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1.
Arthritis Res Ther ; 23(1): 284, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34782006

RESUMO

BACKGROUND: This study aimed to classify the distinct group of patients with axial spondyloarthritis (SpA) on tumour necrosis factor alpha inhibitors (TNFi) according to the baseline characteristics using a clustering algorithm. METHODS: The clinical characteristics and demographic data of patients with axial SpA included in the Korean College of Rheumatology Biologics and Targeted Therapy registry were investigated. The patterns of disease manifestations were examined using divisive hierarchical cluster analysis. After clustering, we compared the clinical characteristics of patients and the drug survival of TNFi between the classified groups. RESULTS: A total of 1042 patients were analysed. The cluster analysis classified patients into two groups: axial group predominantly showing isolated axial manifestations (n = 828) and extra-axial group more frequently showing extra-axial symptoms (n = 214). Almost all extra-axial symptoms (peripheral arthritis, enthesitis, uveitis, and psoriasis) were more frequently observed in the extra-axial group than in the axial group. Moreover, patients in the extra-axial group had shorter disease duration, later disease onset, and higher disease activity than those in the axial group. The disease activity was comparable between the two groups after 1 year of treatment with TNFi. Interestingly, the extra-axial group had a lower drug survival with TNFi than the axial group (p = 0.001). CONCLUSIONS: Cluster analysis of patients with axial SpA using TNFi classified two distinct clinical phenotypes. These clusters had different TNFi drug survival, clinical characteristics, and disease activity.

2.
Brain ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613391

RESUMO

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 (GWAS) 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 GWAS 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, unassociated 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 (SNP)-based heritability was estimated to be 8.5% (s.e. = 0.004) and partitioned heritability was enriched in the central nervous system 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 (MR) analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease (OR = 0.78, 95% CI = 0.65-0.92 in inverse variance weighted (IVW) method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median (WM) method). This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic SNPs (OR = 0.72, 95% CI = 0.57-0.91 in the IVW method; OR = 0.72, 95% CI = 0.53-0.97 in the WM method). Multivariable MR 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 IVW method; OR = 0.68, 95% CI = 0.48-0.97 in the WM 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.

3.
J Invest Dermatol ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34648798

RESUMO

Human skin color is largely determined by genetic factors. Recent genome-wide association studies (GWAS) have reported several genetic variants associated with skin color, mostly in European and African populations. In this study, we performed GWAS in 17,019 Korean women to identify genetic variants associated with facial skin color, quantitatively measured as CIELAB color index. We identified variants in three, one, and six genomic loci associated with facial skin color index L*, a*, and b* values, respectively, and replicated the associations (combined analysis P-value < 5.0 × 10-8). The significant loci included variants in known genes (OCA2 rs74653330, BNC2 rs16935073, rs72620727 near KITLG, and SLC6A17 rs6689641) and to our knowledge previously unreported genes (SCARB1 rs10846744, SYN2 rs12629034, and LINC00486 rs6543678). This is GWAS to elucidate genetic variants of facial skin color in a Korean female population. Further functional characterizations of the investigated genes are warranted to elucidate their contribution to skin pigmentation-related traits.

