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1.
Am J Chin Med ; : 1-16, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138534

RESUMO

The purpose of this study was to evaluate the effects of diosgenin on the D-galactose-induced cerebral cortical widely dispersed apoptosis. Male 12-week-old Wistar rats were divided into four groups: Control (1mg/kg/day of saline, i.p.), DD0 (150mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose+10 or 50mg/kg/day of diosgenin orally). After eight weeks, histopathological analysis, positive TUNEL and Western blotting assays were performed on the excised cerebral cortex from all four groups. The TUNEL-positive apoptotic cells, the components of Fas pathway (Fas, FADD, active caspase-8 and active caspase-3), and mitochondria pathway (t-Bid, Bax, cytochrome c, active caspase-9 and active caspase-3) were increased in the DD0 group compared with the control group, whereas they were decreased in the DD50 group. The components of survival pathway (p-Bad, Bcl-2, Bcl-xL, IGF-1, p-PI3K and p-AKT) were increased in the DD50 group compared to the control group, whereas the levels of Bcl-xL, p-PI3K, and p-AKT were also compensatorily increased in the DD0 group compared to the control group. Taken together, diosgenin suppressed D-galactose-induced neuronal Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced the Bcl-2 family associated pro-survival and IGF-1-PI3K-AKT survival pathways, which might provide neuroprotective effects of diosgenin for prevention of the D-galactose-induced aging brain.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32163326

RESUMO

This study investigated the effects of exercise training on cardiac inflammatory and cardiac fibrotic pathways in female spontaneously hypertensive rats (SHR) which were divided into a sham-operated sedentary hypertensive group (SHR-S), a sedentary hypertensive ovariectomized group (SHR-O), hypertensive ovariectomized group with treadmill exercise training (SHR-OT, 60 min/day, 5 days/week) for 8 weeks. Normotensive female Wistar Kyoto rats (WKY) served as controls. SOD and CAT activities were significantly increased in the SHR-OT group, when compared with the SHR-S or SHR-O groups. The protein levels of ERα and ERß became decreased in the SHR-O group, when compared with the WKY or SHR-S groups, but those were not changed in the SHR-OT group. The protein level of the angiotensin II type I receptor (AT1R) was increased in the SHR-S group, but did not further change those in the SHR-O group, whereas those were decreased in the SHR-OT group. The inflammatory-related protein levels of TNF-α, p-NFκB, COX-2, iNOS and IL-6, as well as the fibrotic-related protein levels of TGF-ß, p-Smad2/3, CTGF, tPA, MMP9 and Collagen I were increased in the SHR-S group and increased further in the SHR-O group, whereas those were decreased in the SHR-OT group. The coexistence of hypertension and ovariectomy additively increased cardiac inflammatory and fibrotic pathways partially through hypertension-enhanced AT1R and ovariectomy-depressed estrogen receptors. Exercise training appeared to suppress hypertensive ovariectomized heart-induced inflammatory and fibrotic pathways possibly through decreasing AT1R, but not through estrogen receptors.

3.
Medicine (Baltimore) ; 99(7): e19142, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049837

RESUMO

BACKGROUND: Depression is a kind of chronic and recurrent mental disorder, the main clinical characteristics of the patients are marked and persistent depression. At the same time, it is often accompanied by chronic physical disease, cognitive impairment, and functional damage, which is one of the common diseases that seriously threaten human health. At present, 3 kinds of oral Chinese patent medicine have clinical comparability in the treatment of depression of liver stagnation and spleen deficiency, but there is no evidence for clinical efficacy and safety. Therefore, this study aims to integrate the clinical related syndromes of direct and indirect comparison by using systematic evaluation and network meta-analysis (NMA). According to the data, the different Chinese patent medicines with the same evidence body for the treatment of the disease are collected, analyzed, and sequenced in a quantitative and comprehensive way, and then the advantages and disadvantages of the efficacy and safety between different Chinese patent medicines are screened out to get the best choice scheme, thus providing reference value and evidence-based theoretical evidence for the clinical optimization of drug selection. METHODS: Comprehensive retrieval of China National Knowledge Infrastructure, Chinese scientific journal database (VIP), China biological feature database (CBM) and WANFANG Data Chinese electronic database and the Cochrane Library, PubMed, Web of Science, and EMBASE foreign database. Search and publish the clinical randomized controlled trials of these 3 Chinese patent medicines combined with fluoxetine compared with fluoxetine. The retrieval time is from the establishment of the database to October 31, 2019. The 2 first authors will screen the literatures that meet the inclusion criteria, extract the data independently according to the predesigned rules, and evaluate the literature quality and bias risk of the included research according to the Cochrane 5.1 manual standard. R and Aggregate Data Drug Information System software were used for data consolidation and NMA to evaluate the ranking probability of all interventions. RESULTS: This result will show that the best oral Chinese patent medicine to assist the treatment of liver stagnation and spleen deficiency depression provides reliable evidence. CONCLUSION: This study will provide systematic evidence-based medicine evidence for TCM assisted treatment of depression of liver stagnation and spleen deficiency type, and help clinicians, patients with depression and decision-makers to make more effective, safer, and economic optimal treatment plan in the decision-making process. PROSPERO REGISTRATION NUMBER: CRD42019115695.


