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Obesity is a complex metabolic disease associated with several health complications, including insulin resistance, hypertension, and type 2 diabetes mellitus. Growing evidence indicates that fatty acid profiles and the activity of desaturating enzymes-stearoyl-CoA desaturase-1 (SCD1), delta-5 desaturase (D5D), and delta-6 desaturase (D6D)-are important factors in the pathophysiology of obesity. This review aims to summarise the current understanding of the alterations in lipid metabolism and desaturase activity in obesity, its complications, and potential therapeutic interventions. A literature review was performed using the PubMed, Scopus, and Web of Science databases. Systematic reviews, meta-analyses, clinical studies, cross-sectional studies, and animal studies that assessed fatty acid profiles and desaturase activity in the context of obesity were included. Obesity is associated with significant changes in the profiles of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs), as well as altered desaturase activity. Increased activity of SCD1 and D6D and decreased activity of D5D are observed even in childhood and correlate with metabolic risk markers. Genetic variation in genes encoding fatty acid desaturases, such as fatty acid desaturase 1 ( Fatty acid profile and desaturase activity are significantly altered in obesity and represent potential biomarkers and therapeutic targets for its treatment and the prevention of related complications. Their assessment may contribute to a more personalised approach to treating obesity and associated metabolic diseases. Show less

This study aimed to infer a causal gene network associated with bone metastasis in lung cancer and to validate its reliability through experimental gene expression analysis. Using DNA microarray data from the Gene Expression Omnibus, we analyzed samples from primary lung cancer and those with bone metastasis. Commonly expressed genes in both groups were identified, and a causal network was inferred using Bayesian network inference with Java Objects based on the Bayesian Dirichlet score. To evaluate the network, we predicted the expression changes of downstream genes following knockdown of a key upstream gene and compared these predictions with mRNA expression levels in fatty acid desaturase 1 (FADS1)-knockdown lung cancer cells. The genes FADS1, cardiotrophin-like cytokine factor 1 (CLCF1), chromosome 4 open reading frame 48, sushi, nidogen and EGF like domains 1, FK506-binding protein 15, and coenzyme Q10A (COQ10A) were identified as directly associated with lung cancer bone metastasis. Among them, FADS1 appeared to have a regulatory role, influencing downstream targets. Notably, CLCF1 and COQ10A showed significantly increased expression in FADS1-knockdown cells, consistent with the network's predictions. These findings suggest that Bayesian network analysis is a reliable machine learning approach for uncovering causal gene relationships in cancer metastasis. Furthermore, FADS1 may serve as a potential therapeutic target in lung cancer bone metastasis. The validity of this network was supported by in vitro experiments using a lung cancer cell line. Show less

Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to identify novel genetic loci associated with GD, explore their clinical implications and investigate their therapeutic potential. We conducted a genome-wide association study from the UK Biobank followed by a meta-analysis, integrating summary statistics from the FinnGen R11, with further replication from Biobank Japan. Using systematic bioinformatic approaches, we performed gene prioritisation, colocalisation analysis, transcriptome-wide association study, Mendelian randomisations, cross-trait genetic correlations, phenome-wide association study, clinical investigations and gene-environment interactions by leveraging data from the FinnGen, Genotype-Tissue Expression project and Liver Cell Atlas single-cell transcriptomics data set. Our study highlighted novel susceptibility loci near candidate genes (ie, This study provides new insights into the genetic basis of GD and highlights the role of hepatocytes in GD pathogenesis. These findings have implications for the personalised prevention strategies and new therapeutic interventions in individuals predisposed to GD. Show less

