Polygenic risk score-based phenome-wide association study of head and neck cancer across two large biobanks.

BACKGROUND: Numerous observational studies have highlighted associations of genetic predisposition of head and neck squamous cell carcinoma (HNSCC) with diverse risk factors, but these findings are constrained by design limitations of observational studies. In this study, we utilized a phenome-wide association study (PheWAS) approach, incorporating a polygenic risk score (PRS) derived from a wide array of genomic variants, to systematically investigate phenotypes associated with genetic predisposition to HNSCC. Furthermore, we validated our findings across heterogeneous cohorts, enhancing the robustness and generalizability of our results. METHODS: We derived PRSs for HNSCC and its subgroups, oropharyngeal cancer and oral cancer, using large-scale genome-wide association study summary statistics from the Genetic Associations and Mechanisms in Oncology Network. We conducted a comprehensive investigation, leveraging genotyping data and electronic health records from 308,492 individuals in the UK Biobank and 38,401 individuals in the Penn Medicine Biobank (PMBB), and subsequently performed PheWAS to elucidate the associations between PRS and a wide spectrum of phenotypes. RESULTS: We revealed the HNSCC PRS showed significant association with phenotypes related to tobacco use disorder (OR, 1.06; 95% CI, 1.05-1.08; P = 3.50 × 10-15), alcoholism (OR, 1.06; 95% CI, 1.04-1.09; P = 6.14 × 10-9), alcohol-related disorders (OR, 1.08; 95% CI, 1.05-1.11; P = 1.09 × 10-8), emphysema (OR, 1.11; 95% CI, 1.06-1.16; P = 5.48 × 10-6), chronic airway obstruction (OR, 1.05; 95% CI, 1.03-1.07; P = 2.64 × 10-5), and cancer of bronchus (OR, 1.08; 95% CI, 1.04-1.13; P = 4.68 × 10-5). These findings were replicated in the PMBB cohort, and sensitivity analyses, including the exclusion of HNSCC cases and the major histocompatibility complex locus, confirmed the robustness of these associations. Additionally, we identified significant associations between HNSCC PRS and lifestyle factors related to smoking and alcohol consumption. CONCLUSIONS: The study demonstrated the potential of PRS-based PheWAS in revealing associations between genetic risk factors for HNSCC and various phenotypic traits. The findings emphasized the importance of considering genetic susceptibility in understanding HNSCC and highlighted shared genetic bases between HNSCC and other health conditions and lifestyles.

Association between genetic risk and adherence to healthy lifestyle for developing age-related hearing loss.

BACKGROUND: Previous studies have shown that lifestyle/environmental factors could accelerate the development of age-related hearing loss (ARHL). However, there has not yet been a study investigating the joint association among genetics, lifestyle/environmental factors, and adherence to healthy lifestyle for risk of ARHL. We aimed to assess the association between ARHL genetic variants, lifestyle/environmental factors, and adherence to healthy lifestyle as pertains to risk of ARHL. METHODS: This case-control study included 376,464 European individuals aged 40 to 69 years, enrolled between 2006 and 2010 in the UK Biobank (UKBB). As a replication set, we also included a total of 26,523 individuals considered of European ancestry and 9834 individuals considered of African-American ancestry through the Penn Medicine Biobank (PMBB). The polygenic risk score (PRS) for ARHL was derived from a sensorineural hearing loss genome-wide association study from the FinnGen Consortium and categorized as low, intermediate, high, and very high. We selected lifestyle/environmental factors that have been previously studied in association with hearing loss. A composite healthy lifestyle score was determined using seven selected lifestyle behaviors and one environmental factor. RESULTS: Of the 376,464 participants, 87,066 (23.1%) cases belonged to the ARHL group, and 289,398 (76.9%) individuals comprised the control group in the UKBB. A very high PRS for ARHL had a 49% higher risk of ARHL than those with low PRS (adjusted OR, 1.49; 95% CI, 1.36-1.62; P < .001), which was replicated in the PMBB cohort. A very poor lifestyle was also associated with risk of ARHL (adjusted OR, 3.03; 95% CI, 2.75-3.35; P < .001). These risk factors showed joint effects with the risk of ARHL. Conversely, adherence to healthy lifestyle in relation to hearing mostly attenuated the risk of ARHL even in individuals with very high PRS (adjusted OR, 0.21; 95% CI, 0.09-0.52; P < .001). CONCLUSIONS: Our findings of this study demonstrated a significant joint association between genetic and lifestyle factors regarding ARHL. In addition, our analysis suggested that lifestyle adherence in individuals with high genetic risk could reduce the risk of ARHL.

