Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 191
Filtrar
1.
Genome Med ; 13(1): 74, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931109

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

2.
Hum Mol Genet ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33783510

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). METHOD: We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (p < 5x10-8) were followed up with Bayesian fine-mapping to localise potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead SNPs was evaluated in the Uganda GPC. FINDINGS: We identified and validated two eGFR loci. At the GATM locus, the association signal (lead SNP rs2433603, p = 1.0x10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the HBB locus, the association signal (lead SNP rs141845179, p = 3.0x10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. INTERPRETATION: In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

3.
J Hum Genet ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33469137

RESUMO

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

4.
J Pers Med ; 10(4)2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33256133

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is the most common late-onset motor neuron disorder, but our current knowledge of the molecular mechanisms and pathways underlying this disease remain elusive. This review (1) systematically identifies machine learning studies aimed at the understanding of the genetic architecture of ALS, (2) outlines the main challenges faced and compares the different approaches that have been used to confront them, and (3) compares the experimental designs and results produced by those approaches and describes their reproducibility in terms of biological results and the performances of the machine learning models. The majority of the collected studies incorporated prior knowledge of ALS into their feature selection approaches, and trained their machine learning models using genomic data combined with other types of mined knowledge including functional associations, protein-protein interactions, disease/tissue-specific information, epigenetic data, and known ALS phenotype-genotype associations. The importance of incorporating gene-gene interactions and cis-regulatory elements into the experimental design of future ALS machine learning studies is highlighted. Lastly, it is suggested that future advances in the genomic and machine learning fields will bring about a better understanding of ALS genetic architecture, and enable improved personalized approaches to this and other devastating and complex diseases.

5.
Pharm Dev Technol ; : 1-29, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33274672

RESUMO

Tocotrienol (TRF) ethosomes were developed and evaluated in vitro for potential transdermal delivery against melanoma. The optimised TRF ethosomal size ranged between 64.9 ± 2.2 nm to 79.6 ± 3.9 nm and zeta potential (ZP) between -53.3 mV to -62.0 ± 2.6 mV. Characterisation of the ethosomes by ATR-FTIR indicated the successful formation of TRF-ethosomes. Scanning electron microscopy (SEM) images demonstrated the spherical shape of ethosomes, and the entrapment efficiencies of all the formulations were above 66%. In vitro permeation studies using full-thickness human skin showed that the permeation of gamma-T3 from the TRF ethosomal formulations was significantly higher (P < 0.05) than from the control. The cumulative amount of gamma-T3 permeated from TRF ethosome after 48 hours was 1.03 ± 0.24 µg cm-2 with a flux of 0.03 ± 0.01 µg cm-2 h-1. Furthermore, the flux of gamma-T3 across the Strat-M ® and the epidermal membrane was significantly higher than that across full-thickness human skin (p < 0.05). In vitro cytotoxicity studies on HaCat cells showed significantly higher cell viability than the pure drug solution (p < 0.05). The enhanced skin permeation and high cell viability associated with this formulation suggest a promising carrier for the transdermal delivery.

6.
Nat Commun ; 11(1): 5980, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239672

RESUMO

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

7.
Eur Heart J ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33206176

RESUMO

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

8.
Pharmacogenomics ; 21(16): 1151-1156, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33124499

RESUMO

Aim: TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. Materials & methods: A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Results: Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Conclusion: Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.

9.
Ann Rheum Dis ; 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106285

RESUMO

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit. METHODS: We performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes. RESULTS: Our analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology and IL6ST as a potential drug target. CONCLUSIONS: In a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies.

10.
Mol Psychiatry ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057169

RESUMO

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

11.
Nat Commun ; 11(1): 4402, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879318

RESUMO

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.


Assuntos
Artrite Reumatoide/genética , Linfócitos T CD4-Positivos/metabolismo , Cromatina , Proteína Forkhead Box O1/genética , Doenças Autoimunes/genética , Linfócitos T CD4-Positivos/citologia , Cromatina/química , Cromatina/genética , Elementos Facilitadores Genéticos , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Cultura Primária de Células , Regiões Promotoras Genéticas , Locos de Características Quantitativas
12.
Artigo em Inglês | MEDLINE | ID: mdl-32889544

RESUMO

OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. CONCLUSION: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.

13.
Hum Mol Genet ; 29(16): 2803-2811, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32691046

RESUMO

The UK Biobank is a prospective study of more than 500 000 participants, which has aggregated data from questionnaires, physical measures, biomarkers, imaging and follow-up for a wide range of health-related outcomes, together with genome-wide genotyping supplemented with high-density imputation. Previous studies have highlighted fine-scale population structure in the UK on a North-West to South-East cline, but the impact of unmeasured geographical confounding on genome-wide association studies (GWAS) of complex human traits in the UK Biobank has not been investigated. We considered 368 325 white British individuals from the UK Biobank and performed GWAS of their birth location. We demonstrate that widely used approaches to adjust for population structure, including principal component analysis and mixed modelling with a random effect for a genetic relationship matrix, cannot fully account for the fine-scale geographical confounding in the UK Biobank. We observe significant genetic correlation of birth location with a range of lifestyle-related traits, including body-mass index and fat mass, hypertension and lung function, even after adjustment for population structure. Variants driving associations with birth location are also strongly associated with many of these lifestyle-related traits after correction for population structure, indicating that there could be environmental factors that are confounded with geography that have not been adequately accounted for. Our findings highlight the need for caution in the interpretation of lifestyle-related trait GWAS in UK Biobank, particularly in loci demonstrating strong residual association with birth location.