With the sharp increase in the incidence of papillary thyroid carcinoma (PTC), the disease-specific survival rate has not improved significantly. Cholesterol metabolism plays a crucial role in tumor proliferation, regulation of tumor immune escape, and tumor drug resistance. However, there are few studies on the role of cholesterol metabolism in the occurrence and development of thyroid cancer (THCA). This study aimed to investigate the predictive value of cholesterol metabolism-related genes (CMRGs) in THCA and the relationship between immune invasion and drug sensitivity. Cholesterol metabolism-related genes we identified from the molecular signatures database, and univariate Cox regression and least absolute shrinkage and selection operator(LASSO) were used to construct a predictive model of cholesterol metabolism-related genes based on the TCGA-THCA dataset. The TCGA dataset was randomly divided into a training group and a validation group to verify the model's predictive value and independent prognostic effect. We then constructed a nomogram and performed enrichment analysis, immune cell infiltration, and drug sensitivity analysis. Finally, TCGA-THCA and GSE33630 datasets were used to detect the expression of signature genes, which was further verified by the HPA database. Six CMRGs (FADS1, NPC2, HSD17B7, ACSL4, APOE, HMGCS2) we identified by univariate Cox and LASSO regression to construct a prognostic model for 155 genes related to cholesterol metabolism. Their prognostic value was confirmed in the validation set, and a highly accurate nomogram was constructed combined with clinical features. We found that the mortality rate of high-risk patients increased by 11.41 times, and the infiltration of immune cells in the high-risk group was significantly reduced. Moreover, through drug sensitivity analysis, we obtained sensitive drugs for different risk groups. The GSE33630 dataset verified the expression of six CMRGs, and the HPA database verified the protein expression of the NPC2 gene. Cholesterol metabolism-related features are a promising biomarker for predicting THCA prognosis and can potentially guide personalized immunization and targeted therapy. Show less

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention. Show less

Osteoarthritis (OA) is a multifactorial disease influenced by both genetic and environmental factors. Recent studies suggest that genetic variants involved in nutrient metabolism may interact with dietary factors to modulate OA risk. Understanding these gene-nutrient interactions could inform personalized prevention strategies for OA. We conducted a cross-sectional study involving 500 participants to explore associations between specific genetic variants and OA susceptibility, considering dietary intake. Genotyping focused on polymorphisms in the FADS1 gene (rs174537) related to omega-3 fatty acid metabolism, the VDR gene (rs2228570) involved in vitamin D metabolism, and the IL-6 gene (rs1800795), a marker of inflammation. Dietary intake of omega-3 fatty acids, vitamin D, and antioxidants was assessed using validated food frequency questionnaires. Gene-nutrient interactions were evaluated using multivariable logistic regression models, adjusting for potential confounders. Individuals carrying the G allele of FADS1 who reported low omega-3 fatty acid intake exhibited a significantly increased risk of OA [Odds Ratio (OR) = 1.45; 95% Confidence Interval (CI): 1.10-1.90; Show less

Dietary guidelines recommend replacing saturated fatty acid with unsaturated fats, particularly polyunsaturated fatty acids. Cohort studies do not suggest a clear benefit of higher intake of polyunsaturated fatty acids but, in contrast, higher circulating linoleic acid (LA) levels-reflective of dietary LA intake, are associated with a reduced risk of type 2 diabetes. However, genetic variants in the fatty acid desaturase 1 gene (FADS1) may influence individual responses to plant-based fats. We explored whether FADS1 variants influence the relationships of LA and α-linolenic acid (ALA) intakes and nut consumption with plasma phospholipid fatty acid profiles and type 2 diabetes risk in a large-scale cohort study and a randomized controlled trial. In the EPIC-InterAct case-cohort (7,498 type 2 diabetes cases, 10,087 subcohort participants), we investigated interactions of dietary and plasma phospholipid fatty acids and nut consumption with FADS1 rs174547 in relation to incident type 2 diabetes using weighted Cox regression. In PREDIMED (492 participants in the Mediterranean Diet + Nuts intervention group, 436 participants in the control group), we compared changes in plasma phospholipid FAs from baseline to year 1. In EPIC-InterAct and PREDIMED, nut consumption was positively associated with LA plasma levels and inversely with arachidonic acid, the latter becoming stronger with increasing number of the minor rs174547 C allele (p interaction EPIC-InterAct: 0.030, PREDIMED: 0.003). Although the inverse association of nut consumption with diabetes seemed stronger in participants with rs174547 CC-genotype (HR: 0.73, 95% CI: 0.54-1.00) compared with CT (0.94, 0.81-1.10) or TT (0.90, 0.78-1.05) in EPIC-InterAct, this interaction was not statistically significant. FADS1 variation modified the effect of nut consumption on circulating FAs. We did not observe clear evidence that it modified the association between nut consumption and type 2 diabetes risk. Show less

