Mendelian randomization identifies age at menarche as an independent causal effect factor for gestational diabetes mellitus.

AIMS: The relationship between age at menarche (AAM) and gestational diabetes mellitus (GDM) risk is still inconclusive. This Mendelian randomization (MR) analysis was used to assess systematically the causal relationship between AAM and GDM risk in human beings. MATERIALS AND METHODS: Single-nucleotide polymorphisms associated with AAM, oestradiol levels, sex hormone-binding globulin (SHBG) levels and bioavailable testosterone (BioT) levels were screened via the genome-wide association study enrolling individuals of European descent. Summary-level data for GDM (123 579 individuals) were extracted from the UK Biobank. An inverse-variance-weighted method was used for the primary MR analysis. Sensitivity analyses were examined via MR-Egger regression, heterogeneity tests, pleiotropy tests and leave-one-out tests. The directionality that exposure causes the outcome was verified using the MR-Steiger test. RESULTS: Genetically predicted early AAM was found to have a causal positive association with a higher risk of GDM (odds ratio = 0.798, 95% confidence interval = 0.649-0.980, p = .031). In the multivariable MR analysis adjusted for oestradiol, SHBG and BioT levels, the causal association between AAM and GDM risk remained (odds ratio = 0.651, 95% confidence interval = 0.481-0.881, p = .006). A 1-SD increase in SHBG or BioT levels was significantly associated with a 41.4% decrease or 20.8% increase in the overall GDM risk (p = 3.71E-05 and .040), respectively. However, after controlling for AAM, oestradiol levels and BioT levels by multivariable MR analysis, there was no direct causal effect of SHBG levels on GDM risk (p = .084). Similarly, after adjusting for AAM, oestradiol levels and SHBG levels by multivariable MR analysis, there was no direct causal effect of BioT levels on the risk of GDM (p = .533). In addition, no direct causal association was identified between oestradiol levels and GDM risk in univariable MR analysis or multivariable MR analysis. CONCLUSION: Genetic variants predisposing individuals to early AAM were independently associated with higher GDM risk. Further research is required to understand the mechanisms underlying this putative causative association. In addition, AAM may be helpful in clinical practice to identify women at risk for GDM; pregnant women who are young for menarche may need to take precautions before GDM develops.

Effects of UBE3A on the insulin resistance in polycystic ovary syndrome through the ubiquitination of AMPK.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive hormonal abnormality and a metabolic disorder, which is frequently associated with insulin resistance (IR). We aim to investigate the potential therapeutic effects of Ubiquitin-protein ligase E3A (UBE3A) on IR in the PCOS rats via Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. METHODS: The PCOS and IR rats model was established by dehydroepiandrosterone (DHEA) and high fat diet (HFD) treatment, and the fat rate, glucose tolerance and insulin tolerance were measured. The IR rats numbers were calculated. Besides, the mRNA levels of glucose transporter 4 (GLUT4) and UBE3A were detected by RT-qPCR. Furthermore, the relationship between was demonstrated by co-IP assay. The phosphorylation and ubiquitination of AMPK were analyzed by western blot. RESULTS: UBE3A was up-regulated in the PCOS rats. UBE3A knockdown significantly decreased the fat rate, glucose tolerance and insulin tolerance in the PCOS and IR rats. Additionally, the GLUT4 levels were significantly increased in PCOS + IR rats. Besides, after UBE3A knockdown, the IR rats were decreased, the p-IRS1 and p-AKT levels were significantly up-regulated. Furthermore, UBE3A knockdown enhanced phosphorylation of AMPK through decreasing the ubiquitination of AMPK. AMPK knockdown reversed the role of UBE3A knockdown in the PCOS + IR rats. CONCLUSIONS: UBE3A knockdown inhibited the IR in PCOS rats through targeting AMPK. Our study indicated that UBE3A might become a potential biological target for the clinical treatment of PCOS.

Expression of VEGFR-2 and Meis1 in the early stage of kidney cancers and its clinical significance. / Meis1与VEGFR-2åœ¨æ—©æœŸè‚¾ç™Œç»„ç»‡ä¸­çš„è¡¨è¾¾åŠå ¶ä¸´åºŠæ„ä¹‰.