Discovering comorbid diseases using an inter-disease interactivity network based on biobank-scale PheWAS data.

MOTIVATION: Understanding comorbidity is essential for disease prevention, treatment and prognosis. In particular, insight into which pairs of diseases are likely or unlikely to co-occur may help elucidate the potential relationships between complex diseases. Here, we introduce the use of an inter-disease interactivity network to discover/prioritize comorbidities. Specifically, we determine disease associations by accounting for the direction of effects of genetic components shared between diseases, and categorize those associations as synergistic or antagonistic. We further develop a comorbidity scoring algorithm to predict whether diseases are more or less likely to co-occur in the presence of a given index disease. This algorithm can handle networks that incorporate relationships with opposite signs. RESULTS: We finally investigate inter-disease associations among 427 phenotypes in UK Biobank PheWAS data and predict the priority of comorbid diseases. The predicted comorbidities were verified using the UK Biobank inpatient electronic health records. Our findings demonstrate that considering the interaction of phenotype associations might be helpful in better predicting comorbidity. AVAILABILITY AND IMPLEMENTATION: The source code and data of this study are available at https://github.com/dokyoonkimlab/DiseaseInteractiveNetwork. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Polygenic risk score-based phenome-wide association for glaucoma and its impact on disease susceptibility in two large biobanks.

BACKGROUND: Glaucoma is a leading cause of worldwide irreversible blindness. Considerable uncertainty remains regarding the association between a variety of phenotypes and the genetic risk of glaucoma, as well as the impact they exert on the glaucoma development. METHODS: We investigated the associations of genetic liability for primary open angle glaucoma (POAG) with a wide range of potential risk factors and to assess its impact on the risk of incident glaucoma. The phenome-wide association study (PheWAS) approach was applied to determine the association of POAG polygenic risk score (PRS) with a wide range of phenotypes in 377, 852 participants from the UK Biobank study and 43,623 participants from the Penn Medicine Biobank study, all of European ancestry. Participants were stratified into four risk tiers: low, intermediate, high, and very high-risk. Cox proportional hazard models assessed the relationship of POAG PRS and ocular factors with new glaucoma events. RESULTS: In both discovery and replication set in the PheWAS, a higher genetic predisposition to POAG was specifically correlated with ocular disease phenotypes. The POAG PRS exhibited correlations with low corneal hysteresis, refractive error, and ocular hypertension, demonstrating a strong association with the onset of glaucoma. Individuals carrying a high genetic burden exhibited a 9.20-fold, 11.88-fold, and 28.85-fold increase in glaucoma incidence when associated with low corneal hysteresis, high myopia, and elevated intraocular pressure, respectively. CONCLUSION: Genetic susceptibility to POAG primarily influences ocular conditions, with limited systemic associations. Notably, the baseline polygenic risk for POAG robustly associates with new glaucoma events, revealing a large combined effect of genetic and ocular risk factors on glaucoma incidents.

Genome-wide polygenic risk scores for hypertensive disease during pregnancy can also predict the risk for long-term cardiovascular disease.

BACKGROUND: Hypertensive disorders during pregnancy are associated with the risk of long-term cardiovascular disease after pregnancy, but it has not yet been determined whether genetic predisposition for hypertensive disorders during pregnancy can predict the risk for long-term cardiovascular disease. OBJECTIVE: This study aimed to evaluate the risk for long-term atherosclerotic cardiovascular disease according to polygenic risk scores for hypertensive disorders during pregnancy. STUDY DESIGN: Among UK Biobank participants, we included European-descent women (n=164,575) with at least 1 live birth. Participants were divided according to genetic risk categorized by polygenic risk scores for hypertensive disorders during pregnancy (low risk, score ≤25th percentile; medium risk, score 25th∼75th percentile; high risk, score >75th percentile), and were evaluated for incident atherosclerotic cardiovascular disease, defined as the new occurrence of one of the following: coronary artery disease, myocardial infarction, ischemic stroke, or peripheral artery disease. RESULTS: Among the study population, 2427 (1.5%) had a history of hypertensive disorders during pregnancy, and 8942 (5.6%) developed incident atherosclerotic cardiovascular disease after enrollment. Women with high genetic risk for hypertensive disorders during pregnancy had a higher prevalence of hypertension at enrollment. After enrollment, women with high genetic risk for hypertensive disorders during pregnancy had an increased risk for incident atherosclerotic cardiovascular disease, including coronary artery disease, myocardial infarction, and peripheral artery disease, compared with those with low genetic risk, even after adjustment for history of hypertensive disorders during pregnancy. CONCLUSION: High genetic risk for hypertensive disorders during pregnancy was associated with increased risk for atherosclerotic cardiovascular disease. This study provides evidence on the informative value of polygenic risk scores for hypertensive disorders during pregnancy in prediction of long-term cardiovascular outcomes later in life.