Assuntos
Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Hepatopatias/tratamento farmacológico , Medicina Tradicional Chinesa , Esplenopatias/tratamento farmacológico , Depressão/complicações , Humanos , Hepatopatias/etiologia , Esplenopatias/etiologia , Revisão Sistemática como Assunto
4.
Transl Psychiatry ; 10(1): 5, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-32066673

RESUMO

Schizophrenia (SCZ) is a highly heritable psychiatric disorder that affects approximately 1% of population around the world. However, early relevant studies did not reach clear conclusions of the genetic mechanisms of SCZ, suggesting that additional susceptibility loci that exert significant influence on SCZ are yet to be revealed. So, in order to identify novel susceptibility genes that account for the genetic risk of SCZ, we performed a systematic family-based study using whole exome sequencing (WES) in 65 Han Chinese families. The analysis of 51 SCZ trios with both unaffected parents identified 22 exonic and 1 splice-site de novo mutations (DNMs) on a total of 23 genes, and showed that 12 genes carried rare protein-altering compound heterozygous mutations in more than one trio. In addition, we identified 26 exonic or splice-site single nucleotide polymorphisms (SNPs) on 18 genes with nominal significance (P < 5 × 10-4) using a transmission disequilibrium test (TDT) in all the families. Moreover, TDT result confirmed a SCZ susceptibility locus on 3p21.1, encompassing the multigenetic region NEK4-ITIH1-ITIH3-ITIH4. Through several different strategies to predict the potential pathogenic genes in silico, we revealed 4 previous discovered susceptibility genes (TSNARE1, PBRM1, STAB1 and OLIG2) and 4 novel susceptibility loci (PSEN1, TLR5, MGAT5B and SSPO) in Han Chinese SCZ patients. In summary, we identified a list of putative candidate genes for SCZ using a family-based WES approach, thus improving our understanding of the pathology of SCZ and providing critical clues to future functional validation.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31926482

RESUMO

Genome-wide approaches including polygenic risk scores (PRSs) are now widely used in medical research; however, few studies have been conducted in low- and middle-income countries (LMICs), especially in South America. This study was designed to test the transferability of psychiatric PRSs to individuals with different ancestral and cultural backgrounds and to provide genome-wide association study (GWAS) results for psychiatric outcomes in this sample. The PrOMIS cohort (N = 3308) was recruited from prenatal care clinics at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. Three major psychiatric outcomes (depression, PTSD, and suicidal ideation and/or self-harm) were scored by interviewers using valid Spanish questionnaires. Illumina Multi-Ethnic Global chip was used for genotyping. Standard procedures for PRSs and GWAS were used along with extra steps to rule out confounding due to ancestry. Depression PRSs significantly predicted depression, PTSD, and suicidal ideation/self-harm and explained up to 0.6% of phenotypic variation (minimum p = 3.9 × 10-6). The associations were robust to sensitivity analyses using more homogeneous subgroups of participants and alternative choices of principal components. Successful polygenic prediction of three psychiatric phenotypes in this Peruvian cohort suggests that genetic influences on depression, PTSD, and suicidal ideation/self-harm are at least partially shared across global populations. These PRS and GWAS results from this large Peruvian cohort advance genetic research (and the potential for improved treatments) for diverse global populations.

6.
Neurosci Bull ; 36(2): 97-109, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31388929

RESUMO

The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia. We used prepulse inhibition (PPI) and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls. Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions. Concurrently, we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in first-episode treatment-naïve schizophrenic patients (n = 117) and in age- and sex-matched healthy controls (n = 86). We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia. Significant correlations between gray matter volumes (GMVs) in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice. Furthermore, these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients. The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients. Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation, providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.

