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Molecular Medicine (Cambridge, Mass.) Jun 2024Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes....
BACKGROUND
Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF.
METHODS
Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses.
RESULTS
We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway.
CONCLUSION
Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.
Topics: Animals; Mice; Mice, Knockout; Ventricular Remodeling; Heart Failure; Ubiquitin-Specific Proteases; Disease Models, Animal; Male; Arrhythmias, Cardiac; Heart Ventricles; Mice, Transgenic; Signal Transduction; Electrocardiography
PubMed: 38937697
DOI: 10.1186/s10020-024-00846-3 -
BMC Psychiatry Jun 2024The inclusion of biomarkers could improve diagnostic accuracy of attention-deficit/hyperactivity disorder (ADHD). One potential biomarker is the ADHD polygenic score...
BACKGROUND
The inclusion of biomarkers could improve diagnostic accuracy of attention-deficit/hyperactivity disorder (ADHD). One potential biomarker is the ADHD polygenic score (PGS), a measure of genetic liability for ADHD. This study aimed to investigate if the ADHD PGS can provide additional information alongside ADHD rating scales and examination of family history of ADHD to distinguish between ADHD cases and controls.
METHODS
Polygenic scores were calculated for 576 adults with ADHD and 530 ethnically matched controls. ADHD PGS was used alongside scores from the Wender-Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale (ASRS) as predictors of ADHD diagnosis in a set of nested logistic regression models. These models were compared by likelihood ratio (LR) tests, Akaike information criterion corrected for small samples (AICc), and Lee R². These analyses were repeated with family history of ADHD as a covariate in all models.
RESULTS
The ADHD PGS increased the variance explained of the ASRS by 0.58% points (pp) (R = 61.11%, R=61.69%), the WURS by 0.61pp (R = 77.33%, R= 77.94%), of ASRS and WURS together by 0.57pp (R=80.84%, R=81.40%), and of self-reported family history by 1.40pp (R = 28.06%, R=29.46%). These increases were statistically significant, as measured by LR tests and AICc.
CONCLUSION
We found that the ADHD PGS contributed additional information to common diagnostic aids. However, the increase in variance explained was small, suggesting that the ADHD PGS is currently not a clinically useful diagnostic aid. Future studies should examine the utility of ADHD PGS in ADHD prediction alongside non-genetic risk factors, and the diagnostic utility of the ADHD PGS should be evaluated as more genetic data is accumulated and computational tools are further refined.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Male; Female; Multifactorial Inheritance; Adult; Psychiatric Status Rating Scales; Case-Control Studies; Genetic Predisposition to Disease; Self Report; Middle Aged
PubMed: 38937684
DOI: 10.1186/s12888-024-05925-7 -
BMC Cancer Jun 2024Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1...
BACKGROUND
Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential.
METHODS
We conducted this five-center case‒control study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association.
RESULTS
We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II.
CONCLUSION
Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions.
Topics: Child; Child, Preschool; Female; Humans; Infant; Male; Adaptor Proteins, Signal Transducing; Case-Control Studies; China; DNA-Binding Proteins; East Asian People; Genetic Predisposition to Disease; Genotype; Kidney Neoplasms; LIM Domain Proteins; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins; Transcription Factors; Wilms Tumor; Multigene Family
PubMed: 38937681
DOI: 10.1186/s12885-024-12557-3 -
BMC Genomics Jun 2024Observational studies have preliminarily revealed an association between smoking and gastroesophageal reflux disease (GERD). However, little is known about the causal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Observational studies have preliminarily revealed an association between smoking and gastroesophageal reflux disease (GERD). However, little is known about the causal relationship and shared genetic architecture between the two. This study aims to explore their common genetic correlations by leveraging genome-wide association studies (GWAS) of smoking behavior-specifically, smoking initiation (SI), never smoking (NS), ever smoking (ES), cigarettes smoked per day (CPD), age of smoking initiation(ASI) and GERD.
METHODS
Firstly, we conducted global cross-trait genetic correlation analysis and heritability estimation from summary statistics (HESS) to explore the genetic correlation between smoking behavior and GERD. Then, a joint cross-trait meta-analysis was performed to identify shared "pleiotropic SNPs" between smoking behavior and GERD, followed by co-localization analysis. Additionally, multi-marker analyses using annotation (MAGMA) were employed to explore the degree of enrichment of single nucleotide polymorphism (SNP) heritability in specific tissues, and summary data-based Mendelian randomization (SMR) was further utilized to investigate potential functional genes. Finally, Mendelian randomization (MR) analysis was conducted to explore the causal relationship between the smoking behavior and GERD.