4.
Arthritis Res Ther ; 23(1): 254, 2021 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-34627335

RESUMO

BACKGROUND: Few studies on rheumatoid arthritis (RA) have generated machine learning models to predict biologic disease-modifying antirheumatic drugs (bDMARDs) responses; however, these studies included insufficient analysis on important features. Moreover, machine learning is yet to be used to predict bDMARD responses in ankylosing spondylitis (AS). Thus, in this study, machine learning was used to predict such responses in RA and AS patients. METHODS: Data were retrieved from the Korean College of Rheumatology Biologics therapy (KOBIO) registry. The number of RA and AS patients in the training dataset were 625 and 611, respectively. We prepared independent test datasets that did not participate in any process of generating machine learning models. Baseline clinical characteristics were used as input features. Responders were defined as those who met the ACR 20% improvement response criteria (ACR20) and ASAS 20% improvement response criteria (ASAS20) in RA and AS, respectively, at the first follow-up. Multiple machine learning methods, including random forest (RF-method), were used to generate models to predict bDMARD responses, and we compared them with the logistic regression model. RESULTS: The RF-method model had superior prediction performance to logistic regression model (accuracy: 0.726 [95% confidence interval (CI): 0.725-0.730] vs. 0.689 [0.606-0.717], area under curve (AUC) of the receiver operating characteristic curve (ROC) 0.638 [0.576-0.658] vs. 0.565 [0.493-0.605], F1 score 0.841 [0.837-0.843] vs. 0.803 [0.732-0.828], AUC of the precision-recall curve 0.808 [0.763-0.829] vs. 0.754 [0.714-0.789]) with independent test datasets in patients with RA. However, machine learning and logistic regression exhibited similar prediction performance in AS patients. Furthermore, the patient self-reporting scales, which are patient global assessment of disease activity (PtGA) in RA and Bath Ankylosing Spondylitis Functional Index (BASFI) in AS, were revealed as the most important features in both diseases. CONCLUSIONS: RF-method exhibited superior prediction performance for responses of bDMARDs to a conventional statistical method, i.e., logistic regression, in RA patients. In contrast, despite the comparable size of the dataset, machine learning did not outperform in AS patients. The most important features of both diseases, according to feature importance analysis were patient self-reporting scales.


Assuntos
Antirreumáticos , Artrite Reumatoide , Reumatologia , Espondilite Anquilosante , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Humanos , Aprendizado de Máquina , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológico
5.
Circ Genom Precis Med ; 14(5): e003399, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34592835

RESUMO

BACKGROUND: Corin is a protease expressed in cardiomyocytes that plays a key role in salt handling and intravascular volume homeostasis via activation of natriuretic peptides. It is unknown if Corin loss-of-function (LOF) is causally associated with risk of coronary artery disease (CAD). METHODS: We analyzed all coding CORIN variants in an Italian case-control study of CAD. We functionally tested all 64 rare missense mutations in Western Blot and Mass Spectroscopy assays for proatrial natriuretic peptide cleavage. An expanded rare variant association analysis for Corin LOF mutations was conducted in whole exome sequencing data from 37 799 CAD cases and 212 184 controls. RESULTS: We observed LOF variants in CORIN in 8 of 1803 (0.4%) CAD cases versus 0 of 1725 controls (P, 0.007). Of 64 rare missense variants profiled, 21 (33%) demonstrated <30% of wild-type activity and were deemed damaging in the 2 functional assays for Corin activity. In a rare variant association study that aggregated rare LOF and functionally validated damaging missense variants from the Italian study, we observed no association with CAD-21 of 1803 CAD cases versus 12 of 1725 controls with adjusted odds ratio of 1.61 ([95% CI, 0.79-3.29]; P=0.17). In the expanded sequencing dataset, there was no relationship between rare LOF variants with CAD was also observed (odds ratio, 1.15 [95% CI, 0.89-1.49]; P=0.30). Consistent with the genetic analysis, we observed no relationship between circulating Corin concentrations with incident CAD events among 4744 participants of a prospective cohort study-sex-stratified hazard ratio per SD increment of 0.96 ([95% CI, 0.87-1.07], P=0.48). CONCLUSIONS: Functional testing of missense mutations improved the accuracy of rare variant association analysis. Despite compelling pathophysiology and a preliminary observation suggesting association, we observed no relationship between rare damaging variants in CORIN or circulating Corin concentrations with risk of CAD.

6.
Brain Sci ; 11(8)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439661

RESUMO

Background and objectives: Parkinson's disease (PD) and schizophrenia often share symptomatology. Psychotic symptoms are prevalent in patients with PD, and similar motor symptoms with extrapyramidal signs are frequently observed in antipsychotic-naïve patients with schizophrenia as well as premorbid families. However, few studies have examined the relationship between PD and schizophrenia. We performed this study to evaluate whether genetic variants which increase PD risk influence the risk of developing schizophrenia, and vice versa. Materials and Methods: Two-sample Mendelian randomization (TSMR) with summary statistics from large-scale genome-wide association studies (GWAS) was applied. Summary statistics were extracted for these instruments from GWAS of PD and schizophrenia; Results: We found an increase in the risk of schizophrenia per one-standard deviation (SD) increase in the genetically-predicted PD risk (inverse-variance weighted method, odds ratio = 1.10; 95% confidence interval, 1.05-1.15; p = 3.49 × 10-5). The association was consistent in sensitivity analyses, including multiple TSMR methods, analysis after removing outlier variants with potential pleiotropic effects, and analysis after applying multiple GWAS subthresholds. No relationships were evident between PD and smoking or other psychiatric disorders, including attention deficit hyperactivity disorder, autism spectrum disorder, bipolar affective disorder, major depressive disorder, Alzheimer's disease, or alcohol dependence. However, we did not find a reverse relationship; genetic variants increasing schizophrenia risk did not alter the risk of PD; Conclusions: Overall, our findings suggest that increased genetic risk of PD can be associated with increased risk of schizophrenia. This association supports the intrinsic nature of the psychotic symptom in PD rather than medication or environmental effects. Future studies for possible comorbidities and shared genetic structure between the two diseases are warranted.

