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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

Omega-3 polyunsaturated fatty acids (PUFAs) are potential targets for the treatment of skin diseases due to their anti-inflammatory and immunomodulatory effects. By leveraging a genetic approach known as Mendelian randomization (MR), we sought to determine the causal impact of PUFAs on the likelihood of developing skin diseases among individuals of European ancestry. We integrated GWAS data from the CHARGE consortium and UK Biobank to identify genetic instruments for omega-3 PUFAs and desaturase activity, using two-sample MR to assess their associations with six skin diseases. Elevated levels of omega-3 fatty acids were found to substantially lower the probability of experiencing atopic dermatitis (0.92, [0.85,0.98]), while increased DPA levels correlated with a substantial increase in the probability of squamous cell carcinoma occurrence (2.25, [1.29,3.92]). Increased DHA levels were also associated with a reduced risk of atopic dermatitis (0.90, [0.84,0.96]) but increased the risk of solar dermatitis (1.38, [1.09,1.73]). In addition, tissue-type specific MR analysis revealed that elevated FADS1 expression in fibroblasts significantly inhibited atopic dermatitis development (β = -0.181, [-0.276,-0.0853]), while elevated FADS2 expression in non-sun-exposed skin tissues was associated with a reduced risk of squamous cell carcinoma (β = -0.562, [-0.833,-0.029]). Conversely, heightened FADS2 expression was strongly linked to a greater likelihood of developing atopic dermatitis in both sun-exposed and sun-protected skin areas (β = 0.107, [0.0348,0.179]; β = 0.192, [0.114,0.0270], respectively). This study reveals the causal role of omega-3 PUFAs and FADS expression in specific tissues and blood in skin diseases. These findings underscore the potential of PUFA biosynthesis pathways as therapeutic targets for skin disease interventions. 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

Fatty acyl desaturases (Fads) are known to play critical roles in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) in fish species. To date, research on Fads in fish has predominantly focused on Fads2, while studies on Fads1 have been rarely reported. Acipenseriformes, commonly known as Chondrostei, are an ancient fish lineage with unique evolutionary history. However, the biological roles and evolutionary status of Fads1 in Chondrostei remain unclear, which constrains our understanding of the evolutionary processes shaping LC-PUFA biosynthesis in this lineage. In this study, we identified and characterized a fads1 gene from Chinese sturgeon (Acipenser sinensis), a critically endangered Chondrostei, using molecular cloning and multiple bioinformatic analyses. The spatio-temporal expression patterns, functional characteristics, and transcriptional regulation in response to dietary fatty acids were investigated. The coding sequence of the fads1 gene was 1317 bp in length, encoding a protein of 438 amino acids. Bioinformatic analyses suggested high conservation of fads genes across Chondrostei despite their complex evolutionary history. Functional characterization in yeast showed that Chinese sturgeon Fads1 exhibited Δ5 desaturation activity, efficiently converting 20:3n-6 to arachidonic acid (ARA) and 20:4n-3 to eicosapentaenoic acid (EPA). Fatty acid composition analysis indicated that Chinese sturgeon could biosynthesize LC-PUFAs when they are deficient in their diets. Taken together, these results suggest that fads1 plays a crucial role in LC-PUFA biosynthesis in Chinese sturgeon, which provides solid theoretical basis for dietary LC-PUFA requirement of Chinese sturgeon. Furthermore, our findings provide novel insights into evolutionary diversification of fads genes in fish species. Show less