OBJECTIVES: To evaluate the expression of myeloid ecotropic viral integration site 1 (Meis1) and vascular endothelial growth factor receptor 2 (VEGFR-2) in early-stage kidney cancers and the clinical significance. METHODS: The cancer tissues and the matched adjacent normal tissues in patients with kidney cancer, who received surgical treatment from April 2005 to September 2018 in the Haikou Hospital Affiliated to Xiangya School of Medicine, Central South University, were collected. The samples included 80 pairs of paraffin specimen, 15 pairs of fresh cancer and the matched adjacent normal tissues from these patients. Real-time PCR and immunohistochemical method were used to detect the expression levels of Meis1 and VEGFR-2 mRNA and protein in kidney tissues and adjacent normal tissues, and the correlation of clinical pathology parameters and the prognosis were analyzed in the patients. RESULTS: The expression levels of Meis1 and VEGFR-2 mRNA and protein in the renal carcinoma tissues were lower than those in the matched adjacent normal tissues (both P<0.01), and the expression levels of Meis1 were positively correlated with that of VEGFR-2 (r=0.681, P<0.01). The analysis of relevant clinical-pathological parameters in the patients showed that: the expression positive rate of Meis1 was significantly related with the pathological type of renal cancer (P<0.01), while the positive rate of Meis1 and VEGFR-2 expression was not related with the gender, age, T stage of patients (all P>0.05), but it was significantly related with the prognosis in the patients (P<0.05). Cox regression analysis showed that: Meis1 was an independent factor for the prognosis of patients (P<0.05). CONCLUSIONS: The mRNA and protein expression levels of Meis1 and VEGFR-2 in the early-stage kidney cancer tissues are significantly decreased compared with those in the adjacent normal tissues. Meis1 may be served as a tumor suppressor to affect the occurrence and development of kidney cancer. Therefore, Meis1 may be used as a biomarker to predict the prognosis of patients with kidney cancer.

BAG3 as a novel prognostic biomarker in kidney renal clear cell carcinoma correlating with immune infiltrates.

PURPOSE: BCL-2-associated athanogene 3 (BAG3) is an anti-apoptotic protein that plays an essential role in the onset and progression of multiple cancer types. However, the clinical significance of BAG3 in kidney renal clear cell carcinoma (KIRC) remains unclear. METHODS: Using Tumor IMmune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) database, we explored the expression, prognostic value, and clinical correlations of BAG3 in KIRC. In addition, immunohistochemistry (IHC) of HKH cohort further validated the expression of BAG3 in KIRC and its impact on prognosis. Gene Set Cancer Analysis (GSCA) was utilized to scrutinize the prognostic value of BAG3 methylation. Gene Ontology (GO) term analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) were used to identify potential biological functions of BAG3 in KIRC. Single-sample gene set enrichment analysis (ssGSEA) was performed to confirm the correlation between BAG3 expression and immune cell infiltration. RESULTS: BAG3 mRNA expression and protein expression were significantly downregulated in KIRC tissues compared to normal kidney tissues, associated with adverse clinical-pathological factors and poor clinical prognosis. Multivariate Cox regression analysis indicated that low expression of BAG3 was an independent prognostic factor in KIRC patients. GSEA analysis showed that BAG3 is mainly involved in DNA methylation and the immune-related pathways in KIRC. In addition, the expression of BAG3 is closely related to immune cell infiltration and immune cell marker set. CONCLUSION: BAG3 might be a potential therapeutic target and valuable prognostic biomarker of KIRC and is closely related to immune cell infiltration.

Mendelian randomization analyses identified bioavailable testosterone mediates the effect of sex hormone-binding globulin on prostate cancer.