The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Mendelian randomization (MR) is a technique employed to explore causal connections between two phenotypes. In our research, bidirectional two-sample MR analyses were utilized to evaluate the causal connections between vitiligo and multiple autoimmune diseases (systemic lupus erythematosus, Graves' disease, inflammatory bowel disease, alopecia areata [AA], type 1 diabetes mellitus [T1MD], and rheumatoid arthritis [RA]). Furthermore, we utilized summary-based Mendelian randomization (SMR) analysis to search for common susceptibility loci between two diseases that reciprocally elevate each other's risk. Finally, colocalization analyses were used to validate the robustness of the selected genes. There was an indication of potential causation between RA and vitiligo (IVW OR = 1.19; 95% CI = 1.05-1.13; p = 0.008). Furthermore, evident causal connections exist between vitiligo and AA (IVW OR = 1.14; 95% CI = 1.04-1.26; p = 0.008), T1MD (IVW OR = 1.14; 95% CI = 1.06-1.23; p < 0.001), and RA (IVW OR = 1.08; 95% CI = 1.03-1.13; p < 0.001). In SMR analyses and colocalization analyses, we identified three shared genes associated with both vitiligo and RA, including: FCRL3, FADS1, and FADS2. Our findings demonstrated that vitiligo and RA mutually act as risk factors for each other. Additionally, vitiligo had significant causal relationships with AA and type 1 diabetes. Show less

Fatty acid desaturase 1 (FADS1) is significantly and specifically upregulated following diabetic corneal injury. However, its role in diabetic keratopathy remains unclear. This study aimed to investigate the impact of FADS1 on wound healing and functional recovery of the diabetic corneal epithelium and explore its potential mechanisms. Using high-glucose-induced corneal epithelial cells and a streptozotocin-induced type 1 diabetic mouse model, FADS1 expression was suppressed via FADS1 small interfering RNA (siRNA). Cell migration was assessed using scratch and transwell assays. Wound healing and functional recovery of the corneal epithelium were evaluated using sodium fluorescein staining, anterior segment optical coherence tomography, hematoxylin and eosin staining, and immunofluorescence staining. FADS1 knockdown promoted wound healing and functional recovery of the diabetic corneal epithelium both in vivo and in vitro. Suppression of FADS1 enhanced high-glucose-induced corneal epithelial cell migration, which was dependent on elevated levels of the upstream metabolite γ-linolenic acid. This effect was mediated through the activation of the mitogen-activated protein kinase signaling pathway and the accumulation of autophagosomes. After diabetic corneal epithelial injury, FADS1 expression is specifically upregulated. Knockdown of FADS1 promotes wound healing and functional recovery, suggesting a novel therapeutic strategy for diabetic keratopathy. Show less

Coagulation defects, including purpura and other haemorrhagic conditions, are a critical area of medical research because of their significant health effects worldwide. Understanding the metabolic basis of these conditions may improve therapeutic strategies. A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal relationships between the levels of 1,400 metabolites and coagulation defects. Colocalization analysis confirmed significant shared genetic influences. Pathway and protein‒protein interaction (PPI) analyses identified rate-limiting enzymes and drug targets. The impacts of lifestyle factors on metabolite levels were also explored through MR. MR analysis revealed four metabolites whose abundance was significantly associated with coagulation defects: docosapentaenoate n3 DPA 22:5n3 (DPA) (OR: 1.594, 95% CI: 1.263-2.011, P < 0.001), 1-palmitoyl-2-stearoyl-gpc (PSPC) (16:0/18:0) (OR: 1.294, 95% CI: 1.134-1.477, P < 0.001), 1-stearoyl-2-docosahexaenoyl-gpc (SDPC) (18:0/22:6) (OR: 1.232, 95% CI: 1.101-1.380, P < 0.001) and hydroxypalmitoyl sphingomyelin (HPSM) (d18:1/16:0 (OH)) (OR: 0.803, 95% CI: 0.719-0.896, P < 0.001). Colocalization analysis provided robust evidence for shared genetic loci. Pathway analysis highlighted the importance of lipid metabolism, identifying key enzymes such as FADS1, FADS2 and TCP1. PPI analysis revealed an interaction between TCP1 and plasminogen, indicating potential therapeutic synergy. Further analysis revealed that lifestyle factors, including dried fruit and oily fish intake, were linked to the abundance of metabolites associated with coagulation risk. This study identifies specific metabolites and metabolic pathways involved in coagulation defects, proposes novel therapeutic targets and highlights the roles of dietary and lifestyle interventions in the management of these conditions. These findings pave the way for personalized strategies to manage coagulation-related conditions. Show less