Kidney renal clear cell carcinoma (KIRC), the predominant subtype of renal cell carcinoma, poses significant health risks. The rapid progression and resistance to targeted therapies highlight the need for new tumor markers and therapeutic targets. FADS1, part of the fatty acid desaturase family, regulates fatty acid synthesis and participates in lipid metabolism. However, its role in KIRC is not well-studied. The study utilized bioinformatics analysis through the TCGA database and other platforms to identify FADS1 expression levels in KIRC. Twenty pairs of KIRC clinical tissue samples were used for qPCR verification. Meanwhile, eight pairs of KIRC clinical tissue samples were used for Western blot verification. Conduct statistical evaluation, including Wilcoxon rank sum test and Kaplan-Meier analysis, to explore the correlation between FADS1 expression and clinical pathological features and immune infiltration. In addition, in vitro experiments were conducted to confirm the biological function of FADS1. The findings indicated that FADS1 is highly expressed in KIRC and contributes to tumor development. FADS1's role in lipid metabolism leads to lipid accumulation within tumor cells, which may influence the occurrence and progression of KIRC. TIMER analysis revealed a correlation between FADS1 expression and the infiltration levels of various immune cells, indicating its potential role in modulating immune characteristics. FADS1 could serve as a prognostic biomarker associated with immunity in KIRC, highlighting its potential as a diagnostic and therapeutic target. The study underscores the importance of further research into FADS1's role in lipid metabolism and immune infiltration to develop effective therapeutic strategies. Show less

The potential causal effects of perinatal exposure to polyunsaturated fatty acids (PUFAs) on child neurodevelopment remains controversial. To infer causation, we assessed the association of perinatal PUFA patterns and child neurodevelopment by using conventional regression analyses and 1-sample Mendelian randomization (MR). Among 1096 mother-child pairs from the French Etude des Déterminants Pré- et Postnatals du Développement de la Santé de L'enfant cohort, patterns of perinatal exposure to PUFAs were previously identified combining PUFA levels from maternal and cord erythrocytes, and colostrum. Child verbal, performance, and full-scale intelligence quotients (IQs) were assessed at ages 5-6 y. Among maternal fatty acid desaturase (FADS) variants genotyped, 2 candidates, rs174546 (FADS1) and rs174634 (FADS3), were selected, as instrumental variables, for the MR analysis. The association of PUFA patterns with child IQ was examined by conventional multivariable linear regression and 2-stage least-squares MR regression. In the conventional approach, the first pattern "high omega-3 long-chain PUFAs (LC-PUFAs), low omega-6 LC-PUFAs" was positively associated with verbal IQ [β (95% confidence interval) = 1.24 (0.27, 2.21) points per 1 standard deviation (SD) increase in pattern] and full-scale IQ [1.11 (0.18, 2.05)]. This pattern was independent of FADS variants, rendering MR analysis inapplicable. The third pattern, "colostrum LC-PUFAs," was positively associated with verbal [1.11 (0.19, 2.02)], performance [1.01 (0.09, 1.93)], and full-scale IQ [1.13 (0.25, 2.01)]. The MR approach, based on genetic instruments strongly associated with the third pattern, supported the beneficial effect on performance IQ [2.93 (0.05, 5.81) points per 1 SD increase in genetically predicted pattern]. The MR also suggested a deleterious effect of the fourth pattern "linoleic acid (LA) and dihomo-gamma-linolenic acid (DGLA)" on performance IQ [-1.66 (-3.22, -0.09)]. These findings supported the potential beneficial effects of perinatal exposure to LC-PUFAs on child neurodevelopment while highlighting possible adverse effects associated with exposure to LA and DGLA. Show less

