Identification of risk genes in Chinese nonobstructive azoospermia patients based on whole-exome sequencing

Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be addressed.This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing.Whole-exome sequencing was performed in 46 male patients diagnosed with NOA.First,screening was performed for 119 genes known to be related to male infertility.Next,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls.Finally,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed.The frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls.Potential risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the testes.Four risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls.This study on clinical NOA patients provides further evidence for the four previously reported risk genes.The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.

Interleukin-17A gene variants and risk of coronary artery disease:a large angiography-based study

Background Recent studies have also revealed that interleukin(IL)-17A plays a key role in atherosclerosis and its complication,but the relationship of its common variants with coronary artery disease(CAD) has not been extensively studied.Methods We systematically screened sequence variations in the IL17A gene and designed an angiog-raphy -based case-controlled study consisting of 1031 CAD patients and 935 control subjects to investigate the association between the selected polymorphisms of IL-17A gene and CAD risk in Chinese Han population.Results Frequencies of IL17A rs8193037 GG homozygote and G allele were significantly higher in the patient group than those in the control group(P【0.001;OR=0.68;95%CI=0.54-0.85).Stratification analysis showed that the IL17A rs8193037 G allele significantly increased the risk of CAD only among male subjects (P=0.001;OR=0.63;95%CI=0.47-0.83).After adjustment for conventional risk factors,binary logistic regression analysis showed that the G allele carriers(GG +AG) had significantly increased CAD risk compared with the AA homozygotes (adjusted P【0.001;OR 0.43;95%CI,0.33- 0.58).ELISA showed augmented IL17A production in plasma of the AMI patients.Conclusions Based on our data,we speculated that the SNP rs8193037 of IL17A gene is significantly associated with CAD risk in Chinese Han population and the rs8193037 G allele which is associated with increased expression of IL17A in AMI patients may be an independent predictive factor for CAD.

Adult neural stem cells and schizophrenia

Schizophrenia(SCZ)is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits.Although many genetic risk factors have been identified,SCZ is also considered as a neurodevelopmental disorder.Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes.Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood.These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination,which have been shown to be closely linked with many psychiatric disorders,such as SCZ.Here in this review,we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors.We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets,which could facilitate the development of novel medication and treatment.

Polymorphisms of estrogen-metabolizing genes and breast cancer risk: a multigenic study

Background Endogenous estrogen plays a very important role in the carcinogenesis and progression of breast cancer. The enzymes involved in the biosynthesis and metabolism of estrogen have been proposed to contribute to this effect. To examine this hypothesis, we conducted a case-control study to investigate the relationship between polymorphisms of genes responsible for estrogen biosynthesis （CYP17, cytochrome P450c17a and CYP19, aromatase cytochrome P450） and estrogen sulfation of inactivation （ SULT1 A1, sulfotransferasel A1 ） and the risk of breast cancer in Chinese women. Methods This study involved 213 breast cancer patients and 430 matched controls. PCR-based restriction fragment length polymorphism （RFLP） and short tandem repeat polymorphism （STRP） assays were used to detect the mononucleotide transition of CYP17 and SULT1A1 and tandem repeat polymorphism of CYP19. Logistic regression analyses were used to determine OR and 95% CI of each and all three high-risk genotypes, of all three genotypes combined, and of estrogen exposure factbrs. The relationship between each high-risk genotype and clinicalpathological characteristics were also assessed. Results The frequency of A2 allele of CYP17 was 49.8% in cases and 49. 1% in controls （P =0. 82）. The frequency of His allele of SULT1A1 was significantly higher in cases （ 13.6% ） than in controls （9. 5% ） （P 〈 0. 05 ）. There was also significant difference of the （TTTA）10 allele of CYP19 which was 12. 4% in cases and 8.2% in controls （P 〈0. 05）. When the CYP17 A2 allele, CYP19 （TITA）1o and SULT1A1 His allele were considered as the “putative high-risk” genotype, there was an increased risk of breast cancer with the number of high-risk genotypes in a dose-response effect （trend, P = 0. 05 ）. In multivariate analysis, the SULT1A1 genotype remained the most significant determinant for breast cancer, with OR =2. 37 （95% CI 1.23 - 4. 74） , followed by CYP19, with OR = 1.75 （95% CI 1.27 - 3.56）. The （TTTA）10 allele of CYP19 was associated with tumor size, and the His allele of SULT1 A1 associated with status of lymph node metastasis. Conclusions This study supports the hypothesis that breast cancer can be initiated by estrogen exposure and that estrogen metabolizing genes are involved in this mechanism. This multigenic model is useful for identifying individuals who are at higher risks of breast cancer.

