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1.
Diabetologia ; 62(9): 1601-1615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203377

RESUMO

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

2.
Clin Epigenetics ; 10(1): 126, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30342560

RESUMO

BACKGROUND: Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear. METHODS: We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat. RESULTS: We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation. CONCLUSIONS: Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.

4.
Nat Genet ; 50(4): 572-580, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29632379

RESUMO

Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.

5.
Hum Mol Genet ; 27(4): 732-741, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29228364

RESUMO

Changes in the mean and variance of gene expression with age have consequences for healthy aging and disease development. Age-dependent changes in phenotypic variance have been associated with a decline in regulatory functions leading to increase in disease risk. Here, we investigate age-related mean and variance changes in gene expression measured by RNA-seq of fat, skin, whole blood and derived lymphoblastoid cell lines (LCLs) expression from 855 adult female twins. We see evidence of up to 60% of age effects on transcription levels shared across tissues, and 47% of those on splicing. Using gene expression variance and discordance between genetically identical MZ twin pairs, we identify 137 genes with age-related changes in variance and 42 genes with age-related discordance between co-twins; implying the latter are driven by environmental effects. We identify four eQTLs whose effect on expression is age-dependent (FDR 5%). Combined, these results show a complicated mix of environmental and genetically driven changes in expression with age. Using the twin structure in our data, we show that additive genetic effects explain considerably more of the variance in gene expression than aging, but less that other environmental factors, potentially explaining why reliable expression-derived biomarkers for healthy-aging have proved elusive compared with those derived from methylation.

6.
Nat Genet ; 49(12): 1747-1751, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29058714

RESUMO

Genetic association mapping produces statistical links between phenotypes and genomic regions, but identifying causal variants remains difficult. Whole-genome sequencing (WGS) can help by providing complete knowledge of all genetic variants, but it is financially prohibitive for well-powered GWAS studies. We performed mapping of expression quantitative trait loci (eQTLs) with WGS and RNA-seq, and found that lead eQTL variants called with WGS were more likely to be causal. Through simulations, we derived properties of causal variants and used them to develop a method for identifying likely causal SNPs. We estimated that 25-70% of causal variants were located in open-chromatin regions, depending on the tissue and experiment. Finally, we identified a set of high-confidence causal variants and showed that these were more enriched in GWAS associations than other eQTLs. Of those, we found 65 associations with GWAS traits and provide examples in which genes implicated by expression are functionally validated as being relevant for complex traits.


Assuntos
Perfilação da Expressão Gênica/métodos , Variação Genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes
7.
J Invest Dermatol ; 137(9): 1887-1894, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28502801

RESUMO

Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait at genome-wide significance (P = 4.1 × 10-9); to our knowledge this is previously unreported. We also confirm previously identified loci, rs12203592 near IRF4 (P = 8.8 × 10-13) and rs4268748 near MC1R (P = 1.2 × 10-15). At all three loci we highlight putative functionally relevant SNPs. There are a number of red hair/low pigmentation alleles of MC1R; we found that together these MC1R alleles explained 4.1% of variance in skin pattern damage. We also show that skin aging and reported experience of sunburns was proportional to the degree of penetrance for red hair of alleles of MC1R. Our work has uncovered genetic contributions to skin aging and confirmed previous findings, showing that pigmentation is a critical determinant of skin aging.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores Reguladores de Interferon/genética , Envelhecimento da Pele/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valores de Referência , Papel (figurativo) , Pigmentação da Pele/genética
8.
Diabetes ; 66(7): 2019-2032, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28341696

RESUMO

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Jejum/metabolismo , Resistência à Insulina/genética , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Afro-Americanos/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Finlândia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Hispano-Americanos/genética , Humanos , Razão de Chances
9.
Genome Res ; 27(4): 545-552, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28302734

RESUMO

Gene expression is dependent on genetic and environmental factors. In the last decade, a large body of research has significantly improved our understanding of the genetic architecture of gene expression. However, it remains unclear whether genetic effects on gene expression remain stable over time. Here, we show, using longitudinal whole-blood gene expression data from a twin cohort, that the genetic architecture of a subset of genes is unstable over time. In addition, we identified 2213 genes differentially expressed across time points that we linked with aging within and across studies. Interestingly, we discovered that most differentially expressed genes were affected by a subset of 77 putative causal genes. Finally, we observed that putative causal genes and down-regulated genes were affected by a loss of genetic control between time points. Taken together, our data suggest that instability in the genetic architecture of a subset of genes could lead to widespread effects on the transcriptome with an aging signature.