The present research evaluated the effect of water-soluble cannabidiol (CBD) emulsion on egg yolk fatty acid profile, liver health, and gene expression in laying hens. 180 Lohmann Brown Classic hens were divided into experimental groups, including a control group, a blank group (emulsifier only), and three groups receiving CBD. Cannabidiol was administered in drinking water for 15 weeks at doses of 20, 40, and 80 mg/kg body weight in group I, group II, and group III, respectively. The analysis indicated that the highest-dose CBD significantly increased yolk polyunsaturated fatty acids (PUFAs), particularly omega-3 and omega-6, as well as the serum HDL level. However, this was accompanied by downregulation of PPAR-γ expression. The histopathology of the liver did not show any differences among the groups, and tissue morphology remained normal without structural alterations. The expression of fatty acid desaturation genes, such as FADS1 and FADS2, remained stable, indicating preserved desaturation function and PUFAs biosynthesis. These results suggest that while the highest dose of CBD enhances lipid mobilization and yolk deposition, it simultaneously may affect PPAR-γ-mediated lipid pathways (e.g., adipogenic programming or lipid storage/transport) despite intact desaturation pathways. While hemp-derived products such as seeds and meals have been tested in poultry diets, the specific role of purified cannabidiol (CBD) in regulating lipid metabolism and liver health in laying hens has not been previously addressed. This is the first study to investigate the molecular impact of purified CBD on lipid metabolism and liver function in laying hens, explaining its potential as a functional feed additive in poultry nutrition. Show less

Hepatoblastoma (HB) is a rare embryonal liver tumor, with an increasing global incidence that underscores the need to understand its genetic etiology. Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4,539 Europeans, 1,047 Latinos, and 378 African Americans (∼1:10 case-control ratio). We conducted a meta-analysis of multiancestry transcriptome-wide analysis (METRO), followed by METRO-Egger sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases. Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted 8 genes among these 28, including OXER1 (meta-analysis P value = 7.34 × 10-6), FADS1 (P value = 4.01 × 10-6), and UGDH (P value = 5.29 × 10-8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (P values = 2.61 × 10-13, 3.62 × 10-3, and 1.95 × 10-9, respectively). We pinpointed eight potential genes associated with HB using data from an ongoing multiancestry genome-wide association study. We conducted the largest HB TWAS to date, prompting further exploration of genes. Show less

Acute respiratory distress syndrome (ARDS) is a severe clinical condition characterized by widespread inflammation and fluid accumulation in the lungs. Endothelial cell (EC) metabolic changes in acute lung injury (ALI) and their relationship to injury remain unclear. Transcriptomic and lipidomic analyses revealed downregulation of PUFA synthesis pathways, particularly omega-3 PUFAs, in pulmonary ECs during LPS-induced ALI. Activation of the PUFA metabolic pathway, through FADS1/2 overexpression or omega-3 fatty acid supplementation, protected ECs from ferroptosis and restored barrier function. In vivo, pulmonary EC-specific overexpression of FADS1/2 contributed to the alleviation of ALI. Overexpression of whole lung FADS1/2, combined with alpha-linolenic acid (ALA) supplementation, also significantly mitigated ALI. PARK7 is identified as an endogenous regulator of FADS1/2, acting through the BMP-BMPR-SMAD1/5/9 signaling. Driven by histone H3K14 lactylation, which is also promoted by the downregulation of FADS1/2, PARK7 upregulation restored FADS1/2 expression and counteracted ferroptosis, thereby forming a protective feedback loop. This study elucidates a novel regulatory axis involving the two major metabolic changes-downregulation of PUFA synthesis and upregulation of histone lactylation-in ALI pathogenesis, which are interconnected through the PARK7-BMP signaling pathway. Targeting this axis offers potential therapeutic strategies for mitigating endothelial dysfunction and ferroptosis in ARDS/ALI. Show less