OBJECTIVE: A better knowledge of the hormonal etiology of prostate cancer is essential for its prevention and treatment. The goal of this study was to provide causal estimates of the connection between sex hormone-binding globulin and prostate cancer and investigate the possible mediating function of other modifiable risk indicators. METHODS: We used two-step, two-sample multivariable Mendelian randomization using single-nucleotide polymorphisms as instrumental variables for exposure and mediators. Single-nucleotide polymorphisms associated with sex hormone-binding globulin and bioavailable testosterone were screened via a genome-wide association study enrolling European-descent adult male individuals. Summary-level data for prostate cancer (79,148 cases and 61,106 controls) were extracted from the PRACTICAL consortium. The total effect of sex hormone-binding globulin on prostate cancer risk was decomposed into direct and indirect effects through the mediator, bioavailable testosterone. An inverse-variance-weighted method was the primary Mendelian randomization analysis method. Sensitivity analyses were performed via Mendelian randomization-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out test. The directionality that exposure causes the outcome was verified using Mendelian randomization-Steiger test. RESULTS: In the univariable Mendelian randomization analysis, genetically predicted higher sex hormone-binding globulin levels had a causal association with lower prostate cancer risk (odds ratio = 0.944, 95% confidence interval = 0.897-0.993, p = 0.027) and an inverse association with bioavailable testosterone level (odds ratio = 0.945, 95% confidence interval = 0.926-0.965, p = 1.62E-07) without controlling for other factors. Moreover, an increase of one standard deviation (59.5 pmol/L) in genetically predicted bioavailable testosterone level was significantly associated with a 22.0% increase in the overall prostate cancer risk (odds ratio = 1.220, 95% confidence interval = 1.064-1.398, p = 0.004) after adjusting for sex hormone-binding globulin level. The effect size ratio of bioavailable testosterone-mediated sex hormone-binding globulin to prostate cancer was further analyzed to clarify the importance of the mediating effect. Notably, the mediator bioavailable testosterone explained 19.28% (95% confidence interval = 10.76%, 73.78%) of the total effect of sex hormone-binding globulin level on prostate cancer risk. CONCLUSION: The results support the potentially protective causal effect of genetically predicted higher sex hormone-binding globulin levels against prostate cancer with mediation by the modifiable risk factor, bioavailable testosterone. More research is needed to determine how this possible sex hormone-binding globulin-bioavailable testosterone-prostate cancer link works. Targeting sex hormone-binding globulin and bioavailable testosterone traits may be a valuable strategy for preventing prostate cancer.

Evaluating the causal relationship between five modifiable factors and the risk of spinal stenosis: a multivariable Mendelian randomization analysis.

Background: Spinal stenosis is a neurological disorder related to the compression of the spinal cord or nerve roots, and its incidence increases yearly. We aimed to use Mendelian randomization (MR) to investigate the causal relationship between several modifiable risk factors and the risk of spinal stenosis. Methods: We obtained genome-wide association study summary data of large-sample projects (more than 100,000 individuals) from public databases. The data were associated with traits, including years of schooling (educational attainment) from the IEU OpenGWAS Project, smoking behavior (never vs. initiation) from the IEU OpenGWAS Project, body mass index (BMI) from the UK Biobank, length of mobile phone use from the UK Biobank, time spent watching television (TV) from the UK Biobank, and spinal stenosis from FinnGen biobank. Spinal stenosis was used as the outcome, whereas the other four traits were used as exposures. Inverse variance weighted (IVW) regressions were used as a primary to estimate the causal-effect size. Several sensitive analyses (including consistency, heterogenicity, and pleiotropy analyses) were conducted to test the stability and reliability of causal estimates. Results: Univariable MR analyses showed that genetically predicted higher educational attainment (IVW; odds ratio (OR) = 0.606; 95% confidence interval (CI): 0.507-0.724; P = 3.37 × 10-8) and never smoking (IVW; OR = 1.388; 95% CI [1.135-1.697]; P = 0.001) were negatively correlated with the risk of spinal stenosis. Meanwhile, a higher BMI (IVW; OR = 1.569; 95% CI [1.403-1.754]; P = 2.35 × 10-8), longer time spent using a mobile phone (IVW; OR = 1.895; 95% CI [1.306-2.750]; P = 0.001), and watching TV (IVW; OR = 1.776; 95% CI [1.245-2.532]; P = 0.002) were positively associated with the risk of spinal stenosis. Multivariable MR analysis indicated that educational attainment (IVW; OR = 0.670; 95% CI [0.465-0.967]; P = 0.032) and BMI (IVW; OR = 1.365; 95% CI [1.179-1.580]; P = 3.12 × 10-5) were independently causally related to the risk of spinal stenosis. Conclusion: Our findings supported the potential causal associations of the five factors (educational attainment, smoking behavior, BMI, length of mobile phone use, and watching TV) with the risk for spinal stenosis. While replication studies are essential, these findings may provide a new perspective on prevention and intervention strategies directed toward spinal stenosis.

Identifying effects of genetic obesity exposure on leukocyte telomere length using Mendelian randomization.