Assuntos
Envelhecimento/genética , Regulação da Expressão Gênica no Desenvolvimento , Transcriptoma , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
10.
Hum Mol Genet ; 26(5): 1003-1017, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28062664

RESUMO

Studies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered the greatest frequency of candidate-causal eQTLs using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g. NADSYN1 and TCF7) that were concealed using microarrays, including four non-coding RNAs. Many of these eQTLs were found to influence the expression of several genes, supporting the notion that risk haplotypes may harbour multiple functional effects. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g. WDFY4) through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. We conclude that to better understand the true functional consequence of regulatory variants, quantification by RNA-Seq should be performed at the exon-level as a minimum, and run in parallel with gene and splice-junction level quantification.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Locos de Características Quantitativas/genética , RNA não Traduzido/genética , Processamento Alternativo/genética , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/biossíntese , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Mapeamento Cromossômico , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Polimorfismo de Nucleotídeo Único , Fator 1 de Transcrição de Linfócitos T/biossíntese , Fator 1 de Transcrição de Linfócitos T/genética
11.
Am J Hum Genet ; 99(3): 567-579, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27588447

RESUMO

Obesity is a global epidemic that is causally associated with a range of diseases, including type 2 diabetes and cardiovascular disease, at the population-level. However, there is marked heterogeneity in obesity-related outcomes among individuals. This might reflect genotype-dependent responses to adiposity. Given that adiposity, measured by BMI, is associated with widespread changes in gene expression and regulatory variants mediate the majority of known complex trait loci, we sought to identify gene-by-BMI (G × BMI) interactions on the regulation of gene expression in a multi-tissue RNA-sequencing (RNA-seq) dataset from the TwinsUK cohort (n = 856). At a false discovery rate of 5%, we identified 16 cis G × BMI interactions (top cis interaction: CHURC1, rs7143432, p = 2.0 × 10(-12)) and one variant regulating 53 genes in trans (top trans interaction: ZNF423, rs3851570, p = 8.2 × 10(-13)), all in adipose tissue. The interactions were adipose-specific and enriched for variants overlapping adipocyte enhancers, and regulated genes were enriched for metabolic and inflammatory processes. We replicated a subset of the interactions in an independent adipose RNA-seq dataset (deCODE genetics, n = 754). We also confirmed the interactions with an alternate measure of obesity, dual-energy X-ray absorptiometry (DXA)-derived visceral-fat-volume measurements, in a subset of TwinsUK individuals (n = 682). The identified G × BMI regulatory effects demonstrate the dynamic nature of gene regulation and reveal a functional mechanism underlying the heterogeneous response to obesity. Additionally, we have provided a web browser allowing interactive exploration of the dataset, including of association between expression, BMI, and G × BMI regulatory effects in four tissues.


Assuntos
Adiposidade/genética , Transcriptoma/genética , Absorciometria de Fóton , Índice de Massa Corporal , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Feminino , Humanos , Gordura Intra-Abdominal/anatomia & histologia , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de RNA , Gêmeos/genética , Reino Unido
12.
Nat Genet ; 48(9): 1094-100, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27479908

RESUMO

Genome-wide association studies of gene expression traits and other cellular phenotypes have successfully identified links between genetic variation and biological processes. The majority of discoveries have uncovered cis-expression quantitative trait locus (eQTL) effects via mass univariate testing of SNPs against gene expression in single tissues. Here we present a Bayesian method for multiple-tissue experiments focusing on uncovering gene networks linked to genetic variation. Our method decomposes the 3D array (or tensor) of gene expression measurements into a set of latent components. We identify sparse gene networks that can then be tested for association against genetic variation across the genome. We apply our method to a data set of 845 individuals from the TwinsUK cohort with gene expression measured via RNA-seq analysis in adipose, lymphoblastoid cell lines (LCLs) and skin. We uncover several gene networks with a genetic basis and clear biological and statistical significance. Extensions of this approach will allow integration of different omics, environmental and phenotypic data sets.