15.
Nature ; 582(7811): 240-245, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499647

RESUMO

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Aldeído-Desidrogenase Mitocondrial/genética , Alelos , Anquirinas/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Europa (Continente)/etnologia , Proteínas do Olho/genética , Extremo Oriente/etnologia , Feminino , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/análise , Fatores de Transcrição/genética , Transcrição Genética
16.
BMC Biol ; 18(1): 47, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366252

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA and instead are enriched in cell type- and stimulation-specific gene regulatory regions. RESULTS: Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (> 500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis-associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis. CONCLUSIONS: This approach utilises multiple functional genomic techniques to follow up GWAS-associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.

17.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
18.
Clin Pharmacol Ther ; 108(2): 287-297, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32128760

RESUMO

Atorvastatin (ATV) is frequently prescribed and generally well  tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10-16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10-7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10-6 ) and 2-OH ATV (P = 1.09 × 10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.19; P = 0.014) in patients (n = 870) primarily discharged on high-dose ATV. In summary, both novel and recognized genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high-dose ATV.

19.
Epilepsia ; 61(4): 810-821, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32112430

RESUMO

OBJECTIVE: Genetic variants in STXBP1, which encodes the conserved exocytosis protein Munc18-1, are associated with a variety of infantile epilepsy syndromes. We aimed to develop an in vivo Caenorhabditis elegans model that could be used to test the pathogenicity of such variants in a cost-effective manner. METHODS: The CRISPR/Cas9 method was used to introduce a null mutation into the unc-18 gene (the C. elegans orthologue of STXBP1), thereby creating a paralyzed worm strain. We subsequently rescued this strain with transgenes encoding the human STXBP1/Munc18-1 protein (wild-type and eight different epilepsy-associated missense variants). The resulting humanized worm strains were then analyzed via behavioral, electrophysiological, and biochemical approaches. RESULTS: Transgenic expression of wild-type human STXBP1 protein fully rescued locomotion in both solid and liquid media to the same level as the standard wild-type worm strain, Bristol N2. Six variant strains (E59K, V84D, C180Y, R292H, L341P, R551C) exhibited impaired locomotion, whereas two (P335L, R406H) were no different from worms expressing wild-type STXBP1. Electrophysiological recordings revealed that all eight variant strains displayed less frequent and more irregular pharyngeal pumping in comparison to wild-type STXBP1-expressing strains. Four strains (V84D, C180Y, R292H, P335L) exhibited pentylenetetrazol-induced convulsions in an acute assay of seizure-like activity, in contrast to worms expressing wild-type STXBP1. No differences were seen between wild-type and variant STXBP1 strains in terms of mRNA abundance. However, STXBP1 protein levels were reduced to 20%-30% of wild-type in all variants, suggesting that the mutations result in STXBP1 protein instability. SIGNIFICANCE: The approach described here is a cost-effective in vivo method for establishing the pathogenicity of genetic variants in STXBP1 and potentially other conserved neuronal proteins. Furthermore, the humanized strains we created could potentially be used in the future for high-throughput drug screens to identify novel therapeutics.


Assuntos
Modelos Animais de Doenças , Epilepsia/genética , Proteínas Munc18/genética , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Humanos , Mutação , Proteínas de Transporte Vesicular/genética
20.
Genet Epidemiol ; 44(5): 425-441, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32190932

RESUMO

In transcriptome-wide association studies (TWAS), gene expression values are predicted using genotype data and tested for association with a phenotype. The power of this approach to detect associations relies, at least in part, on the accuracy of the prediction. Here we compare the prediction accuracy of six different methods-LASSO, Ridge regression, Elastic net, Best Linear Unbiased Predictor, Bayesian Sparse Linear Mixed Model, and Random Forests-by performing cross-validation using data from the Geuvadis Project. We also examine prediction accuracy (a) at different sample sizes, (b) when ancestry of the prediction model training and testing populations is different, and (c) when the tissue used to train the model is different from the tissue to be predicted. We find that, for most genes, the expression cannot be accurately predicted, but in general sparse statistical models tend to outperform polygenic models at prediction. Average prediction accuracy is reduced when the model training set size is reduced or when predicting across ancestries and is marginally reduced when predicting across tissues. We conclude that using sparse statistical models and the development of large reference panels across multiple ethnicities and tissues will lead to better prediction of gene expression, and thus may improve TWAS power.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/normas , Transcriptoma , Teorema de Bayes , Genótipo , Humanos , Modelos Genéticos , Modelos Estatísticos , Linhagem , Fenótipo , Reprodutibilidade dos Testes , Tamanho da Amostra
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...