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1.
BMC Genomics ; 19(1): 942, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558528

RESUMO

BACKGROUND: Norway spruce [Picea abies (L.) Karst.] is ecologically and economically one of the most important conifer worldwide. Our main goal was to develop a large catalog of annotated high confidence gene SNPs that should sustain the development of genomic tools for the conservation of natural and domesticated genetic diversity resources, and hasten tree breeding efforts in this species. RESULTS: Targeted sequencing was achieved by capturing P. abies exome with probes previously designed from the sequenced transcriptome of white spruce (Picea glauca (Moench) Voss). Capture efficiency was high (74.5%) given a high level of exome conservation between the two species. Using stringent criteria, we delimited a set of 61,771 high-confidence SNPs across 13,543 genes. To validate SNPs, a high-throughput genotyping array was developed for a subset of 5571 predicted SNPs representing as many different gene loci, and was used to genotype over 1000 trees. The estimated true positive rate of the resource was 84.2%, which was comparable with the genotyping success rate obtained for P. abies control SNPs recycled from previous genotyping efforts. We also analyzed SNP abundance across various gene functional categories. Several GO terms and gene families involved in stress response were found over-represented in highly polymorphic genes. CONCLUSION: The annotated high-confidence SNP catalog developed herein represents a valuable genomic resource, being representative of over 13 K genes distributed across the P. abies genome. This resource should serve a variety of population genomics and breeding applications in Norway spruce.


Assuntos
Exoma/genética , Picea/genética , Polimorfismo de Nucleotídeo Único , Mapeamento de Sequências Contíguas , DNA de Plantas/isolamento & purificação , DNA de Plantas/metabolismo , Genótipo , Anotação de Sequência Molecular , Folhas de Planta/genética , Análise de Sequência de DNA
2.
Blood ; 132(17): 1842-1850, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

3.
Eval Program Plann ; 68: 166-175, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29605761

RESUMO

The purpose of this study was to test the construct validity of the Evaluation Capacity in Organizations Questionnaire (ECOQ). Conceptually, the ECOQ examines the role of evaluation in organizational development and, most notably in organizational learning. In this model, evaluation capacity building (ECB) initiatives are assumed to contribute to the development of a culture of systematic self-assessment and reflection, which, in turn, leads to increased organizational learning. Our sample consisted of internal evaluators within the federal, provincial or municipal government, not-for-profit organizations, private firms, and colleges or universities in Canada. Exploratory factor analysis (EFA) and latent path analysis (LPA) were conducted to better understand the underlying structural aspect of the organizational capacity to do and use evaluation construct as measured by the ECOQ. The results of our study indicate that the ECOQ effectively assesses an organization's capacity to do and use evaluation. Furthermore, evidence provided by the LPA statistical analysis suggests that an organization's capacity to learn is enhanced by the relationships among the various factors. Implications of using a validated model of an organization's capacity to do and use evaluations in both research and practice are discussed.

4.
PLoS One ; 12(10): e0182472, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29084233

RESUMO

BACKGROUND: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.


Assuntos
Metilação de DNA , Homocisteína/metabolismo , Leucócitos/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Cromossomos Humanos Par 6 , Estudos de Coortes , Ilhas de CpG , Humanos , Polimorfismo de Nucleotídeo Único
5.
Epigenomics ; 9(11): 1403-1422, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28990796

RESUMO

AIM: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. METHODS: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. RESULTS: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. CONCLUSION: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.


Assuntos
Metilação de DNA , Epigênese Genética , Homocisteína/sangue , Leucócitos/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Masculino , Tenascina/genética , Tenascina/metabolismo
6.
Sci Rep ; 7(1): 11207, 2017 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-28894120

RESUMO

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10-6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.

7.
Int J Health Policy Manag ; 6(9): 495-499, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28949461

RESUMO

Written by a group of political science researchers, this commentary focuses on the contributions of political science to public health and proposes research avenues to increase those contributions. Despite progress, the links between researchers from these two fields develop only slowly. Divergences between the approach of political science to public policy and the expectations that public health can have about the role of political science, are often seen as an obstacle to collaboration between experts in these two areas. Thus, promising and practical research avenues are proposed along with strategies to strengthen and develop them. Considering the interdisciplinary and intersectoral nature of population health, it is important to create a critical mass of researchers interested in the health of populations and in healthy public policy that can thrive working at the junction of political science and public health.


Assuntos
Sistemas Políticos , Pesquisa em Sistemas de Saúde Pública , Saúde Pública , Humanos , Colaboração Intersetorial , Política , Saúde Pública/métodos , Pesquisa em Sistemas de Saúde Pública/métodos , Pesquisa em Sistemas de Saúde Pública/organização & administração
8.
PLoS One ; 12(5): e0177768, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28552956

RESUMO

BACKGROUND: Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis. METHODS: A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models. RESULTS: A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96-1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71-0.97, p = 0.021) for venous thrombosis. CONCLUSIONS: A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models.


