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BACKGROUND: The impact of hypertrophic cardiomyopathy (HCM) on cardiovascular and obstetrical outcomes in pregnant women remains unclear, particularly in Asian populations. This study aimed to evaluate the maternal cardiovascular and obstetrical outcomes in Korean women with HCM. METHODS: Using data from the Korean National Health Insurance Service database, we identified women who gave birth via cesarean section or vaginal delivery after being diagnosed with HCM between 2006 and 2019. Maternal cardiovascular and obstetrical outcomes were assessed based on the trimester of pregnancy. RESULTS: This study included 122 women and 158 pregnancies. No maternal deaths were noted; however, 21 cardiovascular events, such as hospital admission for cardiac problems, including heart failure and atrial fibrillation (AF), new-onset AF or ventricular tachycardia (VT) occurred in 14 pregnancies (8.8%). Cardiac events occurred throughout pregnancy with a higher occurrence in the third trimester. Cesarean sections were performed in 49.3% of the cases, and all cardiovascular outcomes occurring after delivery were observed in patients who had undergone cesarean sections. Seven cases involved preterm delivery, and two of these cases were accompanied by cardiac events, specifically AF. Pre-existing arrhythmia (AF: odds ratio (OR): 7.44, 95% confidence interval (CI): 2.61-21.21, P < 0.001; VT: OR: 31.61, 95% CI: 5.85-172.77, P < 0.001) was identified as a predictor for composite outcomes of cardiovascular events or preterm delivery. CONCLUSIONS: Most pregnant women with HCM were well-tolerated. However, cardiovascular complications could occur in some patients. Therefore, planned delivery may be necessary for selected patients, especially the women with pre-existing arrhythmias.
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Cardiomiopatia Hipertrófica , Bases de Dados Factuais , Complicações Cardiovasculares na Gravidez , Humanos , Feminino , Gravidez , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/mortalidade , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Adulto , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/diagnóstico , Fatores de Risco , República da Coreia/epidemiologia , Medição de Risco , Cesárea , Estudos Retrospectivos , Adulto Jovem , Resultado da Gravidez/epidemiologiaRESUMO
This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.
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Encéfalo , População do Leste Asiático , Idoso , Pessoa de Meia-Idade , Humanos , Estudos de Coortes , Encéfalo/diagnóstico por imagem , Córtex Cerebral , Cognição , Imageamento por Ressonância Magnética/métodosRESUMO
In the present study, through the laboratory-to-field scale experiments and trials, we report the development and evaluation of an integrated oil-spill response system capable of oil collection, recovery (separation), and storage, for a timely and effective response to the initial stage of oil-spill accidents. With the laboratory-scale experiments, first, we evaluate that the water-surface waves tend to abate the oil recovery rate below 80% (it is above 95% for the optimized configuration without the waves), which is overcome by installing the hydrophilic (and oleophobic) porous structures at the inlet and/or near the water outlet of the separator. In the follow-up meso-scale towing tank tests with a scaled-up prototype, (i) we optimize the maneuverability of the assembled system depending on the speed and existence of waves, and (ii) evaluate the oil recovery performance (more than 80% recovery for the olive oil and Bunker A fuel oil). Although more thorough investigations and improvements are needed, a recovery rate of over 50% can be achieved for the newly enforced marine fuel oil (low sulfur fuel oil, LSFO) that was not targeted at the time of development. Finally, we perform a series of field tests with a full-scale system, to evaluate the rapid deployment and operational stability in the real marine environment. The overall floating balance and coordination of each functional part are sustained to be stable during the straight and rotary maneuvers up to the speed of 5 knots. Also, the collection of the floating debris (mimicking the spilled oil) is demonstrated in the field test. The present system is now being tested by the Korea Coast Guard and we believe that it will be very powerful to prevent the environmental damage due to the oil spills.