Background: Observational studies have shown that obesity is closely associated with leukocyte telomere length (LTL). However, the causal relationship between obesity and LTL remains unclear. This study investigated the causal relationship between obesity and LTL through the Mendelian randomization approach. Materials and Methods: The genome-wide association study (GWAS) summary data of several studies on obesity-related traits with a sample size of more than 600,000 individuals were extracted from the UK Biobank cohort. The summary-level data of LTL-related GWAS (45 6,717 individuals) was obtained from the IEU Open GWAS database. An inverse-variance-weighted (IVW) algorithm was utilized as the primary MR analysis method. Sensitivity analyses were conducted via MR-Egger regression, IVW regression, leave-one-out test, MR-pleiotropy residual sum, and outlier methods. Results: High body mass index was correlated with a short LTL, and the odds ratio (OR) was 0.957 (95% confidence interval [CI] 0.942-0.973, p = 1.17E-07). The six body fat indexes (whole body fat mass, right leg fat mass, left leg fat mass, right arm fat mass, left arm fat mass, and trunk fat mass) were consistently inversely associated with LTL. Multiple statistical sensitive analysis approaches showed that the adverse effect of obesity on LTL was steady and dependable. Conclusion: The current study provided robust evidence supporting the causal assumption that genetically caused obesity is negatively associated with LTL. The findings may facilitate the formulation of persistent strategies for maintaining LTL.

Mendelian randomization investigation identified the causal relationship between body fat indexes and the risk of bladder cancer.

Background: Observational studies have suggested that obesity is associated with the risk of bladder cancer (BCa). However, their causal relationship remains unclear. This study aimed to prove the causal relationship between obesity and the risk of BCa by using Mendelian randomization. Methods: Single-nucleotide polymorphisms (SNPs) correlated with body fat indexes were screened from several genome-wide association studies (GWAS) with more than 300,000 individuals. Summary-level genetic data of BCa-related GWAS were obtained from a European cohort with a sample size of 218,792. An inverse-variance-weighted (IVW) method was used as the major MR analysis. The MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier methods were used to test the reliability and stability of MR results. Results: Genetically predicted per 1-SD increase in body fat indexes (whole body fat mass, and the right leg, left leg, right arm, left arm, and trunk fat mass) were associated with increased BCa risk with values of 51.8%, 77.9%, 75.1%, 67.2%, 59.7%, and 36.6%, respectively. Sensitivity analyses suggested that the genetically determined risk effect of obesity on BCa was stable and reliable. Conclusions: Our study provided powerful evidence to support the causal hypothesis that the genetically predicted high body fat mass was associated with a risk increase for BCa. The finding is a new idea for drawing up prevention strategies for BCa.

Mendelian randomization study on the causal relationship between leukocyte telomere length and prostate cancer.

BACKGROUND: Leukocyte telomere length (LTL) is related to prostate cancer (PCa). However, the causal relationship between them remains unknown. This study was aimed at identifying the causal direction between LTL and PCa with Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms associated with LTL were identified from a genome-wide association study (GWAS) involving 472,174 individuals. Summary-level data of PCa-related GWAS were extracted from four cohorts comprising 456,717 individuals. An inverse-variance-weighted (IVW) algorithm was used for MR. Sensitivity analyses were performed with MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier analyses. A meta-analysis was also performed to compute the average genetically determined effect of LTL on PCa. RESULTS: A long LTL was associated with an increased risk of PCa in all cohorts, with odds ratios of 1.368 (95% confidence interval [CI]: 1.247 to 1.500, P = 2.84×10-11), 1.503 (95% CI: 1.243 to 1.816, P = 2.57×10-5), 1.722 (95% CI: 1.427 to 2.077, P = 1.48×10-8), and 1.358 (95% CI: 1.242 to 1.484, P = 1.73×10-11) in the IVW analysis. Sensitivity analyses showed that the genetically determined effect of LTL on PCa was stable and reliable. The meta-analysis showed that the genetically determined per 1-standard deviation rise in LTL correlated significantly with an average 40.6% increase in the PCa risk, with an average odds ratio of 1.406 (95% CI: 1.327 to 1.489, P < 0.001). CONCLUSION: The results of this study supported the causal hypothesis that the genetically determined longer LTL was associated with a higher risk of PCa. This finding could serve as a basis for therapeutic strategies for PCa.

Putative causal inference for the relationship between obesity and sex hormones in males: a bidirectional Mendelian randomization study.

