Exome sequencing identifies novel genetic variants associated with varicose veins.

BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.

Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults.

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.

Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study.

BACKGROUND: Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia. METHODS: Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p-values under consecutive timeframes preceding the diagnosis of dementia. FINDINGS: During a median follow-up of 13.7 [Interquartile range, IQR 12.9-14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63-0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76-0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11-1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67-1.91]), stroke (OR 2.34 [2.1-1.37]), diabetes (OR 2.03 [1.89-2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3-5 year, overall time of activity, OR 0.82 [0.73-0.92]), drowsiness (3-5 year, sleep duration, OR 1.13 [1.04-1.24]) and weight loss (0-5 year, weight, OR 0.9 [0.83-0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis. INTERPRETATION: Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.

Exome sequencing identifies genes associated with sleep-related traits.

Sleep is vital for human health and has a moderate heritability. Previous genome-wide association studies have limitations in capturing the role of rare genetic variants in sleep-related traits. Here we conducted a large-scale exome-wide association study of eight sleep-related traits (sleep duration, insomnia symptoms, chronotype, daytime sleepiness, daytime napping, ease of getting up in the morning, snoring and sleep apnoea) among 450,000 participants from UK Biobank. We identified 22 new genes associated with chronotype (ADGRL4, COL6A3, CLK4 and KRTAP3-3), daytime sleepiness (ST3GAL1 and ANKRD12), daytime napping (PLEKHM1, ANKRD12 and ZBTB21), snoring (WDR59) and sleep apnoea (13 genes). Notably, 20 of these genes were confirmed to be significantly associated with sleep disorders in the FinnGen cohort. Enrichment analysis revealed that these discovered genes were enriched in circadian rhythm and central nervous system neurons. Phenotypic association analysis showed that ANKRD12 was associated with cognition and inflammatory traits. Our results demonstrate the value of large-scale whole-exome analysis in understanding the genetic architecture of sleep-related traits and potential biological mechanisms.

Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits.

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan.

Plasma proteomic profiles predict individual future health risk.

Developing a single-domain assay to identify individuals at high risk of future events is a priority for multi-disease and mortality prevention. By training a neural network, we developed a disease/mortality-specific proteomic risk score (ProRS) based on 1461 Olink plasma proteins measured in 52,006 UK Biobank participants. This integrative score markedly stratified the risk for 45 common conditions, including infectious, hematological, endocrine, psychiatric, neurological, sensory, circulatory, respiratory, digestive, cutaneous, musculoskeletal, and genitourinary diseases, cancers, and mortality. The discriminations witnessed high accuracies achieved by ProRS for 10 endpoints (e.g., cancer, dementia, and death), with C-indexes exceeding 0.80. Notably, ProRS produced much better or equivalent predictive performance than established clinical indicators for almost all endpoints. Incorporating clinical predictors with ProRS enhanced predictive power for most endpoints, but this combination only exhibited limited improvement when compared to ProRS alone. Some proteins, e.g., GDF15, exhibited important discriminative values for various diseases. We also showed that the good discriminative performance observed could be largely translated into practical clinical utility. Taken together, proteomic profiles may serve as a replacement for complex laboratory tests or clinical measures to refine the comprehensive risk assessments of multiple diseases and mortalities simultaneously. Our models were internally validated in the UK Biobank; thus, further independent external validations are necessary to confirm our findings before application in clinical settings.

Development of machine learning-based models to predict 10-year risk of cardiovascular disease: a prospective cohort study.

BACKGROUND: Previous prediction algorithms for cardiovascular diseases (CVD) were established using risk factors retrieved largely based on empirical clinical knowledge. This study sought to identify predictors among a comprehensive variable space, and then employ machine learning (ML) algorithms to develop a novel CVD risk prediction model. METHODS: From a longitudinal population-based cohort of UK Biobank, this study included 473 611 CVD-free participants aged between 37 and 73 years old. We implemented an ML-based data-driven pipeline to identify predictors from 645 candidate variables covering a comprehensive range of health-related factors and assessed multiple ML classifiers to establish a risk prediction model on 10-year incident CVD. The model was validated through a leave-one-center-out cross-validation. RESULTS: During a median follow-up of 12.2 years, 31 466 participants developed CVD within 10 years after baseline visits. A novel UK Biobank CVD risk prediction (UKCRP) model was established that comprised 10 predictors including age, sex, medication of cholesterol and blood pressure, cholesterol ratio (total/high-density lipoprotein), systolic blood pressure, previous angina or heart disease, number of medications taken, cystatin C, chest pain and pack-years of smoking. Our model obtained satisfied discriminative performance with an area under the receiver operating characteristic curve (AUC) of 0.762±0.010 that outperformed multiple existing clinical models, and it was well-calibrated with a Brier Score of 0.057±0.006. Further, the UKCRP can obtain comparable performance for myocardial infarction (AUC 0.774±0.011) and ischaemic stroke (AUC 0.730±0.020), but inferior performance for haemorrhagic stroke (AUC 0.644±0.026). CONCLUSION: ML-based classification models can learn expressive representations from potential high-risked CVD participants who may benefit from earlier clinical decisions.