The intrinsic heterogeneity and invasiveness of diffuse gliomas complicate accurate prognosis. Existing approaches are largely constrained by subtype specificity or limited analytical dimensions. To address this gap, a multi- dimension-based prognostic framework encompassing the full glioma spectrum was developed, accompanied by an analysis of the associated immune microenvironment. A total of 3,323 glioma samples from the SEER (n = 2181), CGGA (n = 807), and TCGA (n = 335) datasets were integrated. Differentially expressed genes were screened using the limma package, and a Lasso-Cox-based prognostic signature (Glioma-GDPM) was established. Clinical variables such as age, grade, and IDH mutation status were harmonized through propensity score matching to construct a multi-omics prognostic model (Glioma-GCDPM). GSEA, CIBERSORT-based immune infiltration analysis, and TIDE scoring were used to investigate the biological characteristics of different risk subgroups. Eleven key prognostic genes (such as PRAMEF2 and FADS1) and four clinical factors (age, tumor grade, IDH mutation, and 1p/19q codeletion) were identified. Glioma-GCDPM demonstrated favorable predictive ability in both the internal test cohort (AUC 0.81-0.86) and external validation sets (AUC 0.59-0.83). High-risk tumors exhibited greater invasiveness, with significant enrichment in cell cycle and proliferation-associated pathways. Additionally, a suppressed immune microenvironment was observed, reflected by elevated M2 macrophage infiltration and increased T cell dysfunction scores. The multi-omics model established in this study enables precise stratification of prognostic risk in diffuse glioma patients and reveals immunosuppressive features in high-risk individuals, providing a new basis for personalized treatment strategies. 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

This study elucidated the regulatory mechanisms of age-related meat flavor precursors in naturally grazed Sunit sheep of different ages (6, 18, and 30 months) by analyzing their metabolite and mRNA profiles. The longissimus dorsi muscle was sampled from each group and subjected to metabolomics and transcriptomics analyses. A total of 395 differential metabolites (DMs) and 1482 differentially expressed genes (DEGs) were detected across the age groups. As the age increased, the expression levels of Show less

This study aims to investigate associations between omega-3 polyunsaturated fatty acids (PUFAs) and myopia. Two-sample Mendelian randomization (MR) was conducted to estimate the associations between plasma levels of omega-3 PUFAs and three traits of myopia, including myopia, high myopia (HM), and refractive spherical equivalent (RSE). Summary data-based Mendelian randomization (SMR) and colocalization analysis were conducted to examine the associations between the FADS1 and FADS2 genes and three traits of myopia in European populations. The cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES) was performed to explore the relationship in East Asian adolescents. In the Two-sample MR study, plasma levels of total omega-3 PUFAs (0.993[0.990, 0.996]), Docosahexaenoic acid (DHA) (0.992[0.989, 0.996]), and Eicosapentaenoic Acid (EPA) (0.969[0.955, 0.983]) were found to be significantly and inversely associated with myopia in European populations, and similar results were shown in HM and RSE. SMR ( Show less

The aim of this study was to investigate the improving effect of Schisandrin B (Sch B) on metabolic associated fatty liver disease (MAFLD) by regulating the PPARγ signaling pathway and gut microbiota, and its mechanism in mice. Male C57BL/6 mice were fed with a high-fat diet (HFD) continuously for 16 weeks to establish a MAFLD model. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and lipopolysaccharide (LPS) in serum, as well as the level of malondialdehyde (MDA), and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in the liver tissue were measured. Changes in the gut microbiota of mice was analyzed by 16S rRNA sequencing technology. The expression levels of PPARγ, Plin2, Pck1, Acsl4, and Fads1 proteins, as well as those of zonula occludins 1 (ZO-1) and Occludin proteins in the colon tissue were detected by Western Blot. The results showed that Sch B could alleviate the structure disorder, ballooning degeneration, inflammatory cell infiltration, liver lipid droplets, and fibrosis in liver tissue, lower the levels of AST, ALT, TG, TC, LDL-C, and LPS, increase the level of HDL-C and lower the levels of TNF-α and IL-6 in serum, increase the level of IL-10, and lower the level of MDA and increase the activities of SOD and GSH-Px in liver tissue in MAFLD mice. Sch B could increase the expression levels of PPARγ, Pck1, and Fads1 proteins, but decrease Plin2 and Acsl4 proteins in liver tissue. Sch B could improve the diversity and abundance of the gut microbiota, restore the normal composition of the gut microbiota at the phylum and genus levels, alleviate the disruption of the gut barrier caused by HFD, and enhance the expression of ZO-1 and Occludin proteins in colon tissue in MAFLD mice. This study showed Sch B can improve HFD-induced MAFLD, and the mechanism may be through regulating the PPARγ, Plin2, PCk1, Acsl4 and Fads1 signaling pathway, restoring the diversity of gut microbiota, and improving the gut barrier to delay the progression of MAFLD. Show less

Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. Show less

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder caused by impaired insulin secretion from pancreatic β-cells and insulin resistance in target tissues. Genome-wide association studies have identified over 50 genetic variants linked to T2DM, including polymorphisms associated with the disease. This study investigates the impact of the Show less

Imbalance in fatty acid (FA) metabolism is a critical factor in the development of type 2 diabetes (T2D). This study examined fatty acid composition and desaturase activities in the liver and spinal cord of male Zucker diabetic fatty (ZDF) rats, a genetic model of T2D. Heterozygous lean ZDF fa/+ animals served as controls, while homozygous obese ZDF fa/fa animals represented the diabetic group. FA profiles were determined by gas chromatography, and the activities of Δ5-desaturase (FADS1), Δ6-desaturase (FADS2), Δ9-desaturase (SCD1), and elongase of very long-chain fatty acids (ELOVL) were estimated. T2D rats displayed significantly elevated levels of monounsaturated fatty acids (MUFAs) and increased SCD1 activity in both the liver and spinal cord. In contrast, polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA, C20:4 n-6), were reduced. Since AA plays a fundamental role in neuronal membrane structure and signaling pathways, these alterations have particular relevance to nervous system function. Tissue-specific alterations further suggested impaired FADS1 activity in the liver and reduced elongase/FADS2 activity in the spinal cord. These findings suggest that desaturase imbalance and FA remodeling in the spinal cord might represent characteristic features of T2D and that altered FA metabolism within the nervous system may potentially serve as an early indicator of neuropathy or a predictor of increased susceptibility to diabetes-related complications. 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

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (p < 5 × 10 Show less

Polyunsaturated fatty acids (PUFAs)-fatty acids containing multiple double bonds within their carbon chain-are an indispensable component of the cell membrane. PUFAs, including the omega-6 PUFA arachidonic acid (ARA; C20:4n-6) and the omega-3 PUFAs eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), have been implicated in various (patho)physiological events. These PUFAs are either obtained from the diet or biosynthesized from the essential fatty acids linoleic acid (LA; C18:2n-6) and α-linolenic acid (ALA; C18:3n-3) via enzymatic reactions that are catalyzed by fatty acid elongases (ELOVL2 and ELOVL5) and fatty acid desaturases (FADS1 and FADS2). In this review, we summarize the recent literature studying the role of PUFAs, placing a special emphasis on the newly discovered functions of PUFAs and their biosynthetic pathway as revealed by studies using animal models targeting the PUFA biosynthetic pathway and genetic approaches including genome-wide association studies. 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

Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD. To Identify new potential targets for CKD through metabolites and their regulatory genes. A total of 233 metabolites from the genome-wide association studies (GWAS) Catalog were utilized for Mendelian randomization (MR) with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to very low-density lipoprotein (VLDL) were selected for MR with CKD and metabolites. The total effect of the fatty acid desaturase 1 gene (FADS1) on CKD and metabolite-mediated effects were calculated. Bulk RNA-seq were used to validate FADS1 expression in the kidney tissues of patients with CKD. The cholesteryl esters to total lipids ratio in medium VLDL (odds ratio [OR] = 0.84; P.adj = .039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84; P.adj = .003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18; P.adj = .009) and the triglycerides to total lipids ratio in very small VLDL (OR = 1.1; P.adj < .001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.1; P.adj = .001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96%, respectively, were obtained. The differential expression of FADS1 was observed in the kidney tissues of patients with CKD. FADS1 is a risk factor for CKD and a novel therapeutic target. Four metabolites mediate the detrimental effect of FADS1 in CKD. Show less