Assuntos
Alanina/genética , Carboxipeptidase B2/genética , Predisposição Genética para Doença , Fatores Sexuais , Treonina/genética , Trombose Venosa/genética , Feminino , Humanos , Isoleucina/genética , Masculino , Fatores de Risco
9.
Genet Epidemiol ; 41(5): 455-466, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28421636

RESUMO

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10-8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies.


Assuntos
Biomarcadores/sangue , Lipoproteínas/sangue , Lipoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico/genética , Tromboembolia Venosa/sangue , Tromboembolia Venosa/genética , Adulto , Canadá , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Epigenômica , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Tromboembolia Venosa/diagnóstico
10.
Plant J ; 90(1): 189-203, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28090692

RESUMO

Over the last decade, extensive genetic and genomic resources have been developed for the conifer white spruce (Picea glauca, Pinaceae), which has one of the largest plant genomes (20 Gbp). Draft genome sequences of white spruce and other conifers have recently been produced, but dense genetic maps are needed to comprehend genome macrostructure, delineate regions involved in quantitative traits, complement functional genomic investigations, and assist the assembly of fragmented genomic sequences. A greatly expanded P. glauca composite linkage map was generated from a set of 1976 full-sib progeny, with the positioning of 8793 expressed genes. Regions with significant low or high gene density were identified. Gene family members tended to be mapped on the same chromosomes, with tandemly arrayed genes significantly biased towards specific functional classes. The map was integrated with transcriptome data surveyed across eight tissues. In total, 69 clusters of co-expressed and co-localising genes were identified. A high level of synteny was found with pine genetic maps, which should facilitate the transfer of structural information in the Pinaceae. Although the current white spruce genome sequence remains highly fragmented, dozens of scaffolds encompassing more than one mapped gene were identified. From these, the relationship between genetic and physical distances was examined and the genome-wide recombination rate was found to be much smaller than most estimates reported for angiosperm genomes. This gene linkage map shall assist the large-scale assembly of the next-generation white spruce genome sequence and provide a reference resource for the conifer genomics community.


Assuntos
Genoma de Planta/genética , Picea/genética , Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , DNA de Plantas/genética , Genômica/métodos , Polimorfismo de Nucleotídeo Único/genética , Sintenia
11.
Hum Mol Genet ; 26(3): 637-649, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053049

RESUMO

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Moléculas de Adesão Celular/sangue , Cininogênios/genética , Receptores de Superfície Celular/sangue , Trombose/genética , Moléculas de Adesão Celular/genética , Simulação por Computador , Feminino , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Tempo de Tromboplastina Parcial , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-Traducional/genética , Receptores de Superfície Celular/genética , Trombose/sangue , Trombose/fisiopatologia
12.
J Neurol Neurosurg Psychiatry ; 87(4): 433-40, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25904811

RESUMO

OBJECTIVE: To disentangle the temporal relationship between the APOE-ε4 allele and outcomes of paediatric traumatic brain injury (TBI). METHODS: PubMed, EMBASE, Web of Science, MEDLINE, PsychINFO and HuGE Navigator Genopedia databases were searched from their inception up to January 2015 without language limitations. Included studies were analysed under a dominant genetic model to assess the association between the APOE-ε4 allele and poor outcomes of paediatric TBI at 6 months. Meta-regression was used to assess trends over time. RESULTS: Of the 325 initially identified records, 6 studies were selected and analysed based on inclusion/exclusion criteria. A total of 358 cases of paediatric TBI were included. 2 studies assessed outcomes at multiple time points ranging from 3 to 36 months; 4 studies assessed outcomes at a single time point (either 6 or 12 months). At 6 months, there is 2.36 (95% CI 1.26 to 4.42; p=0.007) times higher odds of poor outcome following TBI in children with at least one APOE-ε4 allele, compared with the children without. Further, the adjusted odds suggested an increasing trend of 7% per month (95% CI -9 to 25; p=0.359). CONCLUSIONS: This meta-analysis provides cumulative evidence that the APOE-ε4 allele is important to the prognosis of paediatric TBI, but may have a different effect compared with adult TBI; moreover, this effect may be time dependent.


Assuntos
Apolipoproteína E4/genética , Lesões Encefálicas/genética , Lesões Encefálicas/terapia , Adolescente , Alelos , Lesões Encefálicas/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Prognóstico , Resultado do Tratamento , Adulto Jovem
13.
Mol Ecol Resour ; 16(2): 588-98, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26391535

RESUMO

Picea mariana is a widely distributed boreal conifer across Canada and the subject of advanced breeding programmes for which population genomics and genomic selection approaches are being developed. Targeted sequencing was achieved after capturing P. mariana exome with probes designed from the sequenced transcriptome of Picea glauca, a distant relative. A high capture efficiency of 75.9% was reached although spruce has a complex and large genome including gene sequences interspersed by some long introns. The results confirmed the relevance of using probes from congeneric species to perform successfully interspecific exome capture in the genus Picea. A bioinformatics pipeline was developed including stringent criteria that helped detect a set of 97,075 highly reliable in silico SNPs. These SNPs were distributed across 14,909 genes. Part of an Infinium iSelect array was used to estimate the rate of true positives by validating 4267 of the predicted in silico SNPs by genotyping trees from P. mariana populations. The true positive rate was 96.2% for in silico SNPs, compared to a genotyping success rate of 96.7% for a set 1115 P. mariana control SNPs recycled from previous genotyping arrays. These results indicate the high success rate of the genotyping array and the relevance of the selection criteria used to delineate the new P. mariana in silico SNP resource. Furthermore, in silico SNPs were generally of medium to high frequency in natural populations, thus providing high informative value for future population genomics applications.