7.
Bioinformatics ; 36(3): 930-933, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393554

RESUMO

SUMMARY: Genome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open-sourced Perl-based pipeline was developed to address the challenges of rapidly processing large-scale multi-cohort GWAS studies including quality control (QC), imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing environments. RICOPILI was created as the Psychiatric Genomics Consortium pipeline for GWAS and adopted by other users. The pipeline features (i) technical and genomic QC in case-control and trio cohorts, (ii) genome-wide phasing and imputation, (iv) association analysis, (v) meta-analysis, (vi) polygenic risk scoring and (vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work. AVAILABILITY AND IMPLEMENTATION: RICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
Hum Genet ; 139(2): 185-198, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31813014

RESUMO

Major psychiatric traits are genetically inter-correlated with one another, but it not well known which genes play pleiotropic effects across different traits. We curated and compared genes identified from large-scale genome-wide association studies for seven psychiatric traits, including depression, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety and neuroticism. We then explored biological functions of the top pleiotropic genes. A total of 243 cross-trait genes were identified for the seven traits. Except for autism spectrum disorder, there was significant enrichment of overlapped genes across these psychiatric traits. Chromosome 5q14.3, 11q23.2, and 7p22.3 are the three genomic regions conferring highest pleiotropic effects for these psychiatric traits. The long non-coding gene LINC00461 showed the highest pleiotropic effects on five psychiatric traits. In silico and functional studies with mice support the vital role of LINC00461 in neurodevelopment. In sum, our study provides insights into the shared genetic liability among major psychiatric traits.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Animais , Transtorno Autístico/genética , Transtorno Autístico/patologia , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/metabolismo , Humanos , Transtornos Mentais/patologia , Camundongos , Fenótipo , RNA Longo não Codificante/genética , Fatores de Risco , Esquizofrenia/genética , Esquizofrenia/patologia
9.
Cell ; 179(3): 589-603, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31607513

RESUMO

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

10.
Curr Protein Pept Sci ; 20(10): 996-1003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389311

RESUMO

Abstract:Throughout the last decade, extensive efforts have been devoted to developing a percutaneous catheter ablation and implantable cardioverter-defibrillator technique for patients suffering from ventricular arrhythmia. Antiarrhythmic drug efficacy for preventing arrhythmias remains disappointing because of adverse cardiovascular effects. Allocryptopine is an isoquinoline alkaloid widely present in medicinal herbs. Studies have indicated that allocryptopine exhibits potential anti-arrhythmic actions in various animal models. The potential therapeutic benefit of allocryptopine in arrhythmia diseases is addressed in this study, focusing on multiple ion channel targets and reduced repolarization dispersion. The limitations of allocryptopine research are clear given a lack of parameters regarding toxicology and pharmacokinetics and clinical efficacy in patients with ventricular arrhythmias. Much remains to be revealed about the properties of allocryptopine.


Assuntos
Antiarrítmicos , Arritmias Cardíacas/tratamento farmacológico , Alcaloides de Berberina , Plantas Medicinais/química , Traqueófitas/química , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Alcaloides de Berberina/química , Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/uso terapêutico , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
11.
Cell ; 178(3): 714-730.e22, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348891

RESUMO

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

12.
J Cell Mol Med ; 23(8): 5340-5348, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124601

RESUMO

The aim of our study was to assess the associations of HSP90AB1 copy number variations (CNVs) with systemic lupus erythematosus (SLE) risk and glucocorticoids (GCs) efficacy, as well as the relationship between HSP90AB1 single-nucleotide polymorphisms (SNPs) and GCs efficacy. HSP90AB1 CNVs and SLE risk were analysed in 519 patients and 538 controls. Patients treated with GCs were followed up for 12 weeks and were divided into sensitive and insensitive groups to investigate the effects of CNVs (419 patients) and SNPs (457 patients) on the efficacy of GCs. Health-related quality of life (HRQoL) was also measured by SF-36 at baseline and week 12 to explore the relationship between CNVs/SNPs and HRQoL improvements in Chinese SLE patients. Our results indicated a statistically significant association between HSP90AB1 CNVs and SLE (PBH  = 0.039), and this association was more pronounced in the female subgroup (PBH  = 0.039). However, we did not detect association of HSP90AB1 CNVs/SNPs with efficacy of GCs. But we found a marginal association between SNP rs13296 and improvement in Role-emotional, while this association was not strong enough to survive in the multiple testing corrections. Collectively, our findings suggest that the copy number of HSP90AB1 is associated with SLE susceptibility. But copy number and polymorphisms of HSP90AB1 may not be associated with efficacy of GCs.