Endometriosis is caused by the migration of endometrial cells to locations outside the uterine lining. Despite the increasing prevalence of endometriosis, there has been limited research on genetic effects, and its molecular mechanisms remain unclear. This study aimed to investigate the mechanisms underlying the development of endometriosis and to identify new genetic targets for endometriosis by integrating data from gene chips, single-cell mapping, and genome-wide association study databases. Using the Gene Expression Omnibus database, we downloaded data on normal endometrium, eutopic endometrium, and ectopic lesion tissues to explore the differentially expressed genes (DEGs) between normal and eutopic endometrium, and between eutopic and ectopic endometrium. Assessment of the relationships between DEGs and endometriosis involved differential expression, expression quantitative trait loci (eQTL), and Mendelian randomization (MR) analyses. Two single-cell atlas datasets were then analyzed to explore the mechanisms underlying disease development and progression. Intersection of MR results with DEGs between normal and eutopic endometrium highlighted 28 candidate biomarker genes (17 upregulated and 11 downregulated). Similarly, we identified two additional candidate biomarker genes by intersecting the DEGs between eutopic and ectopic endometrium with MR results. Among these 30 candidates, further filtering using single-cell datasets revealed that the histamine N-methyltransferase (HNMT), coiled-coil domain containing 28 A (CCDC28A), fatty acid desaturase 1 (FADS1) and mahogunin ring finger 1 (MGRN1) genes were differentially expressed between the normal and eutopic groups, consistent with transcriptomic and MR results. Our findings suggested that eutopic endometrium exhibits epithelial-mesenchymal transition (EMT). Cell communication analysis focused on ciliated epithelial cells expressing CDH1 and KRT23 revealed that, in the eutopic endometrium, ciliated epithelial cells are strongly correlated and interact with natural killer cells, T cells, and B cells. We identified four novel biomarker genes and found evidence for EMT in the eutopic endometrium. The mechanism of endometriosis progression may be closely related to EMT and changes in the immune microenvironment triggered by damage to ciliated epithelial cells. Show less

Calcific aortic valve stenosis (CAVS) can lead to cardiac adverse outcomes; however, currently, no effective pharmacological interventions are available to prevent or delay disease progression. Emerging evidence has identified significant associations between CAVS and key biomarkers, including Lp(a) (lipoprotein [a]), low-density lipoprotein cholesterol, and PCSK9 (proprotein convertase subtilisin/kexin type 9). However, robust evidence from randomized controlled trials is still lacking to substantiate these associations. The EPISODE (Effect of PCSK9 Inhibitors on Calcific Aortic Valve Stenosis) trial is a prospective, evaluator-blinded, randomized controlled trial designed to assess the therapeutic efficacy of PCSK9 inhibitors in patients with CAVS. A total of 160 patients with mild-to-moderate or asymptomatic severe CAVS will be randomly assigned to receive either statin monotherapy or a combination of statins and PCSK9 inhibitors. Participants will undergo follow-up assessments at 3-month intervals for 24 months, including transthoracic ultrasonic cardiogram, computed tomography, and quality-of-life evaluations using the EuroQol-5 Dimension-3 Level questionnaire. The primary end point is the annualized change in peak aortic jet velocity, whereas secondary end points encompass changes in aortic valve area, calcification score, incidence of heart valve surgery, and quality of life. Safety end points include all-cause mortality and cardiovascular events. The trial aims to evaluate the efficacy of PCSK9 inhibitors in modulating disease progression, reducing adverse cardiovascular events, and improving clinical outcomes in patients with CAVS. The anticipated findings are expected to provide critical insights for developing novel therapeutic strategies for early intervention in CAVS. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04968509. Show less