7.
Eur Heart J ; 42(34): 3388-3403, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34333589

RESUMO

AIMS: The aim of this study was to investigate the causal relationship and evidence of an association between increased adiposity and the risk of incident cardiovascular disease (CVD) events or mortality. METHODS AND RESULTS: Observational (informing association) and Mendelian randomization (MR) (informing causality) studies were assessed to gather mutually complementary insights and elucidate perplexing epidemiological relationships. Systematic reviews and meta-analyses of observational and MR studies that were published until January 2021 and evaluated the association between obesity-related indices and CVD risk were searched. Twelve systematic reviews with 53 meta-analyses results (including over 501 cohort studies) and 12 MR studies were included in the analysis. A body mass index (BMI) increase was associated with higher risks of coronary heart disease, heart failure, atrial fibrillation, all-cause stroke, haemorrhagic stroke, ischaemic stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thrombo-embolism. The MR study results demonstrated a causal effect of obesity on all indices but stroke. The CVD risk increase for every 5 kg/m2 increase in BMI varied from 10% [relative risk (RR) 1.10; 95% confidence interval (CI) 1.01-1.21; certainty of evidence, low] for haemorrhagic stroke to 49% (RR 1.49; 95% CI 1.40-1.60; certainty of evidence, high) for hypertension. The all-cause and CVD-specific mortality risks increased with adiposity in cohorts, but the MR studies demonstrated no causal effect of adiposity on all-cause mortality. CONCLUSION: High adiposity is associated with increased CVD risk despite divergent evidence gradients. Adiposity was a causal risk factor for CVD except all-cause mortality and stroke. Half (49%; 26/53) of the associations were supported by high-level evidence. The associations were consistent between sexes and across global regions. This study provides guidance on how to integrate evidence from observational (association) and genetics-driven (causation) studies accumulated to date, to enable a more reliable interpretation of epidemiological relationships.


Assuntos
Isquemia Encefálica , Doenças Cardiovasculares , Acidente Vascular Cerebral , Adiposidade , Doenças Cardiovasculares/epidemiologia , Humanos , Análise da Randomização Mendeliana , Obesidade/complicações , Obesidade/epidemiologia , Estudos Observacionais como Assunto , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia
8.
NPJ Breast Cancer ; 7(1): 93, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272397

RESUMO

Metastasis is the major cause of death in breast cancer patients. Although previous large-scale analyses have identified frequently altered genes specific to metastatic breast cancer (MBC) compared with those in primary breast cancer (PBC), metastatic site-specific altered genes in MBC remain largely uncharacterized. Moreover, large-scale analyses are required owing to the low expected frequency of such alterations, likely caused by tumor heterogeneity and late dissemination of breast cancer. To clarify MBC-specific genetic alterations, we integrated publicly available clinical and mutation data of 261 genes, including MBC drivers, from 4268 MBC and 5217 PBC patients from eight different cohorts. We performed meta-analyses and logistic regression analyses to identify MBC-enriched genetic alterations relative to those in PBC across 15 different metastatic site sets. We identified 11 genes that were more frequently altered in MBC samples from pan-metastatic sites, including four genes (SMARCA4, TSC2, ATRX, and AURKA) which were not identified previously. ARID2 mutations were enriched in treatment-naïve de novo and post-treatment MBC samples, compared with that in treatment-naïve PBC samples. In metastatic site-specific analyses, associations of ESR1 with liver metastasis and RICTOR with bone metastasis were significant, regardless of intrinsic subtypes. Among the 15 metastatic site sets, ESR1 mutations were enriched in the liver and depleted in the lymph nodes, whereas TP53 mutations showed an opposite trend. Seven potential MBC driver mutations showed similar preferential enrichment in specific metastatic sites. This large-scale study identified new MBC genetic alterations according to various metastatic sites and highlights their potential role in breast cancer organotropism.

