Physiological genomics最新文献

{"title":"Genetics and biology of coloration in reptiles: the curious case of the Lemon Frost geckos.","authors":"Longhua Guo,&nbsp;Leonid Kruglyak","doi":"10.1152/physiolgenomics.00015.2023","DOIUrl":"10.1152/physiolgenomics.00015.2023","url":null,"abstract":"<p><p>Although there are more than 10,000 reptile species, and reptiles have historically contributed to our understanding of biology, genetics research into class Reptilia has lagged compared with other animals. Here, we summarize recent progress in genetics of coloration in reptiles, with a focus on the leopard gecko, <i>Eublepharis macularius</i>. We highlight genetic approaches that have been used to examine variation in color and pattern formation in this species as well as to provide insights into mechanisms underlying skin cancer. We propose that their long breeding history in captivity makes leopard geckos one of the most promising emerging reptilian models for genetic studies. More broadly, technological advances in genetics, genomics, and gene editing may herald a golden era for studies of reptile biology.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10103198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mild and moderate chronic hypercapnia elicit distinct transcriptomic responses of immune function in cardiorespiratory nuclei.","authors":"Kirstyn J Grams, Suzanne E Neumueller, Gary C Mouradian, Nicholas J Burgraff, Matthew R Hodges, Lawrence Pan, Hubert V Forster","doi":"10.1152/physiolgenomics.00038.2023","DOIUrl":"10.1152/physiolgenomics.00038.2023","url":null,"abstract":"<p><p>Chronic hypercapnia (CH) is a hallmark of respiratory-related diseases, and the level of hypercapnia can acutely or progressively become more severe. Previously, we have shown time-dependent adaptations in steady-state physiology during mild (arterial Pco₂ ∼55 mmHg) and moderate (∼60 mmHg) CH in adult goats, including transient (mild CH) or sustained (moderate CH) suppression of acute chemosensitivity suggesting limitations in adaptive respiratory control mechanisms as the level of CH increases. Changes in specific markers of glutamate receptor plasticity, interleukin-1ß, and serotonergic modulation within key nodes of cardiorespiratory control do not fully account for the physiological adaptations to CH. Here, we used an unbiased approach (bulk tissue RNA sequencing) to test the hypothesis that mild or moderate CH elicits distinct gene expression profiles in important brain stem regions of cardiorespiratory control, which may explain the contrasting responses to CH. Gene expression profiles from the brain regions validated the accuracy of tissue biopsy methodology. Differential gene expression analyses revealed greater effects of CH on brain stem sites compared with the medial prefrontal cortex. Mild CH elicited an upregulation of predominantly immune-related genes and predicted activation of immune-related pathways and functions. In contrast, moderate CH broadly led to downregulation of genes and predicted inactivation of cellular pathways related to the immune response and vascular function. These data suggest that mild CH leads to a steady-state activation of neuroinflammatory pathways within the brain stem, whereas moderate CH drives the opposite response. Transcriptional shifts in immune-related functions may underlie the cardiorespiratory network's capability to respond to acute, more severe hypercapnia when in a state of progressively increased CH.<b>NEW & NOTEWORTHY</b> Mild chronic hypercapnia (CH) broadly upregulated immune-related genes and a predicted activation of biological pathways related to immune cell activity and the overall immune response. In contrast, moderate CH primarily downregulated genes related to major histocompatibility complex signaling and vasculature function that led to a predicted inactivation of pathways involving the immune response and vascular endothelial function. The severity-dependent effect on immune responses suggests that neuroinflammation has an important role in CH and may be important in the maintenance of proper ventilatory responses to acute and chronic hypercapnia.