Genome-wide association study of occupational attainment as a proxy for cognitive reserve.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65-0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57-0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53-0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48-0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

ICD2Vec: Mathematical representation of diseases.

BACKGROUND: The International Classification of Diseases (ICD) codes represent the global standard for reporting disease conditions. The current ICD codes connote direct human-defined relationships among diseases in a hierarchical tree structure. Representing the ICD codes as mathematical vectors helps to capture nonlinear relationships in medical ontologies across diseases. METHODS: We propose a universally applicable framework called "ICD2Vec" designed to provide mathematical representations of diseases by encoding corresponding information. First, we present the arithmetical and semantic relationships between diseases by mapping composite vectors for symptoms or diseases to the most similar ICD codes. Second, we investigated the validity of ICD2Vec by comparing the biological relationships and cosine similarities among the vectorized ICD codes. Third, we propose a new risk score called IRIS, derived from ICD2Vec, and demonstrate its clinical utility with large cohorts from the UK and South Korea. RESULTS: Semantic compositionality was qualitatively confirmed between descriptions of symptoms and ICD2Vec. For example, the diseases most similar to COVID-19 were found to be the common cold (ICD-10: J00), unspecified viral hemorrhagic fever (ICD-10: A99), and smallpox (ICD-10: B03). We show the significant associations between the cosine similarities derived from ICD2Vec and the biological relationships using disease-to-disease pairs. Furthermore, we observed significant adjusted hazard ratios (HR) and area under the receiver operating characteristics (AUROC) between IRIS and risks for eight diseases. For instance, the higher IRIS for coronary artery disease (CAD) can be the higher probability for the incidence of CAD (HR: 2.15 [95% CI 2.02-2.28] and AUROC: 0.587 [95% CI 0.583-0.591]). We identified individuals at substantially increased risk of CAD using IRIS and 10-year atherosclerotic cardiovascular disease risk (adjusted HR: 4.26 [95% CI 3.59-5.05]). CONCLUSIONS: ICD2Vec, a proposed universal framework for converting qualitatively measured ICD codes into quantitative vectors containing semantic relationships between diseases, exhibited a significant correlation with actual biological significance. In addition, the IRIS was a significant predictor of major diseases in a prospective study using two large-scale datasets. Based on this clinical validity and utility evidence, we suggest that publicly available ICD2Vec can be used in diverse research and clinical practices and has important clinical implications.

Development and validation of a novel strong prognostic index for colon cancer through a robust combination of laboratory features for systemic inflammation: a prognostic immune nutritional index.

BACKGROUND: Systemic inflammation is associated with survival outcomes in colon cancer. However, it is not well-known which systemic inflammatory marker is a powerful prognostic marker in patients with colon cancer. METHODS: A total of 4535 colon cancer patients were included in this study. We developed a novel prognostic index using a robust combination of seven systemic inflammation-associated blood features of the discovery set. The predictability and generality of the novel prognostic index were evaluated in the discovery, validation and replication sets. RESULTS: Among all combinations, the combination of albumin and monocyte count was the best candidate expression. The final formula of the proposed novel index is named the Prognostic Immune and Nutritional Index (PINI). The concordance index of PINI for overall and progression-free survival was the highest in the discovery, validation and replication sets compared to existing prognostic inflammatory markers. PINI was found to be a significant independent prognostic factor for both overall and progression-free survival. CONCLUSIONS: PINI is a novel prognostic index that has improved discriminatory power in colon cancer patients and appears to be superior to existing prognostic inflammatory markers. PINI can be utilised for decision-making regarding personalised treatment as the complement of the TNM staging system.