9.
Br J Sports Med ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34301715

RESUMO

PURPOSE: To determine the potential associations between physical activity and risk of SARS-CoV-2 infection, severe illness from COVID-19 and COVID-19 related death using a nationwide cohort from South Korea. METHODS: Data regarding 212 768 Korean adults (age ≥20 years), who tested for SARS-CoV-2, from 1 January 2020 to 30 May 2020, were obtained from the National Health Insurance Service of South Korea and further linked with the national general health examination from 1 January 2018 to 31 December 2019 to assess physical activity levels. SARS-CoV-2 positivity, severe COVID-19 illness and COVID-19 related death were the main outcomes. The observation period was between 1 January 2020 and 31 July 2020. RESULTS: Out of 76 395 participants who completed the general health examination and were tested for SARS-CoV-2, 2295 (3.0%) were positive for SARS-CoV-2, 446 (0.58%) had severe illness from COVID-19 and 45 (0.059%) died from COVID-19. Adults who engaged in both aerobic and muscle strengthening activities according to the 2018 physical activity guidelines had a lower risk of SARS-CoV-2 infection (2.6% vs 3.1%; adjusted relative risk (aRR), 0.85; 95% CI 0.72 to 0.96), severe COVID-19 illness (0.35% vs 0.66%; aRR 0.42; 95% CI 0.19 to 0.91) and COVID-19 related death (0.02% vs 0.08%; aRR 0.24; 95% CI 0.05 to 0.99) than those who engaged in insufficient aerobic and muscle strengthening activities. Furthermore, the recommended range of metabolic equivalent task (MET; 500-1000 MET min/week) was associated with the maximum beneficial effect size for reduced risk of SARS-CoV-2 infection (aRR 0.78; 95% CI 0.66 to 0.92), severe COVID-19 illness (aRR 0.62; 95% CI 0.43 to 0.90) and COVID-19 related death (aRR 0.17; 95% CI 0.07 to 0.98). Similar patterns of association were observed in different sensitivity analyses. CONCLUSION: Adults who engaged in the recommended levels of physical activity were associated with a decreased likelihood of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 related death. Our findings suggest that engaging in physical activity has substantial public health value and demonstrates potential benefits to combat COVID-19.

10.
Lancet Rheumatol ; 3(10): e698-e706, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34179832

RESUMO

Background: Real-world evidence on the association between autoimmune inflammatory rheumatic diseases, therapies related to these diseases, and COVID-19 outcomes are inconsistent. We aimed to investigate the potential association between autoimmune inflammatory rheumatic diseases and COVID-19 early in the COVID-19 pandemic. Methods: We did an exposure-driven, propensity score-matched study using a South Korean nationwide cohort linked to general health examination records. We analysed all South Korean patients aged older than 20 years who underwent SARS-CoV-2 RT-PCR testing between Jan 1 and May 30, 2020, and received general health examination results from the Korean National Health Insurance Service. We defined autoimmune inflammatory rheumatic diseases (inflammatory arthritis and connective tissue diseases) based on the relevant ICD-10 codes, with at least two claims (outpatient or inpatient) within 1 year. The outcomes were positive SARS-CoV-2 RT-PCR test, severe COVID-19 (requirement of oxygen therapy, intensive care unit admission, application of invasive ventilation, or death), and COVID-19-related death. Adjusted odds ratios (ORs) with 95% CIs were estimated after adjusting for the potential confounders. Findings: Between Jan 1 and May 30, 2020, 133 609 patients (70 050 [52·4%] female and 63 559 [47·6%] male) completed the general health examination and were tested for SARS-CoV-2; 4365 (3·3%) were positive for SARS-CoV-2, and 8297 (6·2%) were diagnosed with autoimmune inflammatory rheumatic diseases. After matching, patients with an autoimmune inflammatory rheumatic disease showed an increased likelihood of testing positive for SARS-CoV-2 (adjusted OR 1·19, 95% CI 1·03-1·40; p=0·026), severe COVID-19 outcomes (1·26, 1·02-1·59; p=0·041), and COVID-19-related death (1·69, 1·01-2·84; p=0·046). Similar results were observed in patients with connective tissue disease and inflammatory arthritis. Treatment with any dose of systemic corticosteroids or disease-modifying antirheumatic drugs (DMARDs) were not associated with COVID-19-related outcomes, but those receiving high dose (≥10 mg per day) of systemic corticosteroids had an increased likelihood of a positive SARS-CoV-2 test (adjusted OR 1·47, 95% CI 1·05-2·03; p=0·022), severe COVID-19 outcomes (1·76, 1·06-2·96; p=0·031), and COVID-19-related death (3·34, 1·23-8·90; p=0·017). Interpretation: Early in the COVID-19 pandemic, autoimmune inflammatory rheumatic diseases were associated with an increased likelihood of a positive SARS-CoV-2 PCR test, worse clinical outcomes of COVID-19, and COVID-19-related deaths in South Korea. A high dose of systemic corticosteroid, but not DMARDs, showed an adverse effect on SARS-CoV-2 infection and COVID-19-related clinical outcomes. Funding: National Research Foundation of Korea.