RESULTS
Consistent genetic correlations were observed through global and local genetic correlation analyses, wherein SI, ES, and CPD showed significantly positive genetic correlations with GERD, while NS and ASI showed significantly negative correlations. HESS analysis also identified multiple significantly associated loci between them. Furthermore, three novel "pleiotropic SNPs" (rs4382592, rs200968, rs1510719) were identified through cross-trait meta-analysis and co-localization analysis to exist between SI, NS, ES, ASI, and GERD, mapping the genes MED27, HIST1H2BO, MAML3 as new pleiotropic genes between SI, NS, ES, ASI, and GERD. Moreover, both smoking behavior and GERD were found to be co-enriched in multiple brain tissues, with GMPPB, RNF123, and RBM6 identified as potential functional genes co-enriched in Cerebellar Hemisphere, Cerebellum, Cortex/Nucleus accumbens in SI and GERD, and SUOX identified in Caudate nucleus, Cerebellum, Cortex in NS and GERD. Lastly, consistent causal relationships were found through MR analysis, indicating that SI, ES, and CPD increase the risk of GERD, while NS and higher ASI decrease the risk.
CONCLUSION
We identified genetic loci associated with smoking behavior and GERD, as well as brain tissue sites of shared enrichment, prioritizing three new pleiotropic genes and four new functional genes. Finally, the causal relationship between smoking behavior and GERD was demonstrated, providing insights for early prevention strategies for GERD.
Topics: Gastroesophageal Reflux; Humans; Polymorphism, Single Nucleotide; Smoking; Genome-Wide Association Study; Genetic Predisposition to Disease; Mendelian Randomization Analysis; Genomics; Multiomics
PubMed: 38937676
DOI: 10.1186/s12864-024-10536-3 -
Causal relationship between prostatic diseases and prostate cancer: a mendelian randomization study.BMC Cancer Jun 2024Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are...
BACKGROUND
Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear.
METHODS
We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance (P < 5 × 10). The accuracy of the results was confirmed using sensitivity analyses.
RESULTS
MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098-0.281, P = 5.079 × 10) while prostatitis had no significant causal effect on PCa (P > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable.
CONCLUSIONS
This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.
Topics: Humans; Male; Mendelian Randomization Analysis; Prostatic Neoplasms; Genome-Wide Association Study; Prostatic Hyperplasia; Prostatitis; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 38937672
DOI: 10.1186/s12885-024-12551-9 -
BMC Nephrology Jun 2024Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with...
BACKGROUND
Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with sarcoidosis is rare and membranous nephropathy (MN) is cited as the most common. The association between the two diseases remained unclear. This article reported a case of co-occurrence of sarcoidosis and anti-PLA2R-associated MN, to provide a possible relationship between these two entities.
CASE PRESENTATION
A 61-year-old Chinese Han woman with a history of sarcoidosis was admitted to our hospital for nephrotic syndrome. Her sarcoidosis was diagnosed according to the adenopathy observed on the computed tomography scan and the biopsy of lymph nodes. The MN presented with nephrotic syndrome with a PLA2R antibody titer of 357RU/ml, and the final diagnosis was based on a renal biopsy. The patient's sarcoidosis was remitted after treatment with prednisone. One year later MN was diagnosed, and she was treated with prednisone combined with calcineurin inhibitors, based on a full dose of renin-angiotensin system (RAS) inhibitor. The patient's sarcoidosis had been in remission while the MN was recurrent, and her renal function deteriorated to end-stage renal disease 6 years later due to discontinuation of immunosuppression. A genetic test led to the identification of the HLA-DRB1*0301 and HLA-DRB1*150 genes associated with both sarcoidosis and MN, which provides a new possible explanation of the co-occurrence of these two diseases.
CONCLUSION
This case suggested for the first time a potential genetic connection between idiopathic MN and sarcoidosis which needs further studies in the future.
Topics: Humans; Glomerulonephritis, Membranous; Female; Middle Aged; Receptors, Phospholipase A2; Sarcoidosis; Genetic Predisposition to Disease; Autoantibodies
PubMed: 38937663
DOI: 10.1186/s12882-024-03649-0 -
Scientific Reports Jun 2024Cervical cancer (CC) is a prevalent gynecological cancer worldwide that significantly impacts the quality of life and the physical and mental well-being of women....