Polygenic risk for type 2 diabetes, lifestyle, metabolic health, and cardiovascular disease: a prospective UK Biobank study.

BACKGROUND: Few studies have examined associations between genetic risk for type 2 diabetes (T2D), lifestyle, clinical risk factors, and cardiovascular disease (CVD). We aimed to investigate the association of and potential interactions among genetic risk for T2D, lifestyle behavior, and metabolic risk factors with CVD. METHODS: A total of 345,217 unrelated participants of white British descent were included in analyses. Genetic risk for T2D was estimated as a genome-wide polygenic risk score constructed from > 6 million genetic variants. A favorable lifestyle was defined in terms of four modifiable lifestyle components, and metabolic health status was determined according to the presence of metabolic syndrome components. RESULTS: During a median follow-up of 8.9 years, 21,865 CVD cases (6.3%) were identified. Compared with the low genetic risk group, participants at high genetic risk for T2D had higher rates of overall CVD events, CVD subtypes (coronary artery disease, peripheral artery disease, heart failure, and atrial fibrillation/flutter), and CVD mortality. Individuals at very high genetic risk for T2D had a 35% higher risk of CVD than those with low genetic risk (HR 1.35 [95% CI 1.19 to 1.53]). A significant gradient of increased CVD risk was observed across genetic risk, lifestyle, and metabolic health status (P for trend > 0.001). Those with favorable lifestyle and metabolically healthy status had significantly reduced risk of CVD events regardless of T2D genetic risk. This risk reduction was more apparent in young participants (≤ 50 years). CONCLUSIONS: Genetic risk for T2D was associated with increased risks of overall CVD, various CVD subtypes, and fatal CVD. Engaging in a healthy lifestyle and maintaining metabolic health may reduce subsequent risk of CVD regardless of genetic risk for T2D.

A deep learning model for screening type 2 diabetes from retinal photographs.

BACKGROUND AND AIMS: We aimed to develop and evaluate a non-invasive deep learning algorithm for screening type 2 diabetes in UK Biobank participants using retinal images. METHODS AND RESULTS: The deep learning model for prediction of type 2 diabetes was trained on retinal images from 50,077 UK Biobank participants and tested on 12,185 participants. We evaluated its performance in terms of predicting traditional risk factors (TRFs) and genetic risk for diabetes. Next, we compared the performance of three models in predicting type 2 diabetes using 1) an image-only deep learning algorithm, 2) TRFs, 3) the combination of the algorithm and TRFs. Assessing net reclassification improvement (NRI) allowed quantification of the improvement afforded by adding the algorithm to the TRF model. When predicting TRFs with the deep learning algorithm, the areas under the curve (AUCs) obtained with the validation set for age, sex, and HbA1c status were 0.931 (0.928-0.934), 0.933 (0.929-0.936), and 0.734 (0.715-0.752), respectively. When predicting type 2 diabetes, the AUC of the composite logistic model using non-invasive TRFs was 0.810 (0.790-0.830), and that for the deep learning model using only fundus images was 0.731 (0.707-0.756). Upon addition of TRFs to the deep learning algorithm, discriminative performance was improved to 0.844 (0.826-0.861). The addition of the algorithm to the TRFs model improved risk stratification with an overall NRI of 50.8%. CONCLUSION: Our results demonstrate that this deep learning algorithm can be a useful tool for stratifying individuals at high risk of type 2 diabetes in the general population.

Effects of unaltered and bioconverted mulberry leaf extracts on cellular glucose uptake and antidiabetic action in animals.