Background: Obesity is a chronic disease with a high prevalence rate and is an established risk factor for human health. Body mass index (BMI) is a common and primary indicator used in assessing obesity. This work aims to investigate the putative causal relationship among BMI, sex hormone-binding globulin (SHBG), bioavailable testosterone (BioT), and estradiol levels. Materials and Methods: We conducted a bidirectional Mendelian randomization study, using single-nucleotide polymorphisms (SNPs) strongly associated with BMI, SHBG, BioT, and estradiol as instrumental variables. All SNPs were identified from the genome-wide association study (GWAS) summary data of large sample studies recruiting more than 150,000 European adult male individuals. The inverse-variance-weighted (IVW) approach was used as a primary algorithm for putative causal estimation. Results: Genetically predicted elevated BMI was associated with decreased SHBG (IVW, ß = -0.103, 95% confidence interval [CI] [-0.113 to -0.092], P = 1.50 × 10-77) and BioT levels (IVW, ß = -0.139, 95% CI [-0.165 to -0.113], P = 9.54 × 10-26) and high estradiol levels (IVW, ß = 0.014, 95% CI [0.009-0.019], P = 2.19 × 10-7). Increased SHBG levels were causally associated with low BMI (IVW, ß = -0.051, 95% CI [-0.098 to -0.005], P = 0.030) and BioT (IVW, ß = -0.126, 95% CI [-0.175 to -0.077], P = 5.97 × 10-7) and high estradiol levels (IVW, ß = 0.046, 95% CI [0.035-0.056], P = 6.51 × 10-17). Conversely, no evidence of an effect of estradiol imbalance on SHBG levels (IVW, ß = 1.035, 95% CI [-0.854 to 2.926], P = 0.283) and BMI (IVW, ß = 0.091, 95% CI [-0.094 to 0.276], P = 0.336) was obtained. However, increased BioT levels were causally associated with lower SHBG levels (IVW, ß = -0.044, 95% CI [-0.061 to -0.026], P = 8.76 × 10-7), not BMI (IVW, ß = -0.006, 95% CI [-0.035 to 0.023], P = 0.679). Conclusions: The findings support a network putative causal relationship among BMI, SHBG, BioT, and estradiol. SHBG, BioT, and estradiol may partly mediate the effect of obesity on male health. Reasonably modulating BioT and estradiol, especially SHBG, facilitated the attenuation of the harmful effects of obesity on male health.

Modifiable risk factors that mediate the effect of educational attainment on the risk of stroke: a network Mendelian randomization study.

BACKGROUND: Stroke is a common cerebrovascular disease with great danger to public health. Educational inequality is a universal issue that influences populations' stroke risk. This study aimed to investigate the causal relationship between education and stroke risk and the contributions of effects mediated by four modifiable factors. MATERIALS AND METHODS: Public large-scale genome-wide association study (GWAS) summary data associated with educational attainment, hypertensive diseases, body mass index (BMI), smoking behavior, time spent on watching the television (TV), and stroke were obtained from European ancestry. The data were used to investigate the causal relationship among educational attainment, hypertensive disease, BMI, smoking, watching TV, and stroke risk. Inverse variance weighted (IVW) method was used as a primary algorithm for estimating causal direction and effect size in univariable and multivariable Mendelian randomization (MR) analyses. RESULTS: Higher educational attainment was a causal protective factor, while hypertensive diseases, higher BMI, smoking, and longer time spent on watching the TV were all causal risk factors for the risk of stroke. Hypertensive disease, BMI, smoking, and watching TV were all mediators for linking the causal relationship between educational attainment and stroke risk. Hypertensive disease, BMI, smoking, and watching TV explained 47.35%, 24.74%, 15.72%, and 2.29% of the variance in educational attainment's effect on stroke risk, respectively. The explained proportion reached 69.32% after integrating the four factors. CONCLUSIONS: These findings support the causal effect of educational attainment on the risk of stroke, with a substantial proportion mediated by modifiable risk factors. Interventions on these modifiable factors would lead to substantial reductions in stroke cases attributable to educational inequality.

Evaluating the causality between skin tanning, radiated disorders, and basal cell carcinoma: a multivariable Mendelian randomization analysis.