Unhealthy dietary habits have been recognized as key contributors to the increasing incidence of non-communicable diseases. Among the healthy nutrients studied, omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have received considerable attention for their benefits in cardiovascular health and inflammation management. Their synthesis is regulated by enzymes encoded by FADS1 and ELOVL2 genes. Single nucleotide polymorphisms (SNPs) within these genes can modify the efficiency of fatty acid conversion, thereby influencing the Omega-3 Index, which reflects omega-3 status, particularly EPA and DHA. This study aimed to assess the impact of FADS1 (rs174537) and ELOVL2 (rs953413) polymorphisms on the effects on fatty acids profiles of fish oil supplementation in healthy individuals. Eighty-six healthy adults aged 20-70 participated in a quasi-experimental intervention involving a 4-week fish oil supplementation rich in EPA and DHA. Dried-blood spots (DBS) were collected before and after the intervention to evaluate lipid profiles. Genotyping for FADS1 and ELOVL2 SNPs was performed using high-resolution melting analysis. Post-supplementation, the percentage of EPA and DHA increased significantly (p < 0.001), leading to an improved Omega-3 Index. Baseline omega-3 percentages did not differ significantly between FADS1 and ELOVL2 genotypes. However, individuals with the ELOVL2 minor allele (GA + AA) genotype benefited more from the fish oil supplementation with increased EPA and DBS Omega-3 Index, indicating a more favorable metabolic response. Genetic variability may influence the metabolic response to fish oil supplementation. These findings underscore the importance of personalized nutrition strategies to optimize health outcomes and prevent non-communicable diseases. Show less

Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and macrophage dysfunction. However, the role of An adenovirus encoding These findings demonstrate that The online version contains supplementary material available at 10.1186/s12944-025-02805-1. Show less

This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to their underlying genetic regulatory mechanisms, to elucidate the role of UFAs in acne pathogenesis. Clinical evidence synthesis: we systematically reviewed randomized controlled trials (RCTs) to evaluate the impact of UFA supplementation on acne treatment outcomes. Genetic analysis: two-sample Mendelian randomization (MR) analysis we used to investigate causal relationships between serum UFA metabolites and acne, identifying potential key regulatory enzymes. The synthesis of these RCT studies confirmed that UFA supplementation improved acne conditions. MR analysis revealed causal links between three serum UFA metabolites and acne, with dihomo-gamma-linolenic acid (DGLA) (OR = 8.457; 95% CI: 2.367-30.214; P-value = 0.001) as a risk factor and arachidonic acid (AA) (OR = 0.209; 95% CI: 0.071-0.618; P-value = 0.005) and eicosapentaenoic acid (EPA) (OR = 0.318; 95% CI: 0.102-0.991; P-value = 0.048) as protective factors. Functional annotation suggested enzymes such as Δ5 desaturase (FADS1) and Δ6 desaturase (FADS2) may play a role in acne regulation. This study offers evidence that supports a connection between UFAs and acne, examining this relationship from both clinical and genetic angles. These findings highlight the role of specific UFAs and their associated metabolic enzymes in the development of acne. Omega-3 UFAs seem to have a protective effect against acne, whereas certain types and ratios of omega-6 UFAs might contribute to acne formation. The varied impacts of UFAs on acne could be attributed to disease processes mediated by specific enzymes. However, the study's limitations include its genetic analysis being primarily based on European populations, which limits the applicability of the findings to other groups. Future research should aim to include a more diverse range of participants to improve the generalizability of the results. Show less

Endothelial lipase (LIPG), a member of the triglyceride lipase family, plays an essential role in human diseases and lipid metabolism. However, its function in goat intramuscular fat (IMF) deposition remains unclear. In this study, we investigated the role of the LIPG gene in IMF deposition by knocking down and overexpressing it in goat intramuscular preadipocytes. We successfully cloned the full-length LIPG gene, which spans 2,131 bp, including a 94 bp 5' untranslated region (5'UTR), a 1,503 bp coding sequence (CDS), and a 534 bp 3' untranslated region (3'UTR). Tissue expression profiles showed that LIPG is expressed in the heart, liver, spleen, Kidney, longest dorsal muscle, and small intestine tissues of goats. LIPG knockdown significantly inhibited both the proliferation of intramuscular preadipocytes and lipid deposition. Moreover, LIPG knockdown markedly decreased mRNA expression of FASN, LPL, CPT1A, CPT1B, FABP3, while increasing the mRNA expression of ATGL, ACOX1, FADS1, and ELOVL6. These findings were further corroborated through LIPG overexpression experiments. Using RNA sequencing (RNA-seq), we identified 1695 differentially expressed genes (DEGs) between the negative control (NC) and LIPG knockdown (Si-LIPG) groups, with KEGG pathway analysis revealing significant enrichment in the PPAR signaling pathway. Additionally, LIPG knockdown significantly upregulated the expression of both mRNA and protein levels of PPARα. The PPARα agonist WY14643 was able to reverse the enhanced lipid deposition induced by LIPG overexpression. In conclusion, our study highlights a key role for LIPG in the regulation of goat intramuscular preadipocyte proliferation and lipid deposition, potentially through the PPARα signaling pathway. These findings provide new insights into the regulatory mechanisms governing IMF deposition and suggest potential strategies for improving goat meat quality. Show less