11.
Alzheimers Res Ther ; 13(1): 117, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154648

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer's disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid ß (Aß) positivity using a large sample of Korean population. METHODS: One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aß positivity (measured by amyloid positron emission tomography). Aß prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. RESULTS: In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aß positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aß positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10-8). Prediction performance for Aß positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74-0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. CONCLUSION: The novel genetic variants associated with FGL2 decreased risk of Aß positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.


Assuntos
Doença de Alzheimer , Estudo de Associação Genômica Ampla , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Fibrinogênio , Humanos , Tomografia por Emissão de Pósitrons , República da Coreia
12.
Sci Rep ; 11(1): 13180, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162918

RESUMO

Previous studies suggested that genetic, environmental factors and their interactions could affect body fat mass (BFM). However, studies describing these effects were performed at a single time point in a population. In this study, we investigated the interaction between genetic and environmental factors in affecting BFM and implicate the healthcare utilization of lifestyle modifications from a personalized and genomic perspective. We examined how nutritional intake or physical activity changes in the individuals affect BFM concerning the genetic composition. We conducted an observational study including 259 adult participants with single nucleotide polymorphism (SNP) genotyping and longitudinal lifestyle monitoring, including food consumption and physical activities, by following lifestyle modification guidance. The participants' lifelog data on exercise and diet were collected through a wearable device for 3 months. Moreover, we measured anthropometric and serologic markers to monitor their potential changes through lifestyle modification. We examined the influence of genetic composition on body fat reduction induced by lifestyle changes using genetic risk scores (GRSs) of three phenotypes: GRS-carbohydrate (GRS-C), GRS-fat (GRS-F), and GRS-exercise (GRS-E). Our results showed that lifestyle modifications affected BFM more significantly in the high GRS class compared to the low GRS class, indicating the role of genetic factors affecting the efficiency of the lifestyle modification-induced BFM changes. Interestingly, the influence of exercise modification in the low GRS class with active lifestyle change was lower than that in the high GRS class with inactive lifestyle change (P = 0.022), suggesting the implication of genetic factors for efficient body fat control.


Assuntos
Tecido Adiposo/fisiologia , Interação Gene-Ambiente , Estilo de Vida , Adulto , Idoso , Antropometria , Composição Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Registros de Dieta , Dieta com Restrição de Carboidratos , Dieta com Restrição de Gorduras , Ingestão de Energia , Exercício Físico , Terapia por Exercício , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Aplicativos Móveis , Obesidade/sangue , Obesidade/fisiopatologia , Obesidade/terapia , Sobrepeso/sangue , Sobrepeso/fisiopatologia , Sobrepeso/terapia , Fenótipo , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Adulto Jovem
13.
Hum Mutat ; 42(8): 969-977, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34005834