The causality of ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue with basal cell carcinoma (BCC) remains unclear. Our objective was to investigate whether ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue have a relation with the occurrence and development of BCCs. In this work, independent genetic variants strongly associated (P < 5e-08) with ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for BCC was obtained from the European Bioinformatics Institute (EBI). Two-sample univariable and multivariable Mendelian randomization (MR) were performed. Sensitivity analyses were preformed via MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. We observed positive causal effect both for ease of skin tanning [odds ratio (OR) = 2.102, 95% confidence interval (CI) = 1.915-2.306, P = 2.71e-55] and radiation-related disorders of the skin and subcutaneous (OR = 1.603, 95% CI = 1.483-1.734, P = 3.41e-32) on occurrence of BCCs based on univariable MR analyses. In the multivariable mendelian randomization (MVMR) analysis of BCC risk, we also observed a direct causal effect of ease of skin tanning (ORMVMR = 1.623, 95% CI = 1.445-1.824, PMVMR =3.41e-16) and radiation-related disorders of the skin and subcutaneous (ORMVMR = 1.208, 95% CI = 1.107-1.319, PMVMR = 2.46e-05) on BCCs. The findings suggest that the high risk of BCCs can be attributed to ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue.

The current landscape of m6A modification in urological cancers.

N6-methyladenosine (m6A) methylation is a dynamic and reversible procession of epigenetic modifications. It is increasingly recognized that m6A modification has been involved in the tumorigenesis, development, and progression of urological tumors. Emerging research explored the role of m6A modification in urological cancer. In this review, we will summarize the relationship between m6A modification, renal cell carcinoma, bladder cancer, and prostate cancer, and discover the biological function of m6A regulators in tumor cells. We will also discuss the possible mechanism and future application value used as a potential biomarker or therapeutic target to benefit patients with urological cancers.

Leukocyte telomere length and bipolar disorder risk: evidence from Mendelian randomization analysis.

Objective: We aim to test whether leukocyte telomere length (LTL) is causally associated with the risk of bipolar disorder (BD) using the Mendelian randomization (MR) method. Methods: Results of a genome-wide association study (GWAS) conducted with 472,174 individuals of European descent were used to screen for single-nucleotide polymorphisms (SNPs) related with LTL traits. Summary-level data for BD (7,647 cases and 27,303 controls) were obtained from UK Biobank. An inverse-variance-weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger, maximum likelihood, MR-pleiotropy residual sum outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS) methods. Finally, the MR Steiger test was utilized to validate the hypothesized relationship between exposure and outcome. Results: Two-sample MR analysis revealed inverse relationships between genetically predicted LTL and BD risk (IVW OR [odds ratio] = 0.800, 95% CI [0.647-0.989] P = 0.039). Genetically predicted LTL exhibits a consistent connection with BD across five MR methods. Sensitivity analyses showed that the genetically determined effect of LTL on BD was stable and reliable. Furthermore, the MR Steiger test demonstrated that LTL was causal for BD rather than the opposite (P < 0.001). Conclusion: Our findings show that genetically determined LTL reduces the risk of BD. More research is required to clarify the mechanisms underlying this apparent causal connection. In addition, these findings may be useful for developing strategies for the prevention and treatment of BD.

Body mass index and the risk of basal cell carcinoma: evidence from Mendelian randomization analysis.

Objective: We aim to test whether body mass index (BMI) is causally associated with the risk of basal cell carcinoma (BCC) using Mendelian randomization (MR) analysis. Methods: Single-nucleotide polymorphisms (SNPs) associated with four BMI-related traits were screened via a genome-wide association study (GWAS) with 681,275, 336,107, 454,884, and 461,460 European-descent individuals, respectively. Summary-level data for BCC (17,416 cases and 375,455 controls) were extracted from UK Biobank. An inverse variance weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. The assumption that exposure causes outcome was verified using the MR Steiger test. Meta-analysis was also used to estimate the average genetically predicted effect of BMI on BCC. Results: Two-sample MR analysis showed inverse associations between genetically predicted BMI and BCC risk. Moreover, when exposure and outcome were switched to see if reverse causation was possible, there was no evidence of a cause-and-effect relationship from BCC to BMI. Finally, the meta-analysis also showed a strong negative causal relationship between BMI and BCC. Conclusion: Genetical predicted higher BMI were associated with lower BCC risk. Further research is required to comprehend the mechanisms underlying this putative causative association.

Four modifiable factors that mediate the effect of educational time on major depressive disorder risk: A network Mendelian randomization study.