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10406807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of microRNA expression in rat kidneys after VEGF inhibitor treatment under different degrees of hypoxia.","authors":"Yaya Xu, Yueniu Zhu, Jiayue Xu, Haoyun Mao, Jiru Li, Xiaodong Zhu, Xiangmei Kong, Jianhua Zhang","doi":"10.1152/physiolgenomics.00023.2023","DOIUrl":"10.1152/physiolgenomics.00023.2023","url":null,"abstract":"<p><p>Previously, we found that the incidence of kidney injury in patients with chronic hypoxia was related to the partial pressure of arterial oxygen. However, at oxygen concentrations that contribute to kidney injury, the changes in the relationship between microRNAs (miRNAs) and the hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) axis and the key miRNAs involved in this process have not been elucidated. Therefore, we elucidated the relationship between VEGF and kidney injury at different oxygen concentrations and the mechanisms mediated by miRNAs. Sprague-Dawley rats were exposed to normobaric hypoxia and categorized into six groups based on the concentration of the oxygen inhaled and injection of the angiogenesis inhibitor bevacizumab, a humanized anti-VEGF monoclonal antibody. Renal tissue samples were processed to determine pathological and morphological changes and HIF-1α, VEGF, and miRNA expression. We performed a clustering analysis of high-risk pathways and key hub genes. The results were validated using two Gene Expression Omnibus datasets (GSE94717 and GSE30718). As inhaled oxygen concentration decreased, destructive changes in the kidney tissues became more severe. Although the kidney possesses a self-protective mechanism under an intermediate degree of hypoxia (10% O₂), bevacizumab injections disrupted this mechanism, and VEGF expression was associated with the ability of the kidney to repair itself. rno-miR-124-3p was identified as a crucial miRNA; a key gene target, <i>Mapk14</i>, was identified during this process. VEGF plays an important role in kidney protection from injury under different hypoxia levels. Specific miRNAs and their target genes may serve as biomarkers that provide new insights into kidney injury treatment.<b>NEW & NOTEWORTHY</b> Renal tolerance to hypoxic environments is limited, and the degree of hypoxia does not show a linear relationship with angiogenesis. VEGF plays an important role in the kidney's self-protective mechanism under different levels of hypoxia. miR-124-3p may be particularly important in kidney repair, and it may modulate VEGF expression through the miR-124-3p/Mapk14 signaling pathway. These microRNAs may serve as biomarkers that provide new insights into kidney injury treatment.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10111458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability.","authors":"Monalisa Hota, Jacob L Barber, Jonathan J Ruiz-Ramie, Charles S Schwartz, Do Thuy Uyen Ha Lam, Prashant Rao, Michael Y Mi, Daniel H Katz, Jeremy M Robbins, Clary B Clish, Robert E Gerszten, Mark A Sarzynski, Sujoy Ghosh, Claude Bouchard","doi":"10.1152/physiolgenomics.00163.2022","DOIUrl":"10.1152/physiolgenomics.00163.2022","url":null,"abstract":"<p><p>Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity.<b>NEW & NOTEWORTHY</b> Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10519406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiling of the bovine endosalpinx and endometrium to identify putative embryokines.","authors":"Quinn Hoorn,&nbsp;Maria Belen Rabaglino,&nbsp;Tatiane Silva Maia,&nbsp;Masroor Sagheer,&nbsp;Dailin Fuego,&nbsp;Zongliang Jiang,&nbsp;Peter James Hansen","doi":"10.1152/physiolgenomics.00064.2023","DOIUrl":"10.1152/physiolgenomics.00064.2023","url":null,"abstract":"<p><p>The objectives of the present study were to characterize the expression of genes encoding for cell signaling ligands in the bovine endosalpinx and endometrium and analyze spatial changes in gene expression. RNA sequencing was performed for the endosalpinx from the ampulla of the oviduct and endometrium from the upper and middle uterine horn and uterine body at <i>day 2</i> after ovulation from ipsilateral and contralateral sides relative to the ovulatory ovary. Of the 17,827 unique mRNA transcripts mapped, 2,072 were affected by cranial-caudal position in the reproductive tract and 818 were affected by side (false discovery rate < 0.05). There were 334 genes encoding for cell signaling ligands, with 128 genes having greater than two transcripts per million on average. A total of 81 cell signaling ligand genes were affected by position and 24 were affected by side. A data set of the transcriptome of two to four cell embryos was used to identify cell signaling ligand genes that were highly expressed in the ampulla for which there was high expression of the receptor in the embryo. The most expressed ligand-receptor pairs were <i>PSAP/SORT1</i>, <i>MIF/CXCR4</i>, <i>GPI/AMFR</i>, and <i>KITLG/KIT</i>. These cell signaling ligands, as well as others whose gene is expressed in the endosalpinx and endometrium, may influence early embryonic development. Spatial changes throughout the reproductive tract highlight the distinctive expression profile of the oviduct versus the endometrium, including a set of the identified genes encoding for cell signaling ligands, and highlight the local influence of the ovary. The results also show the continuity of expression for large numbers of genes in the reproductive tract.