem disease and provide the evidence that alterations of ReHo in the right inferior cerebellar area might be a special marker of ALS with cognitive impairment. Our results are preliminary and further investigations are needed.

UBC9 regulates cardiac sodium channel Nav1.5 ubiquitination, degradation and sodium current density.

Voltage-gated sodium channel Nav1.5 is critical for generation and conduction of cardiac action potentials. Mutations and expression level changes of Nav1.5 are associated with cardiac arrhythmias and sudden death. The ubiquitin (Ub) conjugation machinery utilizes three enzyme activities, E1, E2, and E3, to regulate protein degradation. Previous studies from us and others showed that Nedd4-2 acts as an E3 ubiquitin-protein ligase involved in ubiquitination and degradation of Nav1.5, however, more key regulators remain to be identified. In this study, we show that UBC9, a SUMO-conjugating enzyme, regulates ubiquitination and degradation of Nav1.5. Overexpression of UBC9 significantly decreased Nav1.5 expression and reduced sodium current densities, whereas knockdown of UBC9 expression significantly enhanced Nav1.5 expression and increased sodium current densities, in both HEK293 cells and primary neonatal cardiomyocytes. Overexpression of UBC9 increased ubiquitination of Nav1.5, and proteasome inhibitor MG132 blocked the effect of UBC9 overexpression on Nav1.5 degradation. Co-immunoprecipitation showed that UBC9 interacts with Nedd4-2. UBC9 with mutation C93S, which suppresses SUMO-conjugating activity of UBC9, was as active as wild type UBC9 in regulating Nav1.5 levels, suggesting that UBC9 regulates Nav1.5 expression levels in a SUMOylation-independent manner. Our findings thus identify a key structural element of the ubiquitin-conjugation machinery for Nav1.5 and provide important insights into the regulatory mechanism for ubiquitination and turnover of Nav1.5.

Prevalence and risk factors of impaired fasting glucose and diabetes among Chinese children and adolescents: a national observational study.

The prevalence of impaired fasting glucose (IFG) and diabetes mellitus (DM) has reportedly increased significantly among Chinese children and adolescents. We aimed to examine the prevalence of IFG and DM, the disparities in sex and region and related risk factors among Chinese children and adolescents. A total of 16 434 Chinese children aged 6-17 years were selected from a national cross-sectional survey, and fasting glucose was measured for all participants. Overall, mean fasting plasma glucose (FPG) concentration was (4·64 (sd 0·51)) mmol/l, and the prevalence of DM and IFG was 0·10 and 1·89 %, respectively. Compared with girls, boys had higher FPG concentration (4·69 v. 4·58 mmol/l, r 0·107, P<0·001) and IFG prevalence (2·67 v. 1·07 %, r φ 0·059, P<0·001). Compared with rural children and adolescents, urban children and adolescent had higher FPG concentration (4·65 v. 4·62 mmol/l, r 0·029, P<0·001) and DM prevalence (0·15 v. 0·05 %, r φ 0·016, P<0·01). In addition, self-reported fried foods intake and overweight/obesity were positively associated with IFG, and the proportion of consuming fried foods more than or equal to once per week and overweight/obesity prevalence in boys and urban children and adolescents were significantly higher than girls and rural children and adolescents, respectively (P<0·05). Although the prevalence of IFG and DM was relatively low in Chinese children and adolescents, sex and region disparities were observed, which may be associated with differences in overweight/obesity prevalence and dietary factors.

Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.

Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription.

Low androgen levels are associated with an increased risk of coronary artery disease (CAD), thrombosis and myocardial infarction (MI), suggesting that androgen has a protective role. However, little is known about the underlying molecular mechanism. Our genome-wide association study identified the ADTRP gene encoding the androgen-dependent TFPI regulating protein as a susceptibility gene for CAD and MI. The expression level of ADTRP was regulated by androgen, but the molecular mechanism is unknown. In this study, we identified the molecular mechanism by which androgen regulates ADTRP expression and tested the hypothesis that androgen plays a protective role in cardiovascular disease by activating ADTRP expression. Luciferase assays with an ADTRP promoter luciferase reporter revealed that androgen regulated ADTRP transcription in a dose- and time-dependent manner, and the effect was abolished by three different androgen inhibitors, including pyrvinium pamoate, bicalutamide, and cyproterone acetate. Chromatin-immunoprecipitation showed that the androgen receptor bound to a half androgen response element (ARE, TGTTCT) located at +324bp from the ADTRP transcription start site. The ARE is required for concentration-dependent transcriptional activation of ADTRP. HL-60 monocyte adhesion to EAhy926 endothelial cells (ECs) and transmigration across the EC layer, the two processes critical to development of CAD and MI, were inhibited by androgen, but the effect was rescued by ADTRP siRNA and exacerbated by overexpression of ADTRP and its downstream genes PIK3R3 and MIA3. These data suggest that one molecular mechanism by which androgen confers protection against CAD is stimulation of ADTRP expression.

Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease.

Coronary artery disease (CAD) is the leading cause of death worldwide. GWAS have identified >50 genomic loci for CAD, including ADTRP and MIA3/TANGO1. However, it is important to determine whether the GWAS genes form a molecular network. In this study, we have uncovered a novel molecular network between ADTRP and MIA3/TANGO1 for the pathogenesis of CAD. We showed that knockdown of ADTRP expression markedly down-regulated expression of MIA3/TANGO1. Mechanistically, ADTRP positively regulates expression of PIK3R3 encoding the regulatory subunit 3 of PI3K, which leads to activation of AKT, resulting in up-regulation of MIA3/TANGO1. Both ADTRP and MIA3/TANGO1 are involved in endothelial cell (EC) functions relevant to atherosclerosis. Knockdown of ADTRP expression by siRNA promoted oxidized-LDL-mediated monocyte adhesion to ECs and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1 and MIA3/TANGO1 overexpression, while the over-expression of ADTRP in ECs blunted these processes. Knockdown of MIA3/TANGO1 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes, and vice versa for overexpression of MIA3/TANGO1. We found that ADTRP negatively regulates the levels of collagen VII and ApoB in HepG2 and endothelial cells, which are downstream regulatory targets of MIA3/TANGOI. In conclusion, we have uncovered a novel molecular signaling pathway for the pathogenesis of CAD, which involves a novel gene-gene regulatory network. We show that ADTRP positively regulates PIK3R3 expression, which leads to activation of AKT and up-regulation of MIA3/TANGO1, thereby regulating endothelial cell functions directly relevant to atherosclerosis.