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Óleos Combustíveis , Poluição por Petróleo , Baías , Laboratórios , ÁguaRESUMO
OBJECTIVE: To identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection. METHODS: This study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction. RESULTS: In the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori-positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori-negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori-negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori-positive group (P = 0.0112). CONCLUSION: After H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC.
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Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Estudo de Associação Genômica Ampla , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Humanos , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Proteínas Repressoras/genética , República da Coreia , Neoplasias Gástricas/epidemiologiaRESUMO
BACKGROUND: Correctional institution inmates have reduced access to dental care; however, a quantitative assessment of their oral health condition has not yet been performed in South Korea. Therefore, this study aimed to assess dental caries and compare the prevalence of dental caries and associated factors between inmates and the general South Korean population. METHODS: The dental records of two detention centers in South Korea were retrospectively analyzed to assess the clinical oral health condition of inmates using the Decayed, Missing, and Filled Teeth (DMFT) index and self-reported questionnaire. These data were compared with similar data obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) for the general South Korean population. RESULTS: In total, 642 inmates were analyzed and compared with 13,345 KNHANES participants in the KNHANES. The inmate and KNHANES groups demonstrated significant intergroup differences, with a higher prevalence of untreated caries, DMFT, decayed teeth (DT), and missing teeth (MT) values among the inmates. The prevalence of untreated caries decreased according to the history of dental pain in the inmate group but increased in the KNHANES group. The decrease in DMFT with a history of dental pain was significant only in the inmate group. Furthermore, self-rated oral health was significantly associated with prevalence of untreated caries, DMFT, DT, MT, and filled teeth (FT) in the inmate group but with prevalence of untreated caries, DMFT, DT, and MT in the KNHANES group. It was found that this is because there is an interaction effect by the group. CONCLUSIONS: The oral health of the inmate group was significantly poorer than that of the general group. Since DMFT, DT, MT, and FT values and prevalence of untreated caries in the inmate group were significantly related to their self-rated oral health, suggesting that self-rated oral health should be incorporated into the dental health screenings of correctional institution inmates.
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Cárie Dentária , Perda de Dente , Índice CPO , Cárie Dentária/epidemiologia , Humanos , Prisões Locais , Inquéritos Nutricionais , Dor , Prevalência , República da Coreia/epidemiologia , Estudos Retrospectivos , Perda de Dente/epidemiologiaRESUMO
BACKGROUND: The prevalence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in South Korea and many parts of the world. However, the genetic factors underlying susceptibility to this disease remain elusive. METHODS: To identify genetic variants in patients with NTM-PD, we performed a genome-wide association study with 403 Korean patients with NTM-PD and 306 healthy controls from the Healthy Twin Study, Korea cohort. Candidate variants from the discovery cohort were subsequently validated in an independent cohort. The Genotype-Tissue Expression (GTEx) database was used to identify expression quantitative trait loci (eQTL) and to conduct Mendelian randomisation (MR). RESULTS: We identified a putatively significant locus on chromosome 7p13, rs849177 (OR, 2.34; 95% CI, 1.71 to 3.21; p=1.36×10-7), as the candidate genetic variant associated with NTM-PD susceptibility. Its association was subsequently replicated and the combined p value was 4.92×10-8. The eQTL analysis showed that a risk allele at rs849177 was associated with lower expression levels of STK17A, a proapoptotic gene. In the MR analysis, a causal effect of STK17A on NTM-PD development was identified (ß, -4.627; 95% CI, -8.768 to -0.486; p=0.029). CONCLUSIONS: The 7p13 genetic variant might be associated with susceptibility to NTM-PD in the Korean population by altering the expression level of STK17A.