BACKGROUND: Major depressive disorder (MDD) is a mental illness, which is a notable public health problem that aggravates the global economic burden. This study aimed to investigate the causal relationship between education and MDD risk and the contributions of effects mediated by four modifiable factors. MATERIALS AND METHODS: Instrumental variables were screened from several large-scale genome-wide association study (GWAS) data (years of schooling with 766,345 participants, MDD with 59,851 cases and 113,154 controls, neuroticism with 329,821 individuals, smoking behavior with 195,068 cases and 164,638 controls, body mass index [BMI] with 336,107 individuals, and household income with 397,751 individuals). The data were used to evaluate the association of the four modifiable factors (neuroticism, smoking behavior, BMI, and household income) that mediate the effect of education on MDD risk via Mendelian randomization (MR) analysis. RESULTS: Each standard deviation increase in years of schooling could reduce the risk for MDD by 30.70%. Higher neuroticism and BMI were associated with a higher risk of MDD. Non-smoking status and increased household income were protective factors for MDD. Notably, the mediator neuroticism, BMI, smoking behavior, and household income explained 52.92%, 15.54%, 31.86%, and 81.30% of the effect of years of schooling on MDD risk, respectively. CONCLUSIONS: Longer years of schooling have a protective effect on MDD risk. Reasonable interventions to reduce neuroticism, BMI, smoking, and increasing household income are beneficial for MDD prevention. Our work provides new ideas for the development of prevention strategies for MDD.

Modifiable risk factors of major depressive disorder: A Mendelian randomization study.

Identifying modifiable risk factors early on is essential to prevent major depressive disorder (MDD). This study systematically investigated the causal relationship between 19 modifiable risk factors and MDD. Single-nucleotide polymorphisms (SNPs) associated with 19 potentially modifiable risk factors were screened via the genome-wide association study (GWAS) enrolling individuals of European descent. Summary-level data for MDD (59,851 cases and 113,154 controls) were extracted from the UK Biobank. The inverse-variance-weighted (IVW) method was utilized as the primary analysis. Sensitivity analyses were performed using the MR-Egger method, the Maximum likelihood method, the MR-pleiotropy residual sum outlier (MR-PRESSO) method, and MR-robust adjusted profile score (MR-RAPS) method. MR-Egger regression, heterogeneity tests, pleiotropy tests, and leave-one-out tests were also performed to analyze sensitivity. The MR Steiger test was used to verify the directionality of the exposure to the outcome. Genetically predicted smoking initiation increased the risk of MDD (P = 6.00E-09), while smoking status: never and past tobacco smoking decreased the risk of MDD (all P < 0.01). In addition, education level was inversely associated with MDD risk (all P < 0.01). Genetically instrumented sleeplessness/insomnia, daytime naps, and nap during the day were positively related to the risk of MDD (all P < 0.01). Personal feelings, including guilt, hurt, tension, and worry too long after an embarrassing experience, had a suggestive increased risk for MDD (all P < 0.000). The remaining five modifiable risk factors were all causally associated with the risk of MDD, including neuroticism, neuroticism scores, body mass index (BMI), average total household income before tax, and types of physical activity in the last 4 weeks (all P < 0.01). All 19 potentially modifiable risk factors were causally associated with the risk of MDD. The main hypothesis of this MR study was that identifying and intervening in these 19 potentially modifiable risk factors could be beneficial to the prevention and treatment of MDD and further reduce mortality and economic burden.

Current progress on the curative effects of vasoepididymostomy for patients with obstructive azoospermia: An updated systematic review and meta-analysis of human studies.