RESUMO

Biobanks with exomes linked to electronic health records (EHRs) enable the study of genetic pleiotropy between rare variants and seemingly disparate diseases. We performed robust clinical phenotyping of rare, putatively deleterious variants (loss-of-function [LoF] and deleterious missense variants) in ERCC6, a gene implicated in inherited retinal disease. We analyzed 213,084 exomes, along with a targeted set of retinal, cardiac, and immune phenotypes from two large-scale EHR-linked biobanks. In the primary analysis, a burden of deleterious variants in ERCC6 was strongly associated with (1) retinal disorders; (2) cardiac and electrocardiogram perturbations; and (3) immunodeficiency and decreased immunoglobulin levels. Meta-analysis of results from the BioMe Biobank and UK Biobank showed a significant association of deleterious ERCC6 burden with retinal dystrophy (odds ratio [OR] = 2.6, 95% confidence interval [CI]: 1.5-4.6; p = 8.7 × 10-4 ), atypical atrial flutter (OR = 3.5, 95% CI: 1.9-6.5; p = 6.2 × 10-5 ), arrhythmia (OR = 1.5, 95% CI: 1.2-2.0; p = 2.7 × 10-3 ), and lymphocyte immunodeficiency (OR = 3.8, 95% CI: 2.1-6.8; p = 5.0 × 10-6 ). Carriers of ERCC6 LoF variants who lacked a diagnosis of these conditions exhibited increased symptoms, indicating underdiagnosis. These results reveal a unique genetic link among retinal, cardiac, and immune disorders and underscore the value of EHR-linked biobanks in assessing the full clinical profile of carriers of rare variants.

14.
Nat Genet ; 53(6): 817-829, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34002096

RESUMO

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.


Assuntos
Transtorno Bipolar/genética , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Cromossomos Humanos/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Complexo Principal de Histocompatibilidade/genética , Herança Multifatorial/genética , Fenótipo , Locos de Características Quantitativas/genética , Fatores de Risco
15.
Cancers (Basel) ; 13(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800037

RESUMO

Although computed tomography (CT) scans are very useful for identification or surveillance of malignancy, they are also associated with the risk of cancer caused by ionizing radiation. We investigated the risk of second primary malignancies (SPMs) after frequent abdominopelvic CT scans in a cohort of Korean patients with early gastric cancer (EGC). We performed a cohort study of 11,072 patients who underwent resection for EGC at Samsung Medical Center and validated the results using data from 7908 patients in a Korean National Health Insurance Service cohort. Cox proportional hazards regression model was used to estimate hazard ratios (HRs) for intra-abdominal SPM. During 43,766.5 person-years of the follow-up at our center, 322 patients developed intra-abdominal SPMs. Patients who underwent receiving >8 abdominopelvic CT scans had a significantly greater risk of developing SPM (HR, 2.73; 95% CI, 1.66-4.50; p < 0.001) than those who had with ≤8 scans. For each additional abdominopelvic CT scan, the adjusted HR for SPM was 1.09 (95% confidence interval (CI), 1.03-1.14). Similar results were observed in the Korean National Health Insurance Service cohort (adjusted HR, 1.14; 95% CI, 1.07-1.22). Significantly elevated risk of SPM was still observed when considering a 2-year latency period (adjusted HR, 2.43; 95% CI, 1.37-4.48) and a 3-year latency period (adjusted HR, 2.17; 95% CI, 1.06-4.47). Frequent abdominopelvic CT scans are associated with an elevated risk of SPMs after the treatment of EGC. Thus, physicians need to weigh carefully the clinical benefits of CT examinations against the potential risks of radiation exposure.

16.
J Alzheimers Dis ; 80(3): 1197-1207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33646147

RESUMO

BACKGROUND: Whether the epidemiological association of amyloid-ß (Aß) and tau pathology in late-onset Alzheimer's disease (LOAD) is causal remains unclear. OBJECTIVE: We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aß and tau pathology and the risk of LOAD. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aß1-42 [Aß], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. RESULTS: We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aß (odds ratio [OR], 2.87×10-3 for AD; 95%confidence interval [CI], 1.54×10-4-0.05; p = 8.91×10-5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50-2.52×102; p = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57-7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). CONCLUSION: We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aß and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Fatores de Risco
17.
Cell Death Dis ; 12(4): 290, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731671

RESUMO

Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy. We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. Since LINC00263 was mainly localized in the cytosol and highly enriched in Argonaute 2-immunoprecipitation (Ago2-IP), we hypothesized that LINC00263 acts as a competitive endogenous RNA (ceRNA), and thus sought to identify LINC00263-associated microRNAs. Using small RNA sequencing followed by antisense oligonucleotide pull-down, miR-147a was selected for further study. We found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3'UTR of CAPN2 mRNA. In addition, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression. Furthermore, our findings were validated in various other types of cancer cells including lung cancer, colorectal cancer, neuroblastoma, and melanoma. Collectively, we demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , MicroRNAs/metabolismo , Oncogenes/genética , Células HeLa , Humanos , Fenótipo , Transfecção
18.
Eur Respir J ; 58(2)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33542050

RESUMO

RATIONALE: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. OBJECTIVES: We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. METHODS: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. RESULTS: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.