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Proteínas Reguladoras de Apoptose/genética , Cromossomos Humanos Par 7 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Infecções por Mycobacterium não Tuberculosas/genética , Proteínas Serina-Treonina Quinases/genética , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , República da CoreiaRESUMO
BACKGROUND: Transcriptomic profiles can improve our understanding of the phenotypic molecular basis of biological research, and many statistical methods have been proposed to identify differentially expressed genes (DEGs) under two or more conditions with RNA-seq data. However, statistical analyses with RNA-seq data are often limited by small sample sizes, and global variance estimates of RNA expression levels have been utilized as prior distributions for gene-specific variance estimates, making it difficult to generalize the methods to more complicated settings. We herein proposed a Bartlett-Adjusted Likelihood-based LInear mixed model approach (BALLI) to analyze more complicated RNA-seq data. The proposed method estimates the technical and biological variances with a linear mixed-effects model, with and without adjusting small sample bias using Bartlkett's corrections. RESULTS: We conducted extensive simulations to compare the performance of BALLI with those of existing approaches (edgeR, DESeq2, and voom). Results from the simulation studies showed that BALLI correctly controlled the type-1 error rates at various nominal significance levels and produced better statistical power and precision estimates than those of other competing methods in various scenarios. Furthermore, BALLI was robust to variation of library size. It was also successfully applied to Holstein milk yield data, illustrating its practical value. CONCLUSIONS;: BALLI is statistically more efficient and valid than existing methods, and we conclude that it is useful for identifying DEGs in RNA-seq analysis.
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Bovinos/genética , Biologia Computacional/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Modelos Lineares , Análise de Sequência de RNA/estatística & dados numéricos , Animais , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Funções Verossimilhança , Leite , Modelos Genéticos , Distribuição Aleatória , Tamanho da Amostra , Análise de Sequência de RNA/métodos , Software , TranscriptomaRESUMO
Motivation: Despite the need for separate tools to analyze family-based data, there are only a handful of tools optimized for family-based big data compared to the number of tools available for analyzing population-based data. Results: ONETOOL implements the properties of well-known existing family data analysis tools and recently developed methods in a computationally efficient manner, and so is suitable for analyzing the vast amount of variant data available from sequencing family members, providing a rich choice of analysis methods for big data on families. Availability and implementation: ONETOOL is freely available from http://healthstat.snu.ac.kr/software/onetool/. Supplementary information: Supplementary data are available at Bioinformatics online.
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Big Data , Bases de Dados Factuais , SoftwareRESUMO
An 85-year-old man was admitted with dysarthria. Electrocardiography showed atrial fibrillation and prominent ST-segment elevation in V2-V6. Multiple acute cerebral infarctions were observed in brain images. Coronary angiography showed total occlusion of the mid left anterior descending artery. After thrombus aspiration, no atherosclerotic changes were observed on intravascular ultrasound.
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RATIONALE: Electroconvulsive therapy (ECT) is an effective treatment modality for schizophrenia. However, its antipsychotic-like mechanism remains unclear. OBJECTIVES: To gain insight into the antipsychotic-like actions of ECT, this study investigated how repeated treatments of electroconvulsive seizure (ECS), an animal model for ECT, affect the behavioral and transcriptomic profile of a neurodevelopmental animal model of schizophrenia. METHODS: Two injections of MK-801 or saline were administered to rats on postnatal day 7 (PN7), and either repeated ECS treatments (E10X) or sham shock was conducted daily from PN50 to PN59. Ultimately, the rats were divided into vehicle/sham (V/S), MK-801/sham (M/S), vehicle/ECS (V/E), and MK-801/ECS (M/E) groups. On PN59, prepulse inhibition and locomotor activity were tested. Prefrontal cortex transcriptomes were analyzed with mRNA sequencing and network and pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) analyses were subsequently conducted. RESULTS: Prepulse inhibition deficit was induced by MK-801 and normalized by E10X. In M/S vs. M/E model, Egr1, Mmp9, and S100a6 were identified as center genes, and interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF) signaling pathways were identified as the three most relevant pathways. In the V/E vs. V/S model, mitophagy, NF-κB, and receptor for advanced glycation end products (RAGE) pathways were identified. qPCR analyses demonstrated that Igfbp6, Btf3, Cox6a2, and H2az1 were downregulated in M/S and upregulated in M/E. CONCLUSIONS: E10X reverses the behavioral changes induced by MK-801 and produces transcriptional changes in inflammatory, insulin, and mitophagy pathways, which provide mechanistic insight into the antipsychotic-like mechanism of ECT.