BACKGROUND: Obstructive azoospermia (OA) is an important cause of male infertility, and epididymal OA (EOA) is a common disease. Microsurgical reconstruction is a common technique used in the treatment of EOA. In the present study, we analyzed the effectiveness of microsurgical vasoepididymostomy (MVE) at different levels and compared the differences among several MVE techniques. MATERIALS AND METHODS: A literature search was conducted in the PubMed, Web of Science, and Embase databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The included studies were published in English until May 14, 2021. The R 4.1.2 software was utilized to evaluate the event rate, risk ratio (RR), and 95% confidence interval (CI). RESULTS: A total of 51 studies involving 2853 patients with OA were included in our meta-analysis. The overall mean patency rate of patients who underwent MVE was 67.20% (95% [CI]:63.30%-71.10%), and the overall mean natural pregnancy rate of their partners was 40.05% (95% [CI]: 35.30%-45.60%). The pooled results showed that the patency rate of bilateral MVE was higher than that of unilateral MVE (RR = 1.42; 95% [CI]:1.25-1.61; p < 0.00). A comparison of the anastomotic site of MVE showed that the caudal/corpus area was favorable for the patency rate (RR = 1.17; 95% [CI]:1.04 - 1.32; p < 0.00). The caudal area was also advantageous for the patency rate (RR = 1.20; 95% CI:1.03 - 1.41; p < 0.04). Compared with typical MVE (65.20%, 95% [CI]:61.40%-69.10%), deferential vessel-sparing MVE with a higher overall mean patency rate (83.60%, 95% [CI]:75.40%-91.70%). CONCLUSIONS: The meta-analyses indicated that MVE is a high- and cost-effective therapeutic method for patients with EOA, and deferential vessel-sparing MVE could be mainstream in the near future.

Follicular Fluid-Derived Small Extracellular Vesicles Alleviate DHEA-Induced Granulosa Cell Apoptosis by Delivering LINC00092.

Polycystic ovary syndrome (PCOS) is a perplexing condition in females of reproductive age. Dysplasia of ovarian granulosa cell (GC) is implicated in PCOS. Follicular fluid (FF)-extracellular vesicles (Evs) are important in cell-cell communication during follicular development. The current study elaborated on the function and mechanism of FF-Evs in the viability and apoptosis of GC cells in PCOS development. Human GC cells KGN were treated with dehydroepiandrosterone (DHEA) to mimic a PCOS-like condition in vitro, which were further co-cultured with the FF-derived Evs (FF-Evs). The FF-Evs treatment significantly reduced DHEA-induced apoptosis of KGN cells while promoting cell viability and migration. The lncRNA microarray analysis showed that FF-Evs mainly deliver LINC00092 into the KGN cells. Knockdown of LINC00092 negated the protective effect of FF-Evs against DHEA-induced damage on KGN cells. Moreover, by performing bioinformatics analyses and biotin-labeled RNA pull-down assay, we found that LINC00092 could bind to the RNA binding protein LIN28B and inhibit its binding to pre-microRNA-18-5p, which allowed biogenesis of pre-miR-18-5p and increased the expression of miR-18b-5p, a miRNA with known alleviating role in PCOS by suppressing the PTEN mRNA. Collectively, the present work demonstrates that FF-Evs can alleviate DHEA-induced GC damage by delivering LINC00092.

LINC00092 derived from follicular fluid alleviated the symptoms of PCOS through inactivation of phosphatase and tensin homolog by recruiting KDM5A.

Mounting literatures suggest that follicular fluid-derived exosomes (FF-Evs) influence the progression of progression of polycystic ovary syndrome (PCOS). The present study was designed to dissect the underlying mechanisms by which FF-Evs affect the PCOS. A rat model of PCOS was established using Letrozole induction. After treatment with FF-Evs, rats were examined for alterations in hormones, blood glucose, and lipid levels in serum, oestrus cycle, pathology in the ovaries, and apoptosis of ovarian cells. The functional rescue assays were performed to analyze the impact of long non-coding RNA 00092 (LINC00092) on PCOS rats. The cis-regulatory elements involved in the regulation of phosphatase and tensin homolog (PTEN) expression were analyzed using bioinformatic analysis, followed by verification of the mechanism. FF-Evs treatment ameliorated Letrozole-induced enhancement of weight, insulin resistance, dyslipidemia, and LH/FSH ratio, reduction of luteal cells, granulosa cells, and healthy follicles, prolonged oestrus, oestrous cycle arrest, ovarian tissue fibrosis, and ovarian cell apoptosis in rats, which were counteracted by treatment with shRNA targeting LINC00092. Regarding the mechanism, FF-Evs augmented LINC00092 expression in rats. LINC00092 bound to lysine demethylase 5 A (KDM5A), and KDM5A facilitated the demethylation of H3K4me3 to restrain the transcriptional activity of PTEN. Taken together, FF-Evs delivered LINC00092 repressed the transcriptional activity of PTEN by binding to KDM5A to enhance demethylation of H3K4me3, thereby reducing apoptosis in ovarian cells and alleviating PCOS symptoms.