BACKGROUND: Mulberry is a Korean medicinal herb that shows effective prevention and treatment of obesity and diabetes. Bioconversion is the process of producing active ingredients from natural products using microorganisms or enzymes. METHODS: In this study, we prepared bioconverted mulberry leaf extract (BMLE) with Viscozyme L, which we tested in insulin-sensitive cells (i.e., skeletal muscle cells and adipocytes) and insulin-secreting pancreatic ß-cells, as well as obese diabetic mice induced by co-administration of streptozotocin (100 mg/kg, IP) and nicotinamide (240 mg/kg, IP) and feeding high-fat diet, as compared to unaltered mulberry leaf extract (MLE). RESULTS: BMLE increased the glucose uptake in C2C12 myotubes and 3 T3-L1 adipocytes and increased glucose-stimulated insulin secretion in HIT-T15 pancreatic ß-cells. The fasting blood glucose levels in diabetic mice treated with BMLE or MLE (300 and 600 mg/kg, PO, 7 weeks) were significantly lower than those of the vehicle-treated group. At the same concentration, BMLE-treated mice showed better glucose tolerance than MLE-treated mice. Moreover, the blood concentration of glycated hemoglobin (HbA1C) in mice treated with BMLE was lower than that in the MLE group at the same concentration. Plasma insulin levels in mice treated with BMLE or MLE tended to increase compared to the vehicle-treated group. Treatment with BMLE yielded significant improvements in insulin resistance and insulin sensitivity. CONCLUSION: These results indicate that in the management of diabetic condition, BMLE is superior to unaltered MLE due to at least, in part, high concentrations of maker compounds (trans-caffeic acid and syringaldehyde) in BMLE.

Anti-apoptotic effects of autophagy via ROS regulation in microtubule-targeted and PDGF-stimulated vascular smooth muscle cells.

Autophagy has been studied as a therapeutic strategy for cardiovascular diseases. However, insufficient studies have been reported concerning the influence of vascular smooth muscle cells (VSMCs) through autophagy regulation. The aim of the present study was to determine the effects of VSMCs on the regulation of autophagy under in vitro conditions similar to vascular status of the equipped microtubule target agent-eluting stent and increased release of platelet-derived growth factor-BB (PDGF-BB). Cell viability and proliferation were measured using MTT and cell counting assays. Immunofluorescence using an anti-α-tubulin antibody was performed to determine microtubule dynamic formation. Cell apoptosis was measured by cleavage of caspase-3 using western blot analysis, and by nuclear fragmentation using a fluorescence assay. Autophagy activity was assessed by microtubule-associated protein light chain 3-II (LC-II) using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured using H2DCFDA. The proliferation and viability of VSMCs were inhibited by microtubule regulation. Additionally, microtubule-regulated and PDGF-BB-stimulated VSMCs increased the cleavage of caspase-3 more than only the microtubule-regulated condition, similar to that of LC3-II, implying autophagy. Inhibitory autophagy of microtubule-regulated and PDGF-BB-stimulated VSMCs resulted in low viability. However, enhancement of autophagy maintained survival through the reduction of ROS. These results suggest that the apoptosis of conditioned VSMCs is decreased by the blocking generation of ROS via the promotion of autophagy, and proliferation is also inhibited. Thus, promoting autophagy as a therapeutic target for vascular restenosis and atherosclerosis may be a good strategy.

Alleviation of ascorbic acid-induced gastric high acidity by calcium ascorbate in vitro and in vivo.

Ascorbic acid is one of the most well-known nutritional supplement and antioxidant found in fruits and vegetables. Calcium ascorbate has been developed to mitigate the gastric irritation caused by the acidity of ascorbic acid. The aim of this study was to compare calcium ascorbate and ascorbic acid, focusing on their antioxidant activity and effects on gastric juice pH, total acid output, and pepsin secretion in an in vivo rat model, as well as pharmacokinetic parameters. Calcium ascorbate and ascorbic acid had similar antioxidant activity. However, the gastric fluid pH was increased by calcium ascorbate, whereas total acid output was increased by ascorbic acid. In the rat pylorus ligation-induced ulcer model, calcium ascorbate increased the gastric fluid pH without changing the total acid output. Administration of calcium ascorbate to rats given a single oral dose of 100 mg/kg as ascorbic acid resulted in higher plasma concentrations than that from ascorbic acid alone. The area under the curve (AUC) values of calcium ascorbate were 1.5-fold higher than those of ascorbic acid, and the Cmax value of calcium ascorbate (91.0 ng/ml) was higher than that of ascorbic acid (74.8 ng/ml). However, their Tmax values were similar. Thus, although calcium ascorbate showed equivalent antioxidant activity to ascorbic acid, it could attenuate the gastric high acidity caused by ascorbic acid, making it suitable for consideration of use to improve the side effects of ascorbic acid. Furthermore, calcium ascorbate could be an appropriate antioxidant substrate, with increased oral bioavailability, for patients with gastrointestinal disorders.