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Antipsicóticos , Eletroconvulsoterapia , Esquizofrenia , Ratos , Animais , Maleato de Dizocilpina/farmacologia , NF-kappa B , Esquizofrenia/induzido quimicamente , Esquizofrenia/terapia , Antipsicóticos/farmacologia , Convulsões/induzido quimicamente , Convulsões/metabolismoRESUMO
Data on the impact of arterial stiffness on autonomic function are limited. We sought to investigate whether heart rate recovery (HRR), a predictor of autonomic function, is impaired in patients with increased arterial stiffness. A total of 475 participants (mean age 55.8 ± 11.1 years, 34.3% women) who underwent a treadmill exercise test (TET) for the evaluation of chest pain were retrospectively analyzed. All patients underwent brachial-ankle pulse wave velocity (baPWV) measurement on the same day. HRR was defined as the difference in heart rate from maximal exercise to 1 min of recovery. Participants with the lowest HRR tertile were older and had more cardiovascular risk factors than those with the highest HRR tertile. Simple correlation analysis showed that baPWV was negatively correlated with HRR (r = - 0.327, P < 0.001). In multiple linear regression analysis, there was a significant association between baPWV and HRR, even after adjusting for potential confounders (ß = - 0.181, P < 0.001). In participants who underwent TET, baPWV was negatively correlated with HRR. The results of our study indicate a potential relationship between arterial stiffness and the autonomic nervous system.
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Doenças do Sistema Nervoso Autônomo , Rigidez Vascular , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Rigidez Vascular/fisiologia , Estudos Transversais , Índice Tornozelo-Braço , Teste de Esforço , Estudos Retrospectivos , Análise de Onda de Pulso , Fatores de RiscoRESUMO
Although depression is an emerging disorder affecting many people worldwide, most genetic studies have been performed in European descent populations. Herein, a genome-wide association study (GWAS) was conducted in Korean population to elucidate the genomic loci associated with depressive symptoms. Two independent cohorts were used as discovery datasets, which consisted of 6474 (1484 cases and 4990 controls) and 1654 (557 cases and 1097 controls) Korean participants, respectively. The participants were divided into case and control groups based on the Beck Depression Inventory (BDI). Meta-analysis using the two cohorts revealed that rs6945590 was significantly associated with the risk of depressive symptoms [P = 2.83 × 10-8; odds ratio (OR) = 1.23; 95% confidence interval (CI): 1.15-1.33]. This association was validated in other independent cohorts which were another Korean cohort (258 cases and 1757 controls) and the East Asian study of the Psychiatric Genomics Consortium (PGC) (12,455 cases and 85,548 controls). The predicted expression levels of thromboxane A synthase 1 gene (TBXAS1), which encodes the enzyme thromboxane A synthase 1 and participates in the arachidonic acid (AA) cascade, was significantly decreased in the whole blood tissues of the participants with depressive symptoms. Furthermore, Mendelian randomization (MR) analysis showed a causal association between TBXAS1 expression and the risk of depressive symptoms. In conclusion, as the number of risk alleles (A) of rs6945590 increased, TBXAS1 expression decreased, which subsequently caused an increase in the risk of depressive symptoms.