<b>NEW & NOTEWORTHY</b> Examination of the transcriptome of the endosalpinx and endometrium revealed the degree to which gene expression in the reproductive tract varies spatially. The expression of genes encoding cell signaling molecules that could potentially regulate embryonic development was also identified.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10280436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polycystin-2-dependent transcriptome reveals early response of autosomal dominant polycystic kidney disease.","authors":"Hyun Jun Jung, Eryn E Dixon, Richard Coleman, Terry Watnick, Jeremy F Reiter, Patricia Outeda, Valeriu Cebotaru, Owen M Woodward, Paul A Welling","doi":"10.1152/physiolgenomics.00040.2023","DOIUrl":"10.1152/physiolgenomics.00040.2023","url":null,"abstract":"<p><p>Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in polycystin genes, <i>Pkd1</i> and <i>Pkd2</i>, but the underlying pathogenic mechanisms are poorly understood. To identify genes and pathways that operate downstream of polycystin-2 (PC2), a comprehensive gene expression database was created, cataloging changes in the transcriptome immediately following PC2 protein depletion. To explore cyst initiation processes, an immortalized mouse inner medullary collecting duct line was developed with the ability to knock out the <i>Pkd2</i> gene conditionally. Genome-wide transcriptome profiling was performed using RNA sequencing in the cells immediately after PC2 was depleted and compared with isogenic control cells. Differentially expressed genes were identified, and a bioinformatic analysis pipeline was implemented. Altered expression of candidate cystogenic genes was validated in <i>Pkd2</i> knockout mice. The expression of nearly 900 genes changed upon PC2 depletion. Differentially expressed genes were enriched for genes encoding components of the primary cilia, the canonical Wnt pathway, and MAPK signaling. Among the PC2-dependent ciliary genes, the transcription factor Glis3 was significantly downregulated. MAPK signaling formed a key node at the epicenter of PC2-dependent signaling networks. Activation of Wnt and MAPK signaling, concomitant with the downregulation of Glis3, was corroborated in <i>Pkd2</i> knockout mice. The data identify a PC2 cilia-to-nucleus signaling axis and dysregulation of the Gli-similar subfamily of transcription factors as a potential initiator of cyst formation in ADPKD. The catalog of PC2-regulated genes should provide a valuable resource for future ADPKD research and new opportunities for drug development.<b>NEW & NOTEWORTHY</b> Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Mutations in polycystin genes cause the disease, but the underlying mechanisms of cystogenesis are unknown. To help fill this knowledge gap, we created an inducible cell model of ADPKD and assembled a catalog of genes that respond in immediate proximity to polycystin-2 depletion using transcriptomic profiling. The catalog unveils a ciliary signaling-to-nucleus axis proximal to polycystin-2 dysfunction, highlighting Glis, Wnt, and MAPK signaling.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10287070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in environmental stress over COVID-19 pandemic likely contributed to failure to replicate adiposity phenotype associated with <i>Krtcap3</i>.","authors":"Alexandria M Szalanczy, Gina Giorgio, Emily Goff, Osborne Seshie, Michael Grzybowski, Jason Klotz, Aron M Geurts, Eva E Redei, Leah C Solberg Woods","doi":"10.1152/physiolgenomics.00019.2023","DOIUrl":"10.1152/physiolgenomics.00019.2023","url":null,"abstract":"<p><p>We previously identified keratinocyte-associated protein 3, <i>Krtcap3</i>, as an obesity-related gene in female rats where a whole body <i>Krtcap3</i> knockout (KO) led to increased adiposity compared to wild-type (WT) controls when fed a high-fat diet (HFD). We sought to replicate this work to better understand the function of <i>Krtcap3</i> but were unable to reproduce the adiposity phenotype. In the current work, WT female rats ate more compared to WT in the prior study, with corresponding increases in body weight and fat mass, while there were no changes in these measures in KO females between the studies. The