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Journal of Medical Genetics May 2024Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to...
BACKGROUND AND AIMS
Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.
METHODS
knockout ( ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.
RESULTS
The mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.
CONCLUSIONS
Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.
PubMed: 38816193
DOI: 10.1136/jmg-2023-109779 -
PloS One 2024The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood.
BACKGROUND
The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood.
METHODS
Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1).
RESULTS
There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE.
CONCLUSION
An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.
Topics: Humans; Friedreich Ataxia; Male; Female; Adult; Gadolinium; Heart Ventricles; Child; Adolescent; Magnetic Resonance Imaging; Middle Aged; Young Adult; Contrast Media; Stroke Volume; Fibrosis; Frataxin
PubMed: 38814901
DOI: 10.1371/journal.pone.0303969 -
Frontiers in Pharmacology 2024Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of...
BACKGROUND
Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of pain management studies. In this context, we aimed 1) to decipher the pharmacogenetic variant landscape among Mediterranean populations compared to worldwide populations in order to identify therapeutic biomarkers for personalized pain management and 2) to better understand the biological process of pain management through investigation of pharmacogenes pathways.
MATERIALS AND METHODS
We collected genes and variants implicated in pain response using the Prisma guidelines from literature and PharmGK database. Next, we extracted these genes from genotyping data of 829 individuals. Then, we determined the variant distribution among the studied populations using multivariate (MDS) and admixture analysis with R and STRUCTURE software. We conducted a Chi2 test to compare the interethnic frequencies of the identified variants. We used SNPinfo web server, miRdSNP database to identify miRNA-binding sites. In addition, we investigated the functions of the identified genes and variants using pathway enrichment analysis and annotation tools. Finally, we performed docking analysis to assess the impact of variations on drug interactions.
RESULTS
We identified 63 variants implicated in pain management. MDS analysis revealed that Mediterranean populations are genetically similar to Mexican populations and divergent from other populations. STRUCTURE analysis showed that Mediterranean populations are mainly composed of European ancestry. We highlighted differences in the minor allele frequencies of three variants (rs633, rs4680, and rs165728) located in the gene. Moreover, variant annotation revealed ten variants with potential miRNA-binding sites. Finally, protein structure and docking analysis revealed that two missense variants (rs4680 and rs6267) induced a decrease in COMT protein activity and affinity for dopamine.
CONCLUSION
Our findings revealed that Mediterranean populations diverge from other ethnic groups. Furthermore, we emphasize the importance of pain-related pathways and miRNAs to better implement these markers as predictors of analgesic responses in the Mediterranean region.
PubMed: 38813106
DOI: 10.3389/fphar.2024.1380613 -
Frontiers in Genetics 2024Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors...
Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry.
BACKGROUND
Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts.
METHODS
Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations.
RESULTS
Two genome-wide significant (P < 5 × 10) UACR-associated loci were identified, one in the on chromosome 6 in the meta-analysis of resident African individuals, and another in the region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including , and . PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained.
CONCLUSION
This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.
PubMed: 38812969
DOI: 10.3389/fgene.2024.1372042 -
Turkish Journal of Medical Sciences 2024Chemical biological radiological nuclear threats are at an important point in the agenda of world health today, as they can cause mass deaths. attracts attention as a...
BACKGROUND/AIM
Chemical biological radiological nuclear threats are at an important point in the agenda of world health today, as they can cause mass deaths. attracts attention as a potential biological warfare agent due to its features such as multidrug resistance, a rapid transmission mechanism via aerosol, the absence of a complete treatment protocol for the infection it causes, and the absence of an approved vaccine for protection against the bacteria. suspect samples must be studied by experienced personnel in biosafety level III laboratories. is a difficult and troublesome pathogen to diagnose and many unknowns about today. Therefore, the aim of the study was to determine the molecular differences and potential resistance genes of strains.
MATERIALS AND METHODS
Determination of the molecular differences and potential resistance genes of strains with new bioinformatics approaches by comparatively examining the data of 29 B mallei strains, 10 of which were isolated from Türkiye, on the genome list of the National Biotechnology Information Center (NCBI).
RESULTS
According to the genome annotations of the origins, the origin containing the highest number of CDS which is 5172 was found as the 11th strain obtained in Türkiye in 1949. The origin with the highest number of pseudogenes was determined as 23,344 (China 7) origin. Two hundred and eighty-five pseudogenes found in this strain were obtained from a knee effusion in Myanmar. According to chromosome 2 data, strain was determined as the most similar strain to ATCC 23344, line 11 with NCTC 10229 strain, and SAVP1 strain was determined as the least similar strain. When the antimicrobial resistance gene markers of the isolates included in the study were examined, , were found to be carrying.