Assuntos
Exoma , Variação Genética , Técnicas de Genotipagem/métodos , Picea/classificação , Picea/genética , Polimorfismo de Nucleotídeo Único , Canadá , Análise de Sequência de DNA
14.
Am J Hum Genet ; 96(4): 532-42, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25772935

RESUMO

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.


Assuntos
Predisposição Genética para Doença/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Tetraspaninas/genética , Tromboembolia Venosa/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Razão de Chances
15.
Nat Commun ; 6: 6326, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25716334

RESUMO

The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 × 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart. Over 90% of these pairs are replicated (FDR<5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (P<0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.


Assuntos
Neoplasias do Colo/genética , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Locos de Características Quantitativas , Doenças Autoimunes/genética , Estudos de Casos e Controles , Genótipo , Humanos , Linfócitos , Polimorfismo de Nucleotídeo Único
17.
Blood ; 124(20): 3041-2, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25395143

RESUMO

In this issue of Blood, Ma and colleagues report the first agnostic investigation by a genome-wide association study (GWAS) in search of genetic determinants of a variation in plasma plasminogen levels.


Assuntos
Apolipoproteínas A/genética , Lectinas/genética , Plasminogênio/análise , Plasminogênio/genética , Receptores de Superfície Celular/genética , Fumar/sangue , Feminino , Humanos , Masculino
18.
PLoS One ; 9(9): e108087, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25265411

RESUMO

In order to investigate whether DNA methylation marks could contribute to the incomplete penetrance of the FV Leiden mutation, a major genetic risk factor for venous thrombosis (VT), we measured genome-wide DNA methylation levels in peripheral blood samples of 98 VT patients carrying the mutation and 251 VT patients without the mutation using the dedicated Illumina HumanMethylation450 array. The genome-wide analysis of 388,120 CpG probes identified three sites mapping to the SLC19A2 locus whose DNA methylation levels differed significantly (p<3 10-8) between carriers and non-carriers. The three sites replicated (p<2 10-7) in an independent sample of 214 individuals from five large families ascertained on VT and FV Leiden mutation among which 53 were carriers and 161 were non-carriers of the mutation. In both studies, these three CpG sites were also associated (2.33 10-110.05). In conclusion, our work clearly illustrates some promises and pitfalls of DNA methylation investigations on peripheral blood DNA in large epidemiological cohorts. DNA methylation levels at SLC19A2 are influenced by SNPs in LD with FV Leiden, but these DNA methylation marks do not explain the incomplete penetrance of the FV Leiden mutation.


Assuntos
Metilação de DNA , Fator V/genética , Estudo de Associação Genômica Ampla , Mutação , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Arthritis Rheumatol ; 66(5): 1111-20, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24782176

RESUMO

OBJECTIVE: Associations have been reported between candidate genes and the response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and have yielded conflicting results. This study was undertaken to provide a systematic review of all genetic variant associations with MTX efficacy and toxicity, and to conduct a meta-analysis evaluating the most commonly studied single-nucleotide polymorphism for which prior cumulative analysis has been lacking. METHODS: A systematic review and meta-analysis were performed to identify genetic variant associations with MTX efficacy and toxicity. Studies were identified from the Medline, EMBase, HuGENet Navigator, and Cochrane Library databases through December 2012, and from the 2009-2011 abstracts of the American College of Rheumatology and the European League Against Rheumatism annual meeting proceedings. Additional unpublished genotype data from a Canadian cohort of patients with early RA were also included. RESULTS: Among the 87 identified studies examining genetic associations with MTX efficacy and toxicity, the reduced folate carrier 1 gene (RFC1) variant 80G>A (Arg(27) His, rs1051266) was selected for random-effects meta-analysis. RFC1 80G>A was associated with MTX efficacy in both the recessive model (odds ratio [OR] 1.42, 95% confidence interval [95% CI] 1.04-1.93) and the additive model (OR 1.28, 95% CI 1.10-1.49). Restriction of the sensitivity analyses to studies that involved Caucasian subjects only and that used similar outcome measures (MTX failure versus nonfailure) maintained and improved the associations in both models. No significant association between RFC1 80G>A and MTX toxicity was detected. CONCLUSION: In these analyses of available data from observational studies, RFC1 80G>A was found to be associated with MTX efficacy, but not toxicity, in RA patients. This variant merits further prospective analysis as a potential predictor of MTX efficacy. Variability in the definitions of response in pharmacogenetic studies is a source of data heterogeneity that should be addressed.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Determinismo Genético , Metotrexato/uso terapêutico , Proteína Carregadora de Folato Reduzido/genética , Antirreumáticos/uso terapêutico , Humanos , Estudos Observacionais como Assunto , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Resultado do Tratamento
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