Assuntos
Tecido Adiposo/metabolismo , Teorema de Bayes , Marcadores Genéticos/genética , Linfócitos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Pele/metabolismo , Estudos de Coortes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Locos de Características Quantitativas , Reino Unido
13.
Vet Anaesth Analg ; 43(5): 561-5, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26872297

RESUMO

OBJECTIVE: To evaluate and compare three intravenous (IV) doses of a ketamine-propofol admixture (ketofol) for induction of anaesthesia in unpremedicated rabbits. STUDY DESIGN: Prospective, randomized 'blinded' trial. ANIMALS: Twenty-one healthy female New Zealand rabbits weighing 2.7 ± 0.1 kg. METHODS: Animals were allocated randomly into three groups of seven animals and received 1 (KP1), 3 (KP3) or 5 (KP5) mg kg(-1) of both ketamine and propofol in a 1:1 mg kg(-1) ratio admixture. Cardiorespiratory parameters and arterial blood gases were measured at baseline, 2 and 5 minutes after drug administration. The time to loss of the righting reflex (LORR) and the duration of action and apnoea were recorded. The quality of induction and intubation were scored. Data were compared using a two-way anova or a t-test for unpaired data, as relevant. RESULTS: The time to LORR was the shortest (11 ± 5 seconds) and the duration of action the longest (374 ± 26 seconds) in group KP5. Group KP1 did not lose the righting reflex; instead mild to moderate sedation was observed in this group. The quality of induction in group KP5 was smooth, but ranged from smooth to fair in group KP3. Intubation was not possible in the KP1 group, and 10 animals in the other two groups showed some resistance to intubation. At 2 and 5 minutes, the pulse rate was significantly higher in all three groups compared with baseline, but no statistical differences were seen in arterial blood pressures. Hypoxaemia and dose-dependent respiratory depression were observed in all groups, with periods of apnoea in the KP5 group. CONCLUSIONS AND CLINICAL RELEVANCE: The IV ketamine-propofol admixture had a dose-dependent effect. Haemodynamic function was well maintained in all groups but hypoxemia was observed at the highest doses and oxygen administration is recommended. Addition of premedication or topical lidocaine is advisable to make intubation easier.


Assuntos
Anestésicos Combinados , Anestésicos Intravenosos/administração & dosagem , Ketamina/administração & dosagem , Propofol/administração & dosagem , Animais , Sistema Cardiovascular/efeitos dos fármacos , Feminino , Estudos Prospectivos , Coelhos , Respiração/efeitos dos fármacos , Método Simples-Cego , Seringas
14.
G3 (Bethesda) ; 5(5): 839-47, 2015 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-25758824

RESUMO

Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold ([Formula: see text]). These phenotypes are more heritable ([Formula: see text]) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors.


Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Modelos Biológicos , Fenótipo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade
15.
Nat Genet ; 47(1): 88-91, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25436857

RESUMO

Understanding the genetic architecture of gene expression is an intermediate step in understanding the genetic architecture of complex diseases. RNA sequencing technologies have improved the quantification of gene expression and allow measurement of allele-specific expression (ASE). ASE is hypothesized to result from the direct effect of cis regulatory variants, but a proper estimation of the causes of ASE has not been performed thus far. In this study, we take advantage of a sample of twins to measure the relative contributions of genetic and environmental effects to ASE, and we find substantial effects from gene × gene (G×G) and gene × environment (G×E) interactions. We propose a model where ASE requires genetic variability in cis, a difference in the sequence of both alleles, but where the magnitude of the ASE effect depends on trans genetic and environmental factors that interact with the cis genetic variants.