Suicide loss, changes in medical care utilization, and hospitalization for cardiovascular disease and diabetes mellitus.

AIMS: The impact of suicide loss on family members' cardiometabolic health has little been evaluated in middle-aged and elderly people. We investigated the effect of suicide loss on risks for cardiovascular disease (CVD) and diabetes mellitus (DM) in suicide completers' family members using a national representative comparison group. METHODS AND RESULTS: The study subjects were 4253 family members of suicide completers and 9467 non-bereaved family members of individuals who were age and gender matched with the suicide completers in the Republic of Korea. National health insurance data were used to identify medical care utilization during the year before and after a suicide loss. A recurrent-events survival analysis was performed to estimate the hazard ratios (HRs) of hospitalizations for CVD, DM, or psychiatric disorders, after adjusting for age, residence, and socioeconomic status. Among subjects without a past history of CVD, DM, or psychiatric disorders, the increased risks of recurrent hospitalizations were observed for CVD [HR 1.343, 95% confidence interval (CI) 1.001-1.800 in men; HR 1.240, 95% CI 1.025-1.500 in women] and DM (HR 2.238, 95% CI 1.379-3.362 in men; HR 1.786, 95% CI 1.263-2.527 in women). In subjects with a past history of CVD, DM, or psychiatric disorders, the number of medical care visits decreased after a suicide loss, and suicide completers' family members showed lower rates of hospitalization for CVD and DM than the comparison group. CONCLUSION: Compared with non-bereaved family members, suicide completers' family members without a past history of CVD, DM, or psychiatric disorder showed a high risk of hospitalization for those conditions.

Differential Gene Expression in GPR40-Overexpressing Pancreatic ß-cells Treated with Linoleic Acid.

"G protein-coupled receptor 40" (GPR40), a receptor for long-chain fatty acids, mediates the stimulation of glucose-induced insulin secretion. We examined the profiles of differential gene expression in GPR40-activated cells treated with linoleic acid, and finally predicted the integral pathways of the cellular mechanism of GPR40-mediated insulinotropic effects. After constructing a GPR40-overexpressing stable cell line (RIN-40) from the rat pancreatic ß-cell line RIN-5f, we determined the gene expression profiles of RIN-5f and RIN-40. In total, 1004 genes, the expression of which was altered at least twofold, were selected in RIN-5f versus RIN-40. Moreover, the differential genetic profiles were investigated in RIN-40 cells treated with 30 µM linoleic acid, which resulted in selection of 93 genes in RIN-40 versus RIN-40 treated with linoleic acid. Based on the Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG, http://www.genome.jp/kegg/), sets of genes induced differentially by treatment with linoleic acid in RIN-40 cells were found to be related to mitogen-activated protein (MAP) kinase- and neuroactive ligand-receptor interaction pathways. A gene ontology (GO) study revealed that more than 30% of the genes were associated with signal transduction and cell proliferation. Thus, this study elucidated a gene expression pattern relevant to the signal pathways that are regulated by GPR40 activation during the acute period. Together, these findings increase our mechanistic understanding of endogenous molecules associated with GPR40 function, and provide information useful for identification of a target for the management of type 2 diabetes mellitus.

Murrayafoline A Induces a G0/G1-Phase Arrest in Platelet-Derived Growth Factor-Stimulated Vascular Smooth Muscle Cells.

The increased potential for vascular smooth muscle cell (VSMC) growth is a key abnormality in the development of atherosclerosis and post-angioplasty restenosis. Abnormally high activity of platelet-derived growth factor (PDGF) is believed to play a central role in the etiology of these pathophysiological situations. Here, we investigated the anti-proliferative effects and possible mechanism(s) of murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa Guillamin (Rutaceae), on PDGF-BB-stimulated VSMCs. Murrayafoline A inhibited the PDGF-BB-stimulated proliferation of VSMCs in a concentration-dependent manner, as measured using a non-radioactive colorimetric WST-1 assay and direct cell counting. Furthermore, murrayafoline A suppressed the PDGF-BB-stimulated progression through G0/G1 to S phase of the cell cycle, as measured by [(3)H]-thymidine incorporation assay and cell cycle progression analysis. This anti-proliferative action of murrayafoline A, arresting cell cycle progression at G0/G1 phase in PDGF-BB-stimulated VSMCs, was mediated via down-regulation of the expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, and proliferating cell nuclear antigen (PCNA), and the phosphorylation of retinoblastoma protein (pRb). These results indicate that murrayafoline A may be useful in preventing the progression of vascular complications such as restenosis after percutaneous transluminal coronary angioplasty and atherosclerosis.