CONCLUSION
In terms of public health, it was thought that the data obtained as a result of our study about , which is defined as a biological weapon, is very valuable for creating treatment protocols to be applied to possible epidemics in the future. In addition, the available genetic epidemiological data of these strains belonging to a category that is dangerous to work with in a laboratory environment were reviewed.
Topics: Burkholderia mallei; Humans; Drug Resistance, Bacterial; Turkey
PubMed: 38812620
DOI: 10.55730/1300-0144.5761 -
Scientific Reports May 2024Auricularia heimuer, the third most frequently cultivated edible mushroom species worldwide, has high medicinal value. However, a shortage of molecular marker hinders...
Auricularia heimuer, the third most frequently cultivated edible mushroom species worldwide, has high medicinal value. However, a shortage of molecular marker hinders the efficiency and accuracy of genetic breeding efforts for A. heimuer. High-throughput transcriptome sequencing data are essential for gene discovery and molecular markers development. This study aimed to clarify the distribution of SSR loci across the A. heimuer transcriptome and to develop highly informative EST-SSR markers. These tools can be used for phylogenetic analysis, functional gene mining, and molecular marker-assisted breeding of A. heimuer. This study used Illumina high-throughput sequencing technology to obtain A. heimuer transcriptome data. The results revealed 37,538 unigenes in the A. heimuer transcriptome. Of these unigenes, 24,777 (66.01%) were annotated via comparison with the COG, Pfam, and NR databases. Overall, 2510 SSRs were identified from the unigenes, including 6 types of SSRs. The most abundant type of repeats were trinucleotides (1425, 56.77%), followed by mononucleotides (391, 15.58%) and dinucleotides (456, 18.17%). Primer pairs for 102 SSR loci were randomly designed for validity confirmation and polymorphism identification; this process yielded 53 polymorphic EST-SSR markers. Finally, 13 pairs of highly polymorphic EST-SSR primers were used to analyze the genetic diversity and population structure of 52 wild A. heimuer germplasms, revealing that the 52 germplasms could be divided into three categories. These results indicated that SSR loci were abundant in types, numbers, and frequencies, providing a potential basis for germplasm resource identification, genetic diversity analysis, and molecular marker-assisted breeding of A. heimuer.
Topics: Microsatellite Repeats; Expressed Sequence Tags; Gene Expression Profiling; Transcriptome; Genetic Markers; Agaricales; High-Throughput Nucleotide Sequencing; Basidiomycota; Polymorphism, Genetic; Molecular Sequence Annotation; Phylogeny
PubMed: 38811679
DOI: 10.1038/s41598-024-63080-1 -
Scientific Reports May 2024Research efforts on genomic structure and ecology of wild populations of Vitis vinifera L. offer insights on grape domestication processes and on the assortment...
Research efforts on genomic structure and ecology of wild populations of Vitis vinifera L. offer insights on grape domestication processes and on the assortment evolution of the cultivated forms. Attention is also paid to the origin of traditional, long-cultivated varieties, often producing renowned and valuable wines. The genetic relationships between 283 Vitis vinifera cultivated varieties (subsp. sativa) and 65 individuals from 9 populations of the sylvestris subspecies mainly from northern Italy were explored by means of molecular markers (27 nuclear and 4 chloroplastic microsatellites). Several episodes of contamination of the wild germplasm by the pollen of specific grape cultivars were detected, implying concern for maintaining the purity of the wild form. At the same time, events of introgression from the wild subspecies resulted playing a crucial role in the emergence of several cultivated varieties with a clear admixed genome ancestry sativa-sylvestris. These included Lambruscos originated from the flat areas crossed by the Po and Adige rivers in northern Italy, while other cultivars still called Lambrusco but typical of hilly areas did not show the same admixed genome. Historical and ecological evidences suggesting an adaptative recent post-domestication process in the origin of several Italian Lambruscos are discussed.
Topics: Vitis; Italy; Microsatellite Repeats; Genetic Variation; Genome, Plant; Phylogeny; Domestication; Genetic Introgression
PubMed: 38811676
DOI: 10.1038/s41598-024-62774-w -
Scientific Reports May 2024The loss of biodiversity in marine populations is one of the consequences of the increased events of extreme environmental conditions in the oceans, which can condition...