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Depressão , Estudo de Associação Genômica Ampla , Humanos , Depressão/genética , Predisposição Genética para Doença , Tromboxano-A Sintase/genética , República da Coreia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: In previous studies, several asthma phenotypes were identified using clinical and demographic parameters. Transcriptional phenotypes were mainly identified using sputum and bronchial cells. Objective: We aimed to investigate asthma phenotypes via clustering analysis using clinical variables and compare the transcription levels among clusters using gene expression profiling of the blood. Methods: Clustering analysis was performed using 6 parameters: age of asthma onset, body mass index, pack-years of smoking, forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity, and blood eosinophil counts. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and RNA was extracted from selected PBMCs. Transcriptional profiles were generated (Illumina NovaSeq 6000) and analyzed using the reference genome and gene annotation files (hg19.refGene.gft). Pathway enrichment analysis was conducted using GO, KEGG, and REACTOME databases. Results: In total, 355 patients with asthma were included in the analysis, of whom 72 (20.3%) had severe asthma. Clustering of the 6 parameters revealed 4 distinct subtypes. Cluster 1 (n = 63) had lower predicted FEV1 % and higher pack-years of smoking and neutrophils in sputum. Cluster 2 (n = 43) had a higher proportion and number of eosinophils in sputum and blood, and severe airflow limitation. Cluster 3 (n = 110) consisted of younger subjects with atopic features. Cluster 4 (n = 139) included features of late-onset mild asthma. Differentially expressed genes between clusters 1 and 2 were related to inflammatory responses and cell activation. Th17 cell differentiation and interferon gamma-mediated signaling pathways were related to neutrophilic inflammation in asthma. Conclusion: Four clinical clusters were differentiated based on clinical parameters and blood eosinophils in adult patients with asthma form the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) cohort. Gene expression profiling and molecular pathways are novel means of classifying asthma phenotypes.
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Adherence to lifestyle recommendations is crucial in managing hypertension, independent of medical treatment. This study aimed to evaluate the implementation of adherence to lifestyle recommendations and analyze the trends in adherence to lifestyle recommendations among patients with hypertension in Korea from 2007 to 2021 using the Korea National Health and Nutrition Examination Survey (KNHANES). The study included adults aged ≥20 years. Factors such as regular physical activity, smoking and alcohol abstinence, weight and stress management, and adherence to a healthy diet were analyzed. In 2021, A doublefold increase was observed in the proportion of patients with hypertension who adhered to sodium restriction compared to 2007. However, 70% of patients with hypertension consume more sodium than recommended. Moreover, potassium intake has steadily decreased since 2014, with only 23.8% of patients with hypertension meeting the recommended intake. The body mass index (BMI) and waist circumference of patients with hypertension have gradually increased, with fewer patients maintaining an appropriate weight. The neglect of diet and weight control among young patients with hypertension who experience high stress levels poses challenges in modifying their lifestyles. Patients with hypertension in Korea still consume high amounts of sodium, whereas potassium intake is gradually decreasing. Additionally, obesity rates have been increasing, especially among young patients with hypertension. A multidisciplinary approach is necessary for improving the lifestyle habits of hypertensive patients.
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Conflicting findings have been reported regarding the association between Agent Orange (AO) exposure and type 2 diabetes. This study aimed to examine whether AO exposure is associated with the development of type 2 diabetes and to verify the causal relationship between AO exposure and type 2 diabetes by combining DNA methylation with DNA genotype analyses. An epigenome-wide association study and DNA genotype analyses of the blood of AO-exposed and AO-unexposed individuals with type 2 diabetes and that of healthy controls were performed. Methylation quantitative trait locus and Mendelian randomisation analyses were performed to evaluate the causal effect of AO-exposure-identified CpGs on type 2 diabetes. AO-exposed individuals with type 2 diabetes were associated with six hypermethylated CpG sites (cg20075319, cg21757266, cg05203217, cg20102280, cg26081717, and cg21878650) and one hypo-methylated CpG site (cg07553761). Methylation quantitative trait locus analysis showed the methylation levels of some CpG sites (cg20075319, cg20102280, and cg26081717) to be significantly different. Mendelian randomisation analysis showed that CpG sites that were differentially methylated in AO-exposed individuals were causally associated with type 2 diabetes; the reverse causal effect was not significant. These findings reflect the need for further epigenetic studies on the causal relationship between AO exposure and type 2 diabetes.