Lifestyle Plays Bigger Part Than Genes In Cancer Risk

The world’s biggest study of cancer in twins has shown that the risk ofdeveloping the disease depends on how you live rather than who are your parents.Although genetic factors play a minor role in some cancers, including those of

Convergent synaptic and circuit substrates underlying autism genetic risks

There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

Genetic and environmental risk factors for primary open-angle glaucoma

Background Primary open-angle glaucoma (POAG) is characterized by optic nerve damage and consists of a group of genetically heterogeneous disorders. This study was to investigate the associations of genetic and environmental factors with POAG in a hospital-based Chinese population Methods Thirty-two adult onset POAG patients and 96 age-sex matched control subjects were studied by multivariable logistic regression analysis for the relationships between POAG and its risk factors including family history, diabetes, hypertension, cardiovascular diseases, cigarette smoking, alcohol consumption and polymorphisms of the myocilin and the optineurin genes Results Univariate analysis showed that POAG was related to family history, cardiovascular disease, alcohol consumption and a myocilin sequence alteration (T353I) ( P <0 04) Multivariable logistic regression analysis confirmed that POAG was significantly associated with family history ( OR =20 2), hypertension ( OR =3 58), cigarette smoking ( OR =10 8), alcohol consumption ( OR =0 028) and T353I ( OR =6 03, all P <0 05) Conclusions Family history, hypertension, cigarette smoking and T353I in the myocilin gene are risk factors for POAG Alcohol consumption, however, has a protective effect

Evaluation of bacterial pathogen diversity,abundance and health risks in urban recreational water by amplicon next-generation sequencing and quantitative PCR

The microbial quality of urban recreational water is of great concern to public health.The monitoring of indicator organisms and several pathogens alone is not sufficient to accurately and comprehensively identify microbial risks.To assess the levels of bacterial pathogens and health risks in urban recreational water,we analyzed pathogen diversity and quantified four pathogens in 46 water samples collected from waterbodies in Beijing Olympic Forest Park in one year.The pathogen diversity revealed by 16 S r RNA gene targeted next-generation sequencing（NGS） showed that 16 of 40 genera and 13 of 76 reference species were present.The most abundant species were Acinetobacter johnsonii,Mycobacterium avium and Aeromonas spp.Quantitative polymerase chain reaction（q PCR） of Escherichia coli（uid A）,Aeromonas（aer A）,M.avium（16S r RNA）,Pseudomonas aeruginosa（oaa） and Salmonella（inv A） showed that the aer A genes were the most abundant,occurring in all samples with concentrations of 10^（4–6） genome copies/100 m L,followed by oaa,inv A and M.avium.In total,34.8% of the samples harbored all genes,indicating the prevalence of these pathogens in this recreational waterbody.Based on the q PCR results,a quantitative microbial risk assessment（QMRA） showed that the annual infection risks of Salmonella,M.avium and P.aeruginosa in five activities were mostly greater than the U.S.EPA risk limit for recreational contacts,and children playing with water may be exposed to the greatest infection risk.Our findings provide a comprehensive understanding of bacterial pathogen diversity and pathogen abundance in urban recreational water by applying both NGS and q PCR.