The loss of biodiversity in marine populations is one of the consequences of the increased events of extreme environmental conditions in the oceans, which can condition the persistence of populations to future scenarios of climate change. Therefore, it is extremely necessary to explore and monitor the genetic diversity of natural populations. In the Southeast Pacific Ocean (SEPO), specifically on the coast of Chile, the presence of the copepod Acartia tonsa has been indicated solely using morphological evidence, due to the absence of genetic information. In the present work, the genetic diversity, population structure and phylogenetic position within the genus Acartia, of populations identified morphologically as A. tonsa, was evaluated by amplification of the mitochondrial cytochrome c oxidase subunit I and nuclear marker 18 s. Our results showed that the populations identified as A. tonsa correspond to a new monophyletic group endemic to SEPO (GMYC = 1.00; PTP = 0.95). The populations showed moderate to high genetic diversity with an incipient structuring between populations and biogeographic zones. Our results suggest that despite the homogenizing effect of the Humboldt Current, isolation by distance and contrasting environmental conditions at different geographic scales have an important influence on the genetic diversity of zooplankton in the SEPO region.
Topics: Animals; Copepoda; Pacific Ocean; Phylogeny; Genetic Variation; Electron Transport Complex IV; Chile; Biodiversity; Zooplankton
PubMed: 38811606
DOI: 10.1038/s41598-024-62080-5 -
Drug Metabolism and Disposition: the... May 2024Heart failure (HF) is a chronic disease affecting 1-2% of the global population. I-labeled -iodobenzylguanidine (mIBG) is FDA-approved for cardiac imaging and prognosis...
Heart failure (HF) is a chronic disease affecting 1-2% of the global population. I-labeled -iodobenzylguanidine (mIBG) is FDA-approved for cardiac imaging and prognosis risk assessment in patients with HF. As a norepinephrine analog, mIBG is believed to be transported into adrenergic nerve terminals by the neuronal norepinephrine transporter (NET) and hence image sympathetic innervation of the myocardium. We previously showed that mIBG is an excellent substrate of organic cation transporter 3 (OCT3), an extraneuronal transporter expressed in cardiomyocytes. Here we evaluated the in vivo impact of Oct3 on mIBG disposition and tissue distribution using Oct3 knockout mice. and mice were administered with mIBG intravenously, and mIBG plasma pharmacokinetics and tissue exposures were determined. In mice, mIBG exhibited extensive accumulation in multiple tissues (heart, salivary gland, liver, adrenal gland). No difference was observed in overall plasma exposure between mice. Strikingly, cardiac mIBG was depleted in mice, resulting in 83% reduction in overall cardiac exposure (AUC: 12.7 versus 2.1 µghr/g). mIBG tissue exposure (AUC) was also reduced by 66%, 36%, and 31% in skeletal muscle, salivary gland, and lung respectively in mice. Our data demonstrated that Oct3 is the primary transporter responsible for cardiac mIBG uptake in vivo; and suggested that cardiac mIBG imaging mainly measures OCT3 activity in cardiomyocytes but not NET-mediated uptake in adrenergic nerve endings. Our findings challenge the current paradigm in interpreting cardiac mIBG imaging results and suggest OCT3 as a potential genetic risk marker for HF prognosis. I-mIBG is used for cardiac imaging and risk assessment in heart failure patients. Contrary to the current belief that mIBG tracks cardiac sympathetic innervation due to its uptake by the neuronal norepinephrine transporter, we have demonstrated that cardiac mIBG uptake is mediated by the extraneuronal transporter Oct3. Our findings warrant a re-evaluation of the scientific rationale behind cardiac mIBG imaging and further suggest OCT3 as a risk factor for disease progression in heart failure patients.
PubMed: 38811159
DOI: 10.1124/dmd.124.001709 -
European Respiratory Review : An... Apr 2024COPD is a major cause of morbidity and mortality globally. While the significance of environmental exposures in disease pathogenesis is well established, the functional... (Review)
Review
COPD is a major cause of morbidity and mortality globally. While the significance of environmental exposures in disease pathogenesis is well established, the functional contribution of genetic factors has only in recent years drawn attention. Notably, many genes associated with COPD risk are also linked with lung function. Because reduced lung function precedes COPD onset, this association is consistent with the possibility that derangements leading to COPD could arise during lung development. In this review, we summarise the role of leading genes (, , , and ) identified by genome-wide association studies in lung development and COPD. Because many COPD genome-wide association study genes are enriched in lung epithelial cells, we focus on the role of these genes in the lung epithelium in development, homeostasis and injury.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Genome-Wide Association Study; Genetic Predisposition to Disease; Lung; Phenotype; Risk Factors; Animals; Genetic Markers; Prognosis
PubMed: 38811034
DOI: 10.1183/16000617.0019-2024