15.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
16.
J Med Imaging (Bellingham) ; 6(3): 031407, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30766895

RESUMO

Contrast-enhanced digital mammography (CEDM) reveals neovasculature of breast lesions in a two-dimensional contrast enhancement map. Contrast-enhanced digital breast tomosynthesis (CEDBT) provides contrast enhancement in three dimensions, which may improve lesion characterization and localization. We aim to compare CEDM and CEDBT for lesion assessment. Women with breast imaging-reporting and data system 4 or 5 suspicious breast lesion(s) were recruited in our study and were imaged with CEDM and CEDBT in succession under one breast compression. Two radiologists assessed CEDM and CEDBT with both images displayed side-by-side and compared (1) contrast enhancement of lesions and (2) lesion margin using a five-point scale ranging from - 2 (CEDM much better) to + 2 (CEDBT much better). Biopsy identified 19 malignant lesions with contrast enhancement. Our results show that CEDBT provides better lesion margins than CEDM with limited reduction in contrast enhancement. CEDBT delivers less radiation dose compared to CEDM + DBT. Synthetic CEDM can be generated from CEDBT data and provides lesion contrast enhancement comparable to CEDM. CEDBT has potential for clinical applications, such as treatment response monitoring and guidance for biopsy.

17.
J Clin Rheumatol ; 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30768443

RESUMO

OBJECTIVES: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life. METHODS: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction. RESULTS: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms. CONCLUSIONS: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.

18.
Nat Genet ; 51(1): 63-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30478444

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Encéfalo/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Risco
19.
Sci Rep ; 8(1): 11360, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054501

RESUMO

Genome-wide association studies depend on accurate ascertainment of patient phenotype. However, phenotyping is difficult, and it is often treated as an afterthought in these studies because of the expense involved. Electronic health records (EHRs) may provide higher fidelity phenotypes for genomic research than other sources such as administrative data. We used whole genome association models to evaluate different EHR and administrative data-based phenotyping methods in a cohort of 16,858 Caucasian subjects for type 1 diabetes mellitus, type 2 diabetes mellitus, coronary artery disease and breast cancer. For each disease, we trained and evaluated polygenic models using three different phenotype definitions: phenotypes derived from billing data, the clinical problem list, or a curated phenotyping algorithm. We observed that for these diseases, the curated phenotype outperformed the problem list, and the problem list outperformed administrative billing data. This suggests that using advanced EHR-derived phenotypes can further increase the power of genome-wide association studies.


Assuntos
Doença/genética , Estudo de Associação Genômica Ampla , Algoritmos , Registros Eletrônicos de Saúde , Humanos , Herança Multifatorial/genética , Fenótipo , Curva ROC , Fatores de Risco
20.
Genes Genomics ; 40(10): 1069-1079, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29907909

RESUMO

Although the current glucocorticoids (GCs) treatment for systemic lupus erythematosus (SLE) is effective to a certain extent, the difference in therapeutic effect between patients is still a widespread problem. Some patients can have repeated attacks that greatly diminish their quality of life. This study was conducted to investigate the relationship between HSP90AA2 polymorphisms and disease susceptibility, GCs efficacy and health-related quality of life (HRQoL) in Chinese SLE patients. A case-control study was performed in 470 SLE patients and 470 normal controls. Then, 444 patients in the case group were followed up for 12 weeks to observe efficacy of GCs and improvement of HRQoL. Two single nucleotide polymorphisms (SNPs) of HSP90AA2 were selected for genotyping: rs1826330 and rs6484340. HRQoL was assessed using the SF-36 questionnaire. The minor T allele of rs1826330 and the TT haplotype formed by rs1826330 and rs6484340 showed associations with decreased SLE risk (T allele: PBH = 0.022; TT haplotype: PBH = 0.033). A significant association between rs6484340 and improvement of HRQoL was revealed in the follow-up study. Five subscales of SF-36 were appeared to be influenced by rs6484340: total score of SF-36 (additive model: PBH = 0.026), physical function (additive model: PBH = 0.026), role-physical (recessive model: PBH = 0.041), mental health (dominant model: PBH = 0.047), and physical component summary (additive model: PBH = 0.026). No statistical significance was found between HSP90AA2 gene polymorphisms and GCs efficacy. These results revealed a genetic association between HSP90AA2 and SLE. Remarkably, HSP90AA2 has an impact on the improvement of HRQoL in Chinese population with SLE.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Glucocorticoides/uso terapêutico , Proteínas de Choque Térmico HSP90/genética , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Qualidade de Vida/psicologia , Adulto , Estudos de Casos e Controles , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/psicologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
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