Cervical cancer (CC) is a prevalent gynecological cancer worldwide that significantly impacts the quality of life and the physical and mental well-being of women. However, there have been limited studies utilizing Mendelian randomization (MR) analysis to investigate the connection between immune cells and CC. This study is to investigate the causal effects of immune traits on CC and non-neoplastic conditions of the cervix. The GWAS data for 731 immunophenotypes and six GWAS data for CC from the FinnGen database were downloaded. Subsequently, a two-sample MR analysis was conducted using the MR Egger, Weighted median, Inverse variance weighted (IVW), Simple mode, and Weighted mode methods. Our study has identified the potential causal effects of immune traits on inflammatory diseases of the cervix, other noninflammatory disorders of the cervix uteri, carcinoma in situ of cervix uteri, adenocarcinomas of cervix, squamous cell neoplasms and carcinoma of cervix, as well as malignant neoplasm of the cervix uteri, with the respective numbers being 8, 6, 11, 8, 23, and 12, respectively. A strong correlation between classic monocytes and various cervical diseases was revealed. Furthermore, we discovered that B cells expressing BAFF-R have the ability to impede the advancement of malignant CC, specifically squamous cell neoplasms and carcinoma of cervix. Our study has demonstrated a significant association between immune traits and both CC and non-neoplastic conditions of the cervix through two-sample Mendelian randomization, providing valuable insights for future clinical research.
Topics: Humans; Female; Mendelian Randomization Analysis; Uterine Cervical Neoplasms; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 38937531
DOI: 10.1038/s41598-024-65957-7 -
Annals of the Rheumatic Diseases Jun 2024Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to...
OBJECTIVES
Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism.
METHODS
We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms.
RESULTS
Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression.
CONCLUSIONS
These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.
PubMed: 38937070
DOI: 10.1136/ard-2024-225585 -
Medical Mycology Jun 2024Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In...
Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%-66.7%, 42.4%-46.9%, and 50.0%-71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000-2009 and 2010-2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.
Topics: Humans; Antifungal Agents; Fusarium; Scedosporium; Microbial Sensitivity Tests; World Health Organization; Mycoses; Fusariosis; Ascomycota; Invasive Fungal Infections
PubMed: 38935914
DOI: 10.1093/mmy/myad128 -
Medical Mycology Jun 2024In response to the growing global threat of fungal infections, in 2020 the World Health Organisation (WHO) established an Expert Group to identify priority fungi and...
In response to the growing global threat of fungal infections, in 2020 the World Health Organisation (WHO) established an Expert Group to identify priority fungi and develop the first WHO fungal priority pathogen list (FPPL). The aim of this systematic review was to evaluate the features and global impact of invasive infections caused by Pichia kudriavzevii (formerly known as Candida krusei). PubMed and Web of Science were used to identify studies published between 1 January 2011 and 18 February 2021 reporting on the criteria of mortality, morbidity (defined as hospitalisation and length of stay), drug resistance, preventability, yearly incidence, and distribution/emergence. Overall, 33 studies were evaluated. Mortality rates of up to 67% in adults were reported. Despite the intrinsic resistance of P. kudriavzevii to fluconazole with decreased susceptibility to amphotericin B, resistance (or non-wild-type rate) to other azoles and echinocandins was low, ranging between 0 and 5%. Risk factors for developing P. kudriavzevii infections included low birth weight, prior use of antibiotics/antifungals, and an underlying diagnosis of gastrointestinal disease or cancer. The incidence of infections caused by P. kudriavzevii is generally low (∼5% of all Candida-like blood isolates) and stable over the 10-year timeframe, although additional surveillance data are needed. Strategies targeting the identified risk factors for developing P. kudriavzevii infections should be developed and tested for effectiveness and feasibility of implementation. Studies presenting data on epidemiology and susceptibility of P. kudriavzevii were scarce, especially in low- and middle-income countries (LMICs). Thus, global surveillance systems are required to monitor the incidence, susceptibility, and morbidity of P. kudriavzevii invasive infections to inform diagnosis and treatment. Timely species-level identification and susceptibility testing should be conducted to reduce the high mortality and limit the spread of P. kudriavzevii in healthcare facilities.
Topics: Humans; Drug Resistance, Fungal; Antifungal Agents; World Health Organization; Pichia; Incidence; Risk Factors; Candidiasis
PubMed: 38935911
DOI: 10.1093/mmy/myad132