Assuntos
Epistasia Genética/genética , Regulação da Expressão Gênica/genética , Interação Gene-Ambiente , Análise de Sequência de RNA , Transcriptoma , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Alelos , Sequência de Bases , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Variação Genética , Haplótipos/genética , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , RNA Mensageiro/biossíntese
16.
J Gerontol A Biol Sci Med Sci ; 70(7): 809-16, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25123647

RESUMO

To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis ß [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging.


Assuntos
Envelhecimento/sangue , Proteômica , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteínas de Transporte/sangue , Estudos de Coortes , Citocinas/sangue , Proteínas do Olho/sangue , Feminino , Humanos , Proteína 6 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , Metaloproteinase 12 da Matriz/sangue , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/sangue , Fenótipo , Gêmeos , Reino Unido
17.
Nat Commun ; 5: 5719, 2014 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-25502755

RESUMO

DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.


Assuntos
Caspases/genética , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Loci Gênicos , Genoma Humano , Proteínas de Neoplasias/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Caspases/sangue , Ilhas de CpG , Diabetes Mellitus Tipo 2/sangue , Epigenômica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Insulina/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/sangue , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Proteína Quinase C beta/sangue , Proteína Quinase C beta/genética , Receptores Acoplados a Proteínas-G/sangue , Receptores Acoplados a Proteínas-G/genética , Ácido Taurocólico/sangue , Gêmeos Monozigóticos
18.
Epigenetics ; 9(10): 1382-96, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25424692

RESUMO

Smoking is a major risk factor in many diseases. Genome wide association studies have linked genes for nicotine dependence and smoking behavior to increased risk of cardiovascular, pulmonary, and malignant diseases. We conducted an epigenome wide association study in peripheral-blood DNA in 464 individuals (22 current smokers and 263 ex-smokers), using the Human Methylation 450 K array. Upon replication in an independent sample of 356 twins (41 current and 104 ex-smokers), we identified 30 probes in 15 distinct loci, all of which reached genome-wide significance in the combined analysis P < 5 × 10(-8). All but one probe (cg17024919) remained significant after adjusting for blood cell counts. We replicated all 9 known loci and found an independent signal at CPOX near GPR15. In addition, we found 6 new loci at PRSS23, AVPR1B, PSEN2, LINC00299, RPS6KA2, and KIAA0087. Most of the lead probes (13 out of 15) associated with cigarette smoking, overlapped regions of open chromatin (FAIRE and DNaseI hypersensitive sites) or/and H3K27Ac peaks (ENCODE data set), which mark regulatory elements. The effect of smoking on DNA methylation was partially reversible upon smoking cessation for longer than 3 months. We report the first statistically significant interaction between a SNP (rs2697768) and cigarette smoking on DNA methylation (cg03329539). We provide evidence that the metSNP for cg03329539 regulates expression of the CHRND gene located circa 95 Kb downstream of the methylation site. Our findings suggest the existence of dynamic, reversible site-specific methylation changes in response to cigarette smoking , which may contribute to the extended health risks associated with cigarette smoking.


Assuntos
Metilação de DNA , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Análise de Sequência de RNA
19.
Nat Genet ; 46(7): 669-77, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24929828

RESUMO

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.


Assuntos
Loci Gênicos/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Pneumopatias/genética , Capacidade Vital/genética , Estudos de Coortes , Bases de Dados Genéticas , Seguimentos , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Pneumopatias/patologia , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Locos de Características Quantitativas/genética , Testes de Função Respiratória , Espirometria
20.
Elife ; 3: e01381, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24771767

RESUMO

Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ∼70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.DOI: http://dx.doi.org/10.7554/eLife.01381.001.


Assuntos
Epistasia Genética , Herança Multifatorial , Característica Quantitativa Herdável , Bioestatística , Humanos
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