Lung cancer is the second most common malignancy globally and the leading cause of cancer-related deaths. Interleukin-39 (IL-39), a member of the IL-12 family secreted by B cells, acts as a pro-inflammatory cytokine and induces IL-23p19 expression in endothelial cells. Recent findings suggest reduced IL-39 expression in autoimmune thyroid disorders and breast cancer, indicating its possible role in disease progression. To evaluate the role of IL-39 as an early prognostic biomarker in lung cancer. A case-control study was conducted between February and September 2024, involving 180 individuals aged 45-77. The cohort included 90 lung cancer patients (45 with small-cell carcinoma and 45 with non-small cell carcinoma) and 90 healthy controls. Blood samples were analyzed using ELISA to quantify IL-39 and additional tests, including CBC, liver enzymes (ALT, AST, ALP), and lipid profile (cholesterol, triglycerides). Statistical analysis was performed to assess correlations and diagnostic performance. IL-39 levels were significantly lower in stage IV compared to stage III in both cancer types, with a greater reduction observed in small-cell carcinoma. Significant negative correlations were found between IL-39 and total cholesterol, NLR, ALT, AST, and ALP, while positive correlations were noted with hemoglobin and triglycerides. IL-39 demonstrated excellent diagnostic accuracy in small-cell carcinoma with a cut-off value of 3.26950 pg/mL (sensitivity 100%, specificity 100%, AUC 1.000). In non-small cell carcinoma, the cut-off value was 4.88700 pg/mL (sensitivity 63.5%, specificity 92.6%, AUC 0.689). IL-39 shows promise as a predictive and diagnostic biomarker in lung cancer, particularly in small-cell carcinoma, and may play a protective role in disease modulation through immune-related pathways. Show less

Polyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows. In vivo conversion of omega-3 and omega-6 PUFAs from short- to long-chain counterparts occurs via a shared metabolic pathway involving fatty acid desaturases and elongase. This analysis leveraged genome-wide association study (GWAS) summary statistics for RBC and plasma PUFAs, along with expression quantitative trait loci (eQTL) to estimate tissue-specific genetically predicted gene expression effects for delta-5 desaturase (FADS1), delta-6 desaturase (FADS2), and elongase (ELOVL2) on changes in RBC and plasma biomarkers. Using colocalization, we identified shared variants associated with both increased gene expression and changes in RBC PUFA levels in relevant PUFA metabolism tissues (i.e., adipose, liver, muscle, and whole blood). We observed differences in RBC versus plasma PUFA levels for genetically predicted increase in FADS1 and FADS2 gene expression, primarily for omega-6 PUFAs linoleic acid (LA) and arachidonic acid (AA). The colocalization analysis identified rs102275 to be significantly associated with a 0.69% increase in total RBC membrane-bound LA levels (p = 5.4 × 10 Show less

Agrin, encoded by AGRN , plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS. We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants. Perinatal phenotyping revealed FADS in the family, and genomic testing identified novel null variants in AGRN . First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1₉₅₂₊₃del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN. This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN . Show less

Activation of cell cycle regulatory pathways has been detected during pathological cardiomyocyte growth. However, it has remained unclear whether DNA synthesis pathways play a direct role in cardiomyocyte hypertrophy. We previously discovered in a mouse model of hypertrophic cardiomyopathy that there was increased DNA synthesis, which led to cardiomyocyte endoreplication and replication stress-induced DNA damage. We hypothesized that targeting cardiomyocyte endoreplication pathways could reduce pathological myocardial hypertrophy. We utilized murine models of hypertrophic cardiomyopathy secondary to mutations in cardiac Mybpc3 (myosin-binding protein C3) We discovered that p21 protein peaked during the early stages of hypertrophic growth in both murine hypertrophic cardiomyopathy models and a pressure overload hypertrophy model. Using genetic manipulation of p21 expression, we discovered that cardiomyocyte endoreplication and hypertrophic growth were negatively correlated with p21 expression. Mechanistically, we discovered that p21 bound to PCNA (proliferating cell nuclear antigen), which led to a reduction of PCNA binding to POLD1 (DNA polymerase delta 1). Directly targeting PCNA or POLD1 prevented cardiomyocyte DNA synthesis and hypertrophic cardiomyocyte growth. Cardiomyocyte-selective overexpression of p21 using an adeno-associated virus vector reduced long-term pathological left ventricular hypertrophy and improved diastolic function in a preclinical murine model of hypertrophic cardiomyopathy (Myh6 Our results demonstrate that PCNA-POLD1-mediated cardiomyocyte endoreplication drives hypertrophic cardiomyocyte growth, and p21 serves as a negative regulator of this process. Targeting these pathways demonstrates therapeutic potential in preventing pathological myocardial hypertrophy. Show less