prior study was conducted before the COVID-19 pandemic, while the current study started after initial lockdown orders and was completed during the pandemic in a generally less stressful environment. We hypothesize that the environmental changes impacted stress levels and may explain the failure to replicate our results. Analysis of corticosterone (CORT) at euthanasia showed a significant study-by-genotype interaction where WT had significantly higher CORT relative to KO in <i>study 1</i>, with no differences in <i>study 2</i>. These data suggest that decreasing <i>Krtcap3</i> expression may alter the environmental stress response to influence adiposity. We also found that KO rats in both studies, but not WT, experienced a dramatic increase in CORT after their cage mate was removed, suggesting a separate connection to social behavioral stress. Future work is necessary to confirm and elucidate the finer mechanisms of these relationships, but these data indicate the possibility of <i>Krtcap3</i> as a novel stress gene.<b>NEW & NOTEWORTHY</b> Obesity is linked to both genetics and environmental factors such as stress. <i>Krtcap3</i> has previously been identified as a gene associated with adiposity, and our work here demonstrates that environmental stress may influence the role of <i>Krtcap3</i> on both food intake and adiposity. Obesity is strongly influenced by stress in humans, so the identification of novel genes that link stress and obesity will greatly advance our understanding of the disease.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41208983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of a prognostic model toward lung squamous cell carcinoma based on m⁷G-related genes in the cancer genome atlas.","authors":"Yongheng Wang, Yimin Liu, Rui Wang, Fuyuan Cao, Yi Guan, Yulu Chen, Binbin An, Sisi Qin, Sanqiao Yao","doi":"10.1152/physiolgenomics.00149.2022","DOIUrl":"10.1152/physiolgenomics.00149.2022","url":null,"abstract":"<p><p>Lung squamous cell carcinoma (LUSC) is a non-small cell lung cancer with a poor prognosis owing to late diagnosis. New molecular markers are urgently needed to improve the diagnosis and prognosis of LUSC. 7-Methylguanosine (m⁷G) modifications, a tRNA modification, are common in eubacteria, eukaryotes, and a few archaea. These modifications promote the turnover and stability of some mRNAs to prevent mRNA decay, improve translation efficiency, and reduce ribosomal pausing but are associated with poor survival in human cancer cells. However, expression of m⁷G-related genes in LUSC and their association with prognosis remain unclear. In the present study, we identified nine differentially expressed genes related to prognosis by comparing the expression profiles of tumor tissues (502 LUSC reports) with normal tissues (49 adjacent nontumor lung tissue reports). The genes included six upregulated genes (<i>KLK7</i>, <i>LCE3E</i>, <i>AREG</i>, <i>KLK6</i>, <i>ZBED2</i>, and <i>MAPK4</i>) and three downregulated genes (<i>ADH1C</i>, <i>NTS</i>, and <i>ERLIN2</i>). Based on these nine genes, patients with LUSC were classified into low- and high-risk groups to analyze the trends in prognosis. We found that the nine m⁷G-related genes play important roles in immune regulation, hormone regulation, and drug sensitivity through pathways including antigen processing and presentation, adherent plaques, extracellular matrix receptor interactions, drug metabolism of cytochrome <i>P</i>-450, and metabolism of cytochrome <i>P</i>-450 to xenobiotics; the functions of these genes are likely accomplished in part by m⁶A modifications. The effect of m⁷G-related genes on the diagnosis and prognosis of LUSC was further indicated by population analysis.<b>NEW & NOTEWORTHY</b> Based on the differential expression of 7-methylguanosine (m⁷G) modification-associated genes between normal and lung squamous cell carcinoma (LUSC) tissues, and considering the performance of our m⁷G-related gene risk profiles as independent risk factors in predicting overall survival, we conclude that m⁷G modification is closely linked to the development of LUSC. In addition, this study offers a new genetic marker for predicting the prognosis of patients with LUSC and presents a crucial theoretical foundation for future investigations on the relationship between m⁷G modification-related genes, immunity, and drug sensitivity in LUSC.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41208985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring shared genetics between maximal oxygen uptake and disease: the HUNT study.","authors":"Ada N Nordeidet,&nbsp;Marie Klevjer,&nbsp;Ulrik Wisløff,&nbsp;Mette Langaas,&nbsp;Anja Bye","doi":"10.1152/physiolgenomics.00026.