Delayed 18F-FDG PET/CT with oral small dosage diuretics in diagnosing urogenital cancers / 中国医学影像技术

Objective To investigate the value of delayed 18F-FDG PET/CT with oral intake small dosage diuretics for diagnosing urogenital cancers.Methods Patients with suspected urogenital system cancers were divided into routine dosage diuretic group (n=12) and small dosage diuretics group (n=35).All patients underwent whole-body PET/CT followed by delayed scanning after oral 40 mg or 20 mg Furosemide respectively.The urine maximum standard uptake value (SUVmax) and T/U (the ratio of urine and lesion SUVmax) before and after diuresis were compared respectively.Diagnostic efficacy for malignant urogenital system cancers of small dosage group was calculated.Results The urine SUVmax and T/U were statistically different between routine whole body and delayed scans in both groups (P＜0.05).SUVmax and T/U of routine and delayed scans had no statistical differences between the two groups (P＞0.05).In small dosage group,the sensitivity,specificity,positive predictive value,negative predictive value and accuracy of delayed imaging and routine imaging was 96.77％ (30/31)and 61.29％ (19/31),75.00％ (3/4) and 50.00％ (2/4),96.77％ (30/31) and 90.48％ (19/21),75.00％ (3/4)and 14.29％ (2/14),94.29％ (33/35) and 60.00％ (21/35),respectively.The sensitivity and accuracy were statistically different between routine and delayed imaging (P＜0.001).Conclusion Delayed PET/CT imaging with oral small dosage Furosemide has the same efficacy as PET/CT using routine dosage diuretics,which is useful for diagnosing urogenital cancers.

In Vivo Assessment of Neurodegeneration in Type C Niemann-Pick Disease by IDEAL-IQ

OBJECTIVE: To noninvasively assess the neurodegenerative changes in the brain of patients with Niemann-Pick type C (NPC) disease by measuring the lesion tissue with the iterative decomposition of water and fat with echo asymmetry and least square estimation-iron quantification (IDEAL-IQ). MATERIALS AND METHODS: Routine brain MRI, IDEAL-IQ and 1H-proton magnetic resonance spectroscopy (1H-MRS, served as control) were performed on 12 patients with type C Niemann-Pick disease (4 males and 8 females; age range, 15–61 years; mean age, 36 years) and 20 healthy subjects (10 males and 10 females; age range, 20–65 years; mean age, 38 years). The regions with lesion and the normal appearing regions (NARs) of patients were measured and analyzed based on the fat/water signal intensity on IDEAL-IQ and the lipid peak on 1H-MRS. RESULTS: Niemann-Pick type C patients showed a higher fat/water signal intensity ratio with IDEAL-IQ on T2 hyperintensity lesions and NARs (3.7–4.9%, p < 0.05 and 1.8–3.0%, p < 0.05, respectively), as compared to healthy controls (HCs) (1.2–2.3%). After treatment, the fat/water signal intensity ratio decreased (2.2–3.4%), but remained higher than in the HCs (p < 0.05). The results of the 1H-MRS measurements showed increased lipid peaks in the same lesion regions, and the micro-lipid storage disorder of NARs in NPC patients was detectable by IDEAL-IQ instead of 1H-MRS. CONCLUSION: The findings of this study suggested that IDEAL-IQ may be useful as a noninvasive and objective method in the evaluation of patients with NPC; additionally, IDEAL-IQ can be used to quantitatively measure the brain parenchymal adipose content and monitor patient follow-up after treatment of NPC.

Preparation and Preclinical Study of 99mTc-labeled Prostate Cancer Aptamer / 中山大学学报(医学科学版)

[Objective]To radiolabel the PSMA aptamer A10-3.2 with 99mTc , and explore its biological characteristics in vivo and in vitro.[Methods]Using Succinimidyl 6-hydrazinonicotinate hydrochloride (SHNH) as the bifunctional chelating agent to label aptamer A10-3.2 with 99mTc, then tested for the stability in vitro, the specific uptake by prostate cancer LNCaP cells (PSMA+) , the characteristics of SPECT/CT imaging and biodistribution in LNCaP tumor-bearing NOD/SCID mice.[Results]The labeling rate and radiochemical purity of the products (99mTc-SHNH-A10-3.2) are(71.31 ± 6.78)% and 97.03%,respectively. 99mTc-SHNH-A10-3.2 had obvious target specificity for PSMA positive prostate cancer LNCaP cells, its uptake rate was significantly higher than PSMA nega?tive PC-3 cells (P<0.01). And in tumor-bearing mice, the tumor has a certain uptake and a high ratio of the tumor tissue to the mus?cle.[Conclusion]This study successfully constructed 99mTc-labeled PSMA-targeted aptamer A10-3.2, which has a good stability and targeting in vivo and in vitro, has a high tumor tissue/muscle ratio in tumor-bearing mice, which show that it may be a potential target?ed molecular imaging agent for prostate cancer.