Fermented soshiho-tang with Lactobacillus plantarum enhances the antiproliferative activity in vascular smooth muscle cell.

BACKGROUND: Soshiho-tang (SST) is a traditional medicine widely used for the treatment of chronic hepatitis. SST has been shown to confer a variety of pharmacological activities, including prevention of hepatotoxicity, promotion of liver regeneration, and modulation of liver fibrosis. In this study, we investigated the antiproliferative activity of native and fermented (FSST) formulations of SST in vascular smooth muscle cells (VSMCs) and examined the potential underlying mechanisms driving these effects. METHODS: SST, along with preparations fermented with Lactobacillus plantarum KFRI-144 (S-A144), L. amylophilus KFRI-161 (S-A161) and L. bulgaricus KFRI-344 (S-A344), were investigated to determine their effects on the proliferation and viability of VSMCs, along with the signalling pathways underlying these effects. RESULTS: S-A144 exhibited a strong, dose-dependent inhibition of VSMC proliferation relative to untreated controls, but the others did not affect. In addition, S-A144 significantly decreased the phosphorylation of Akt and PLCγ1 in a dose-dependent manner and induced cell cycle arrest at the G0/G1 phase characterised by decreased expression of CDKs, cyclins and PCNA. CONCLUSIONS: The findings suggest that S-A144 exhibit enhanced inhibition of PDGF-BB-induced VSMC proliferation comparison to S-AOR through the suppression of cell cycle progression and expression of cell cycle-related proteins, along with the downregulation of Akt phosphorylation.

The Impact of Lifestyle on Cardiovascular Risk in Patients with Gout: a Population-based Cohort Study.

AIMS: Gout is associated with a significant burden of cardiovascular disease. The aim of this study was to evaluate the impact of a favorable lifestyle on incident cardiovascular events in patients with gout. METHODS: We identified 9 110 patients with gout from the UK Biobank cohort based on self-report and/or hospital diagnostic codes. Lifestyle behaviors, including smoking status, physical activity, obesity, and diet, were categorized into three patterns: favorable (3-4 healthy factors), intermediate (2 healthy factors), and unfavorable (0-1 healthy factor). The cardiovascular risk of participants with and without gout was estimated based on their serum uric acid levels and lifestyle patterns. RESULTS: Among 9 110 patients with gout and 457 596 participants without gout, the median follow-up duration was 8.9 years. The incidence rate of cardiovascular disease was significantly higher in the gout population than in the non-gout population (11.38 vs 5.49 per 1000 person-years). The gout population consistently exhibited a high cardiovascular risk, irrespective of uric acid levels, whereas a positive correlation was observed between uric acid levels and cardiovascular risk in the non-gout population. Adopting a favorable lifestyle pattern was associated with a lower risk of cardiovascular disease in both gout and non-gout populations. Across all categories of uric acid, a favorable lifestyle was found to reduce cardiovascular risk in patients with gout. CONCLUSION: Patients with gout remain at high risk of developing cardiovascular disease despite having normal uric acid levels. Lifestyle modifications may represent an effective and cost-efficient therapeutic approach for preventing cardiovascular events in this population.

Harnessing Artificial Intelligence in Multimodal Omics Data Integration: Paving the Path for the Next Frontier in Precision Medicine.

The integration of multiomics data with detailed phenotypic insights from electronic health records marks a paradigm shift in biomedical research, offering unparalleled holistic views into health and disease pathways. This review delineates the current landscape of multimodal omics data integration, emphasizing its transformative potential in generating a comprehensive understanding of complex biological systems. We explore robust methodologies for data integration, ranging from concatenation-based to transformation-based and network-based strategies, designed to harness the intricate nuances of diverse data types. Our discussion extends from incorporating large-scale population biobanks to dissecting high-dimensional omics layers at the single-cell level. The review underscores the emerging role of large language models in artificial intelligence, anticipating their influence as a near-future pivot in data integration approaches. Highlighting both achievements and hurdles, we advocate for a concerted effort toward sophisticated integration models, fortifying the foundation for groundbreaking discoveries in precision medicine.