We assessed the coverage of molecular drug susceptibility testing (mDST) among patients with pulmonary multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in South Korea and identified factors influencing the lack of mDST implementation. This retrospective study included patients with pulmonary MDR/RR-TB who initiated tuberculosis (TB) treatment between January 2015 and September 2021. Data were obtained from the K-TB-N cohort, an integrated national TB database linking three datasets. We assessed mDST coverage, temporal trends and factors associated with the lack of mDST implementation. mDST was defined as the use of the Xpert MTB/RIF assay or line probe assay (LPA) for isoniazid and rifampicin (first-line LPA). In total, 4637 patients were included in the analysis. Of the 4637 patients, 1342 (28.9%) did not undergo mDST; whereas, 3295 (71.1%) underwent mDST. Over the study period, a statistically significant annual increase in mDST coverage was observed, escalating from 49.1% in 2015 to 96.9% in 2021 (p<0.001). Throughout the study, the coverage of the Xpert MTB/RIF assay remained lower than that of LPA (22.1% vs 64.2%, p<0.001). Multivariable logistic regression analysis identified several factors independently associated with a decreased likelihood of mDST being conducted, including TB treatment initiation in secondary general hospitals, small hospitals or primary clinics, as well as in non-public-private mix (PPM) participating institutions. In addition, transfers between PPM-participating and non-participating institutions during the treatment period and sputum acid-fast bacilli smear-negative status were significantly associated with lower mDST uptake. Although the increasing mDST coverage is a positive development, further efforts are needed to achieve nationwide and universal implementation, particularly for the Xpert MTB/RIF assay, in South Korea. Show less

Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. Here, we addressed this gap by analysing the influence of HLA variation on longevity in Europeans. We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Associations were evaluated with logistic regression, adjusting for multiple testing and population structure. Subsequently, significant associations (adjusted P ≤ 0.05) were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank. Furthermore, epitope binding and immunogenicity predictions were performed to detect potential mechanisms linking HLA alleles to longevity. Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity (adjusted P = 2.80 × 10 The novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele. This hypothesis is based on prior research that has identified a male-specific association between HLA-DRB1*15:01:01 and AD. Additionally, it is likely that this link is mediated by increased immune reactivity against APOB-100, which is promoted by HLA-DRB1*15:01:01. Show less

Demyelination diseases are characterized by injury to large (A-type) myelinated nerve fibers, and by secondary damage to small (C-type) sensory fibers, which leads to chronic pain symptoms, such as allodynia. The mechanisms underlying the interactions between the two fiber types are not clear. This study aims to investigate the role of lysophosphatidic acid (LPA) signaling in satellite glial cells (SGCs) within the dorsal root ganglia (DRG) in demyelination-induced chronic pain. A demyelination model was established by injecting cobra venom into the tibial nerve of 8-10-week-old Sprague-Dawley rats to selectively damage A-fiber myelin. Myelin morphology was observed via transmission electron microscopy (TEM) at 1, 3, 7, and 14 days post-injection. Pain behaviors (mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain) were assessed to evaluate progression. In vivo electrophysiology was performed to analyze sensory conduction and excitability changes in A- and C-type neurons. Immunofluorescence staining assessed SGC activation, LPA1 receptor (LPA1R) expression, and connexin 43 (Cx43) dynamics in the L4 DRG over time. Pharmacological interventions targeting LPA1R and SGC activation were applied to evaluate their effects on pain behaviors, cytokine release, and neuronal excitability using RT-PCR, ELISA, and spinal electrophysiology. Cobra venom induced a selective A-fiber demyelination and persistent pain in rats. It also upregulated the expression of LPA1R on SGCs that surround large DRG neurons, which normally mediate non-noxious input, and increased gap junction-mediated coupling via Cx43, leading to the activation of SGCs surrounding small nociceptive neurons. The activated SGCs released inflammatory mediators that increased nociceptive neuron excitability, driving chronic pain. In support of these results, pharmacological inhibition of LPA1R-mediated SGCs activation reversed this process. Our study demonstrates that LPA-LPA1R signaling in SGCs drives A-fiber demyelination-induced neuropathic pain by promoting Cx43-mediated SGC-neuron crosstalk and cytokine release. Targeting this pathway may represent a promising strategy to alleviate demyelination-associated chronic pain. Show less