Clinical value of 99mTc-MDP SPECT/CT whole body bone imaging in diagnosis of bone metastasis of pros-tate cancer / 实用医学杂志

Objective To investigate the clinical value of 99mTc-MDP SPECT/CT whole body bone imaging in the diagnosis of bone metastasis of prostate cancer. Methods A total of 107 cases with prostate cancer were di-agnosed by SPECT whole body bone imaging from January 2013 to November 2016. SPECT/CT imaging of some ab-normal density collective focus found in whole body bone imaging were further carried out. Six months later ,whole body bone imaging and SPECT/CT were made again for review. In all diagnosis above ,99mTc-MDP were selected as bone imaging agent. According to the results of follow-up visit clinical and imaging diagnosis ,diagnostic perfor-mance indicators of whole body bone imaging and SPECT/CT were calculated. Results The different part of whole body bone imaging and SPECT/CT in the diagnosis of bone metastases was statistically significant(x2 = 23.000, P < 0.001). The diagnosis specificity and coincidence rate of SPECT/CT for bone metastasis were 100.0% and 98.1% respectively and they were significantly higher than those of whole body bone imaging(65.0% and 80.4%respectively). The differences were statistically significant(P < 0.05). After SPECT/CT diagnosis,a total of 193 undetermined lesions were found and 83 lesions of these were final diagnosed of bone metastases. Pelvic lesions were most in bone metastases ,accounting for 50.6%. Conclusion Whole body bone imaging can effectively determine the undetermined lesions , further SPECT/CT can significantly improve the diagnostic accuracy of prostate cancer bone metastasis.

Prevalence and genotype distribution of human papillomavirus infection among female sex workers in Guangxi, China: implications for interventions.

Human papillomavirus (HPV) infection is a major public health concern in women, but information on HPV among female sex workers in China is limited. The aim of the study was to estimate the prevalence and genotype distribution of HPV infection among female sex workers in two cities in Guangxi, China. A total of 811 female sex workers were recruited from venues between July and September of 2009. Data on socio-demographic and behavior characteristics were collected, and cervical swabs were collected to determine HPV infection and genotype distribution. The overall prevalence of infection with any HPV type was 38.9%. HPV type 52 was the most prevalent type with prevalence of 11%, followed by HPV types 16, 58, 53, and CP8304, with prevalences of 6.5%, 5.7%, 5.6%, and 4.8%, respectively. HPV 16 or 18 accounted for 23.2% of all HPV positive cases. Age group <20 years was significantly associated with infection of the high-risk and multiple types of HPV infection. A higher prevalence of multiple HPV infection was observed among female sex workers from the outdoor venues (14.0%; 95%CI, 10.6%-17.3%). These findings have important implications for developing HPV prevention programs including HPV vaccination in female sex workers.

Selective inhibition of the cyanobacterium, Microcystis, by a Streptomyces sp.

A Streptomyces strain, NT0401, was isolated from soil that selectively inhibited Microcystis strains but did not affect other microorganisms. Based on its morphology, physiology and 16S rDNA sequence, it was identified as Streptomyces grisovariabilis. The active substance produced by NT0401 was a water-soluble compound with a Mr <1 kDa that was stable over a broad pH range and at 100 degrees C for 20 min. This organism should be a potential environment-friendly strain for control of Microcystis blooms.

Effects of resveratrol on the proliferation and CaN of vascular smooth muscle cell induced by angiotensin II / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effects of resveratrol (Res) on the proliferation of VSMCs induced by Ang I and the expression of calmodulin (CaM) and calcineurin (CaN) in the proliferation of VSMCs treated by Ang 1 and to discuss the mechanism.</p><p><b>METHODS</b>Rabbit arterial VSMCs were cultured in vitro and VSMCs were identified with the method of immunocytochemistry. A cell proliferating model of VSMCs induced by AngII was established. VSMCs were cultured for 4-8 passages. The experiments were randomly divided into control group, AngII group (0.1 micromol/L) and AngII + Res groups with different concentrations(20, 40, 80, 160) micromol/L. VSMCs proliferation was determined with MTT colorimetric method. CaM was detected with Coomassie brilliant blue method and CaN was determined by enzyme reaction phosphorus measurement.</p><p><b>RESULTS</b>Rabbit VSMCs were cultured successfully and could be passaged. After immunocytochemistry staining, all the cells cytoplasm were stained and positive. Cell proliferation, CaM and CaN activities were increased significantly in VSMCs proliferation induced by AngII (P <0.05, P < 0.01). The index of AngII + Res groups were obviously reduced compared with AngII group ( P < 0.01).</p><p><b>CONCLUSION</b>The VSMCs proliferation induced by AngII can be inhibited by Res significantly, and the inhibiting mechanism of Res may be related to inhibiting CaM and CaN activities then restraining the proliferation of VSMCs in a dose dependent manner.</p>