The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have numerous benefits, including strong anti-inflammatory and triglyceride-lowering properties. EPA and DHA are primarily obtained by consuming fatty fish; however, they are also endogenously synthesized primarily in the liver from α-linolenic acid (ALA) through a pathway mediated by the delta-6 desaturase (D6D) enzyme. Previous reports in rodents and humans suggest that dietary proteins such as soy and dairy may impact this pathway differently. The primary aim was to investigate the effects of diets containing either soy or milk protein on the expression, abundance, and enzymatic activity of the desaturases and elongases regulating hepatic omega-3 fatty acid biosynthesis. Male C57BL/6N mice (n = 16 per group) were fed a moderate-fat diet for 8 weeks containing either 1% or 3% energy from ALA. Protein content (15% energy) corresponded to either skim milk powder (SMP) or soy protein isolate (SPI). Hepatic fatty acid content was quantified by gas chromatography-flame ionization detection. Gene expression and protein expression were assessed by RT-qPCR and western blotting, respectively. D6D activity was measured in isolated hepatic microsomes. Fat oxidation was examined using a high-resolution respirometer. Hepatic omega-3 fatty acids (ALA, SDA, EPA, DPAn-3) were lower in SPI-fed mice compared to SMP-fed mice. Fads1, Fads2, Elovl2, and Elovl5 expression was higher in SPI-fed mice compared to those fed SMP, while Srebp-1c expression was lower and Cpt1a expression higher in SPI-fed mice. Consistent with the changes seen at the gene expression levels, FADS2 protein abundance was higher in SPI-fed mice, whereas ELOVL5 protein expression was lower in the SPI groups. Little to no differences in microsomal D6D activity and mitochondrial respiration were detected. Our findings suggest that SPI-related reductions in hepatic omega-3 fatty acid content occur independent of changes in desaturase gene expression, protein expression, enzymatic activity, or mitochondrial respiration. Further studies investigating the influence of dietary proteins on ALA metabolism are therefore warranted. Show less

Observational studies have suggested associations between dietary polyunsaturated fatty acids (PUFAs) and cancer risk; however, causal inference regarding skin cancer remains limited due to potential recall bias, confounding, and reverse causation. This study aimed to evaluate the causal association between genetically predicted circulating PUFA levels and the risk of skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. We conducted a 2-sample Mendelian randomization (MR) study using genome-wide association study summary statistics from the UK Biobank (PUFAs, n=115,006) and the FinnGen consortium (BCC, n=26,272; SCC, n=4,663; melanoma, n=5,753). Genetic instruments were derived for omega-3, docosahexaenoic acid, omega-6, linoleic acid, and the omega-6:3 ratio. Multiple MR methods-including inverse-variance weighted, MR-Egger, weighted median, weighted mode, and MR-PRESSO-were applied to test for consistency and assess pleiotropy and heterogeneity. A higher genetically predicted linoleic acid to total fatty acid ratio was associated with a significantly lower risk of BCC and SCC. Conversely, higher genetically proxied serum omega-3 levels were associated with increased risks of BCC, SCC, and melanoma. The risk effect on SCC was attenuated upon exclusion of rs174528, a variant in the fatty acid desaturase 1 ( This MR analysis supports a causal role of circulating PUFAs in skin cancer development and highlights the importance of FADS-mediated endogenous PUFA metabolism. These findings provide novel insights into the genetic and metabolic underpinnings of skin cancer susceptibility. Show less

Epidemiological studies report inconsistent findings regarding the association between dietary polyunsaturated fatty acid (PUFA) intake and cancer risk. Genetic variations-particularly single-nucleotide polymorphisms (SNPs) in the Show less

Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84-0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87-0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05-1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring MYRF, FADS1, and FADS2 as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including FADS1, FADS2, FADS3, and SYT7. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD. Show less