To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships between TCM constitutions, uric acid levels, and various cardiovascular risk factors. A cross-sectional study involving 683 patients diagnosed with HUA was conducted. Patients' TCM constitutions were classified using the standardise "Classification and Determination of TCM Constitution" questionnaire. Serum uric acid (UA), lipid profiles, ApoB, and homocysteine (Hcy) levels were measured. Among 683 HUA patients, phlegm-dampness (22.99% ) and damp-heat constitution (20.06% ) were the most common TCM constitution types. UA, ApoB, and Hcy levels in patients with phlegm-damp constitution were significantly higher than those in other constitutions (P< 0.05). UA levels were negatively correlated with HDL-C (r=-0.472, P= 0.027) and positively correlated with ApoB (r= 0.618, P= 0.012) and Hcy (r= 0.492, P= 0.018). Phlegm-damp and damp-heat constitutions are the most common TCM constitution types in HUA patients and are associated with higher levels of UA, ApoB, and Hcy. These constitutional types are independently associated with increased cardiovascular risk. Show less

Exposure to persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD) increases metabolic disorder risk. In this study, we show that a single intraperitoneal injection of TCDD (10 μg/kg) in C57BL/6J mice induced body weight gain, lipid accumulation in the liver and adipose tissue, macrophage infiltration, and elevated hepatic and serum triglyceride levels after 12 weeks. Despite serum aryl hydrocarbon receptor (AhR) ligand levels normalizing by 12 weeks, the persistent effects suggest TCDD sequestration in fat tissue. TCDD inhibited the expression of mitochondrial proteins (COX1, TOM20, TFAM, H2AX) and reduced mitochondrial oxygen consumption. Liver-specific AhR knockout ameliorated TCDD-induced mitochondrial dysfunction, lipid accumulation, and macrophage infiltration. Mechanistically, TCDD-induced hepatic plasminogen activator inhibitor-1 (PAI-1) promoted adipocyte hypertrophy. In the liver, PAI-1 disrupted the interaction between tissue-type plasminogen activator (tPA) and apolipoprotein B (ApoB), thereby enhancing very-low-density lipoprotein (VLDL) assembly. These findings reveal that hepatocyte-derived circulating PAI-1, upregulated via hepatic AhR activation, contributes to adipocyte hypertrophy and hepatosteatosis through the intracellular modulation of the tPA-PAI-1 axis. Thus, hepatic AhR activation drives mitochondrial dysfunction and obesity, even after a single TCDD exposure. Show less

Hypertrophic cardiomyopathy (HCM), associated with left ventricular hypertrophy, can lead to significant morbidity. Given the hereditary association, identifying population-specific genetic markers and gender disparities could enable better screening and management strategies. The study aimed to observe the genetic patterns of HCM and investigate its gender associations among the Indian population. A prospective analysis was performed based on the medical records of patients with HCM. Genetic testing was conducted among those with a family history of HCM or sudden cardiac death. Genetic testing results, echocardiography, and clinical outcomes were documented. The prevalence of HCM types and genetic abnormalities were estimated in the study population and were compared between the two genders. The study included 103 patients with a mean age of 56.3 ± 13.9 years. Genetic analysis was conducted in 48/103 individuals based on the hereditary linkage. Only 50% of the 48 individuals had known genes associated with HCM. About 48% had apical or midapical HCM, and 31.1% had reverse curvature HCM. About 38% of apical and 60% of neutral or reverse curvature were associated with genetic abnormalities. The more commonly associated genes were MYBPC3 and MYH7. The current study also identified genetic variants in several emerging genes in Indian HCM patients. Our study findings indicate that the prevalence of different types of HCM is different in the Indian population. With only 50% of the hereditary HCM linked to known genes, the study calls for further screening of genes associated with HCM in the Indian population. Show less