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Agente Laranja , Metilação de DNA , Diabetes Mellitus Tipo 2 , Epigênese Genética , Veteranos , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Masculino , República da Coreia/epidemiologia , Pessoa de Meia-Idade , Ilhas de CpG , Feminino , Estudo de Associação Genômica Ampla , Idoso , Locos de Características Quantitativas , Análise da Randomização Mendeliana , Estudos de Casos e ControlesRESUMO
Despite previous efforts to build statistical models for predicting the risk of suicidal behavior using machine-learning analysis, a high-accuracy model can lead to overfitting. Furthermore, internal validation cannot completely address this problem. In this study, we created models for predicting the occurrence of suicide attempts among Koreans at high risk of suicide, and we verified these models in an independent cohort. We performed logistic and penalized regression for suicide attempts within 6 months among suicidal ideators and attempters in The Korean Cohort for the Model Predicting a Suicide and Suicide-related Behavior (K-COMPASS). We then validated the models in a test cohort. Our findings indicated that several factors significantly predicted suicide attempts in the models, including young age, suicidal ideation, previous suicidal attempts, anxiety, alcohol abuse, stress, and impulsivity. The area under the curve and positive predictive values were 0.941 and 0.484 after variable selection and 0.751 and 0.084 in the test cohort. The corresponding values for the penalized regression model were 0.943 and 0.524 in the original training cohort and 0.794 and 0.115 in the test cohort. The prediction model constructed through a prospective cohort study of the suicide high-risk group showed satisfactory accuracy even in the test cohort. The accuracy with penalized regression was greater than that with the "classical" logistic model.
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Aprendizado de Máquina , Ideação Suicida , Tentativa de Suicídio , Humanos , Tentativa de Suicídio/estatística & dados numéricos , Masculino , Feminino , República da Coreia/epidemiologia , Adulto , Adulto Jovem , Estudos Prospectivos , Modelos Logísticos , Pessoa de Meia-Idade , Adolescente , Fatores de RiscoRESUMO
BACKGROUND: More than 200 asthma-associated genetic variants have been identified in genome-wide association studies (GWASs). Expression quantitative trait loci (eQTL) data resources can help identify causal genes of the GWAS signals, but it can be difficult to find an eQTL that reflects the disease state because most eQTL data are obtained from normal healthy subjects. METHODS: We performed a blood eQTL analysis using transcriptomic and genotypic data from 433 Korean asthma patients. To identify asthma-related genes, we carried out colocalization, Summary-based Mendelian Randomization (SMR) analysis, and Transcriptome-Wide Association Study (TWAS) using the results of asthma GWASs and eQTL data. In addition, we compared the results of disease eQTL data and asthma-related genes with two normal blood eQTL data from Genotype-Tissue Expression (GTEx) project and a Japanese study. RESULTS: We identified 340,274 cis-eQTL and 2,875 eGenes from asthmatic eQTL analysis. We compared the disease eQTL results with GTEx and a Japanese study and found that 64.1% of the 2,875 eGenes overlapped with the GTEx eGenes and 39.0% with the Japanese eGenes. Following the integrated analysis of the asthmatic eQTL data with asthma GWASs, using colocalization and SMR methods, we identified 15 asthma-related genes specific to the Korean asthmatic eQTL data. CONCLUSIONS: We provided Korean asthmatic cis-eQTL data and identified asthma-related genes by integrating them with GWAS data. In addition, we suggested these asthma-related genes as therapeutic targets for asthma. We envisage that our findings will contribute to understanding the etiological mechanisms of asthma and provide novel therapeutic targets.