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00026.2023","url":null,"abstract":"<p><p>Low cardiorespiratory fitness, measured as maximal oxygen uptake (V̇o_2max), is associated with all-cause mortality and disease-specific morbidity and mortality and is estimated to have a large genetic component (∼60%). However, the underlying mechanisms explaining the associations are not known, and no association study has assessed shared genetics between directly measured V̇o_2max and disease. We believe that identifying the mechanisms explaining how low V̇o_2max is related to increased disease risk can contribute to prevention and therapy. We used a phenome-wide association study approach to test for shared genetics. A total of 64,479 participants from the Trøndelag Health Study (HUNT) were included. Genetic variants previously linked to V̇o_2max were tested for association with diseases related to the cardiovascular system, diabetes, dementia, mental disorders, and cancer as well as clinical measurements and biomarkers from HUNT. In the total population, three single-nucleotide polymorphisms (SNPs) in and near the follicle-stimulating hormone receptor gene (<i>FSHR</i>) were found to be associated (false discovery rate < 0.05) with serum creatinine levels and one intronic SNP in the Rap-associating DIL domain gene (<i>RADIL</i>) with diabetes type 1 with neurological manifestations. In males, four intronic SNPs in the PBX/knotted homeobox 2 gene (<i>PKNOX2</i>) were found to be associated with endocarditis. None of the association tests in the female population reached overall statistical significance; the associations with the lowest <i>P</i> values included other cardiac conduction disorders, subdural hemorrhage, and myocarditis. The results might suggest shared genetics between V̇o_2max and disease. However, further effort should be put into investigating the potential shared genetics between inborn V̇o_2max and disease in larger cohorts to increase statistical power.<b>NEW & NOTEWORTHY</b> To our knowledge, this is the first genetic association study exploring how genes linked to cardiorespiratory fitness (CRF) relate to disease risk. By investigating shared genetics, we found indications that genetic variants linked to directly measured CRF also affect the level of blood creatinine, risk of diabetes, and endocarditis. Less certain findings showed that genetic variants of high CRF might cause lower body mass index, healthier HDL cholesterol, and lower resting heart rate.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41208986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Nf1</i> in heart development: a potential causative gene for congenital heart disease: a narrative review.","authors":"Dun Wang,&nbsp;Xue Wen,&nbsp;Li-Li Xu,&nbsp;Qing-Xing Chen,&nbsp;Tian-Xing Yan,&nbsp;Hai-Tao Xiao,&nbsp;Xue-Wen Xu","doi":"10.1152/physiolgenomics.00024.2023","DOIUrl":"https://doi.org/10.1152/physiolgenomics.00024.2023","url":null,"abstract":"<p><p>Congenital heart disease is the most frequent congenital disorder, affecting a significant number of live births. Gaining insights into its genetic etiology could lead to a deeper understanding of this condition. Although the <i>Nf1</i> gene has been identified as a potential causative gene, its role in congenital heart disease has not been thoroughly clarified. We searched and summarized evidence from cohort-based and experimental studies on the issue of <i>Nf1</i> and heart development in congenital heart diseases from various databases. Available evidence demonstrates a correlation between <i>Nf1</i> and congenital heart diseases, mainly pulmonary valvar stenosis. The mechanism underlying this correlation may involve dysregulation of epithelial-mesenchymal transition (EMT). The <i>Nf1</i> gene affects the EMT process via multiple pathways, including directly regulating the expression of EMT-related transcription factors and indirectly regulating the EMT process by regulating the MAPK pathway. This narrative review provides a comprehensive account of the <i>Nf1</i> involvement in heart development and congenital cardiovascular diseases in terms of epidemiology and potential mechanisms. RAS signaling may contribute to congenital heart disease independently or in cooperation with other signaling pathways. Efficient management of both NF1 and cardiovascular disease patients would benefit from further research into these issues.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41208982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}