Assuntos
Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Infecção por Mycobacterium avium-intracellulare , Estudo de Associação Genômica Ampla , Humanos , Infecções por Mycobacterium não Tuberculosas/genética , Complexo Mycobacterium avium , Micobactérias não Tuberculosas
19.
J Alzheimers Dis ; 80(1): 197-207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523000

RESUMO

BACKGROUND: While atypical antipsychotic medications are widely used for treating depressive disorders, their long-term effects on the risk of subsequent dementia have not been studied adequately. OBJECTIVE: To investigate whether the risk of dementia differs according to the use of atypical antipsychotic drugs, and compare the effects of antipsychotic agents on dementia risk in individuals with late-life depressive disorders. METHODS: A nationwide population-based retrospective cohort study was conducted using data from the National Health Insurance Service-Senior Cohort of South Korea. Atypical antipsychotic dosages were standardized using a defined daily dose, and the cumulative dosage was calculated. Participants were observed from January 2008 to December 2015. Cox proportional hazard regression analysis was used to estimate the hazard ratios. RESULTS: The cohort included 43,788 elderly adults with depressive disorders: 9,901 participants (22.6%) were diagnosed with dementia. Findings showed that atypical antipsychotics were prescribed to 1,967 participants (4.5%). Compared with non-users, users of atypical antipsychotics experienced a significantly higher risk for dementia with an adjusted hazard ratio (aHR) of 1.541 (95% confidence interval [CI], 1.415-1.678). A cumulative dose-response relationship was observed (test for trend, p < 0.0001). Among atypical antipsychotics, risperidone displayed the highest risk for dementia (aHR 1.767, [95% CI, 1.555-2.009]). CONCLUSION: In this study of elderly individuals with depressive disorders, atypical antipsychotic use was associated with a significantly higher risk of subsequent dementia. Healthcare professionals should be aware of this potential long-term risk. A limitation that should be mentioned is that we could not exclude patients with bipolar depression.


Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Demência/tratamento farmacológico , Demência/epidemiologia , Transtorno Depressivo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Risperidona/efeitos adversos
20.
J Invest Dermatol ; 141(3): 555-562, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32835660

RESUMO

Variation in skin pigmentation can be affected by both environmental factors and intrinsic factors such as age, gender, and genetic variation. Recent GWASs revealed that genetic variants of genes functionally related to a pigmentation pathway were associated with skin pigmentary traits. However, these GWASs focused on populations with European ancestry, and only a few studies have been performed on Asian populations, limiting our understanding of the genetic basis of skin pigmentary traits in Asians. To evaluate the genetic variants associated with facial pigmented spots, we conducted a GWAS analysis of objectively measured facial pigmented spots in 17,019 Korean women. This large-scale GWAS identified several genomic loci that were significantly associated with facial pigmented spots (five previously reported loci and two previously unreported loci, to our knowledge), which were detected by UV light: BNC2 at 9p22 (rs16935073; P-value = 2.11 × 10-46), PPARGC1B at 5q32 (rs32579; P-value = 9.04 × 10-42), 10q26 (rs11198112; P-value = 9.66 × 10-38), MC1R at 16q24 (rs2228479; P-value = 6.62 × 10-21), lnc01877 at 2q33 (rs12693889; P-value = 1.59 × 10-11), CDKN2B-AS1 at 9p21 (rs643319; P-value = 7.76 × 10-9), and MFSD12 at 19p13 (rs2240751; P-value = 9.70 × 10-9). Further functional characterization of the candidate genes needs to be done to fully evaluate their contribution to facial pigmented spots.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Dermatoses Faciais/genética , Predisposição Genética para Doença , Hiperpigmentação/genética , Pigmentação da Pele/genética , Adulto , Dermatoses Faciais/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hiperpigmentação/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , República da Coreia/epidemiologia
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