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Asma , Estudo de Associação Genômica Ampla , Humanos , Estudo de Associação Genômica Ampla/métodos , Predisposição Genética para Doença , Asma/genética , Perfilação da Expressão Gênica , República da Coreia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Established genetic risk factors for Alzheimer's disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10-9) and hippocampal volume (p = 5.1 × 10-12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-ß accumulation (p = 0.03) and measures of memory (p = 1.0 × 10-4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer's Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10-6) and AddNeuroMed (rs138412600, p = 5.9 × 10-5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Estudo de Associação Genômica Ampla , Humanos , Imageamento por Ressonância Magnética , Proteínas do Tecido Nervoso , UbiquitinasRESUMO
Previous studies have focused on only 1 or 2 echocardiographic parameters as prognostic markers in patients with acute ischemic stroke (AIS). A total of 900 patients with AIS who underwent transthoracic echocardiography (72.6 ± 12.0 years and 60% males) were retrospectively reviewed. Composite clinical events, including all-cause mortality, non-fatal stroke, non-fatal myocardial infarction, and coronary revascularization, were assessed during clinical follow-ups. During a median follow-up of 3.3 years (interquartile range 0.6-5.1 years), there were 151 (16.8%) composite events. In the multivariable analyses after controlling for potential confounders, left ventricular ejection fraction (LVEF) < 62% (hazard ratio [HR] 1.62; 95% confidence interval [CI] 1.14-2.30; p = 0.007) and AV sclerosis (AVs) (HR 1.56; 95% CI 1.10-2.21; p = 0.013) were independent prognostic factors associated with composite events. Multivariable analyses showed that HR for composite events gradually increased according to LVEF and AVs: HR was 2.6-fold higher in the highest-risk group than in the lowest group (p < 0.001). Compared with a clinical model (global chi-square = 69.6), LVEF, AVs, and both of them were significantly improved outcome prediction in sequential Cox model analysis (global chi-square = 75.6, 75.7, and 78.8, respectively; p < 0.05 for each) for each. In patients with AIS, LVEF < 62%, and the presence of AV sclerosis can predict future vascular events. Patients with AIS exhibiting reduced LVEF and AV sclerosis may benefit from aggressive secondary prevention.
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Valva Aórtica/diagnóstico por imagem , Isquemia Encefálica/terapia , Ecocardiografia Doppler em Cores , Doenças das Valvas Cardíacas/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/fisiopatologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/mortalidade , Causas de Morte , Feminino , Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/fisiopatologia , Doenças das Valvas Cardíacas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Esclerose , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/mortalidade , Volume Sistólico , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia , Função Ventricular EsquerdaRESUMO
Genome-wide association studies of gastric cancer (GC) cases have revealed common gastric cancer susceptibility loci with low effect size. We investigated rare variants with high effect size via whole-exome sequencing (WES) of subjects with familial clustering of gastric cancer. WES of DNAs from the blood of 19 gastric cancer patients and 36 unaffected family members from 14 families with two or more gastric cancer patients were tested. Linkage analysis combined with association tests were performed using Pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) software. Based on the logarithm of odds (LOD) and permutation-based composite likelihood ratio test (CLRT) from pVAAST, MUC4 was identified as a predisposing gene (LOD P-value = 1.9×10-5; permutation-based P-value of CLRT ≤ 9.9×10-9). In a larger cohort consisting of 597 GC patients and 9,759 healthy controls genotyped with SNP array, we discovered common variants in MUC4 regions (rs148735556, rs11717039, and rs547775645) significantly associated with GC supporting the association of MUC4 with gastric cancer. And the MUC4 variants were found in higher frequency in The Cancer Genome Atlas Study (TCGA) germline samples of patients with multiple cancer types. Immunohistochemistry indicated that MUC4 was downregulated in the noncancerous gastric mucosa of subjects with MUC4 germline missense variants, suggesting that loss of the protective function of MUC4 predisposes an individual to gastric cancer. Rare variants in MUC4 can be novel gastric cancer susceptibility loci in Koreans possessing the familial clustering of gastric cancer.