The spatial transcriptomic landscape of human gingiva in health and periodontitis

The gingiva is a key oral barrier that protects oral tissues from various stimuli.A loss of gingival tissue homeostasis causes periodontitis,one of the most prevalent inflammatory diseases in humans.The human gingiva exists as a complex cell network comprising specialized structures.To understand the tissue-specific pathophysiology of the gingiva,we applied a recently developed spatial enhanced resolution omics-sequencing(Stereo-seq)technique to obtain a spatial transcriptome(ST)atlas of the gingiva in healthy individuals and periodontitis patients.By utilizing Stereo-seq,we identified the major cell types present in the gingiva,which included epithelial cells,fibroblasts,endothelial cells,and immune cells,as well as subgroups of epithelial cells and immune cells.We further observed that inflammation-related signalling pathways,such as the JAK-STAT and NF-κB signalling pathways,were significantly upregulated in the endothelial cells of the gingiva of periodontitis patients compared with those of healthy individuals.Additionally,we characterized the spatial distribution of periodontitis risk genes in the gingiva and found that the expression of IFI16 was significantly increased in endothelial cells of inflamed gingiva.In conclusion,our Stereo-seq findings may facilitate the development of innovative therapeutic strategies for periodontitis by mapping periodontitis-relevant genes and pathways and effector cells.

The exploration of the correlation between the risk of obesity and the promoter methylation of PRDM16 gene

Objective To explore the association between the Cp G methylation level of positive regulatory domain containing 16(PRDM16)gene promoter and obesity or body mass index(BMI).Methods A total of 116 patients(91female adults and 25 male adults)with abdominal operation in a municipal hospital of Henan province were enrolled in this study and they were divided into

Progress and Implications from Genetic Studies of Bipolar Disorder

With the advancements in gene sequencing technologies,including genome-wide association studies,polygenetic risk scores,and high-throughput sequencing,there has been a tremendous advantage in mapping a detailed blueprint for the genetic model of bipolar disorder(BD).To date,intriguing genetic clues have been identified to explain the development of BD,as well as the genetic association that might be applied for the development of susceptibility prediction and pharmacogenetic intervention.Risk genes of BD,such as CACNA1C,ANK3,TRANK1,and CLOCK,have been found to be involved in various pathophysiological processes correlated with BD.Although the specific roles of these genes have yet to be determined,genetic research on BD will help improve the prevention,therapeutics,and prognosis in clinical practice.The latest preclinical and clinical studies,and reviews of the genetics of BD,are analyzed in this review,aiming to summarize the progress in this intriguing field and to provide perspectives for individualized,precise,and effective clinical practice.

β-fibrinogen gene -455A/G polymorphism and plasma fibrinogen level in Chinese stroke patients

Abstract Objectives To investigate the relationship between the β-fibrinogen gene -455A/G polymorphism and plasma fibrinogen level and to determine the influence of the mutation on ischemic stroke. Methods Ninety-one patients (63.5±10.1 years) with ischemic stroke and 74 elderly control subjects (60.6±10.8 years) without any thromboembolic events and 98 healthy blood donators as young control (37.5±13.3 years) were enrolled in this trial. The β-fibrinogen gene -455A/G polymorphism was analyzed for all subjects by PCR-RFLP with the restrictive enzyme Hae Ⅲ, while plasma fibrinogen levels were obtained from the prothrombin time (PT) assay. For statistical analysis, the parameters were compared between any two different groups by the unpaired Student’s t test and the Chi-square test. Before analysis, log transformations for concentrations of fibrinogen were carried out.Results H2 allele frequency was higher in male ischemic stroke patients than in the elderly control (22.7% vs 7.1%, χ 2=5.56, P【0.02). There was no significant difference between the female groups. In those patients without any thromboembolic events (both elderly and young control groups), the frequency of H2 decreased with age (≤40, 21.3%; 41-59, 15.4%; and ≥60, 10.2%). In the male elderly and young control groups, the level of plasma fibrinogen was lower in the H1H1 genotype (287±96*!mg/dl and 234±58*!mg/dl) than in H1H2 and H2H2 (331±44*!mg/dl and 307±55*!mg/dl; t=2.53 and 9.67, P【0.05). In the female elderly groups, this tendency was not found.Conclusion Plasma fibrinogen expression is affected by the β-fibrinogen gene -455A/G polymorphism, and the H2 allele may be a risk factor for ischemic stroke in Chinese males.