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1.
Nat Commun ; 10(1): 1209, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872577

RESUMO

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.


Assuntos
Doenças Cardiovasculares/genética , Ilhas de CpG/genética , Epigênese Genética , Doenças Metabólicas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Tecido Adiposo/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Metilação de DNA , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lipídeos/sangue , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
2.
Epigenetics ; 13(9): 975-987, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30264654

RESUMO

Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3×10-7) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9×10-5), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1×10-5) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

3.
Hum Mol Genet ; 26(16): 3221-3231, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28535255

RESUMO

Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea have been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation. To investigate if DNA methylation in blood is associated with coffee and tea consumption, we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed. After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated with men or with the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.


Assuntos
Café , Metilação de DNA , Chá , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cafeína/administração & dosagem , Cafeína/sangue , Estudos de Coortes , DNA/sangue , Estradiol/sangue , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
4.
Circ Cardiovasc Genet ; 10(1)2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28213390

RESUMO

BACKGROUND: Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. METHODS AND RESULTS: To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P<1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P=8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P=0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (PTC=0.004, PHDL-C=0.008 and Ptriglycerides=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. CONCLUSIONS: We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.


Assuntos
Doença das Coronárias/genética , Metilação de DNA , Dislipidemias/genética , Epigênese Genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Locos de Características Quantitativas , Idoso , Biomarcadores/sangue , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Ilhas de CpG , Estudos Transversais , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Epigenômica/métodos , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
5.
PLoS Med ; 14(1): e1002215, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28095459

RESUMO

BACKGROUND: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. CONCLUSIONS: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.


Assuntos
Índice de Massa Corporal , Doença da Artéria Coronariana/genética , Metilação de DNA , Regulação da Expressão Gênica , Leucócitos/metabolismo , Metabolismo dos Lipídeos , Idoso , Doença da Artéria Coronariana/etiologia , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Análise da Randomização Mendeliana , Obesidade/complicações , Análise de Sequência com Séries de Oligonucleotídeos
6.
BMC Med Genomics ; 9(1): 72, 2016 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-27884142

RESUMO

BACKGROUND: Oxidative stress has been related to type 2 diabetes (T2D) and cardiovascular disease (CVD), the leading global cause of death. Contributions of environmental factors such as oxidative stress on complex traits and disease may be partly mediated through changes in epigenetic marks (e.g. DNA methylation). Studies relating differential methylation with intermediate phenotypes and disease endpoints may be useful in identifying additional candidate genes and mechanisms involved in disease. METHODS: To investigate the role of epigenetic variation in oxidative stress marker levels and subsequent development of CVD and T2D, we performed analyses of genome-wide DNA methylation in blood, ten markers of oxidative stress (total glutathione [TGSH], reduced glutathione [GSH], oxidised glutathione [GSSG], GSSG to GSH ratio, homocysteine [HCY], oxidised low-density lipoprotein (oxLDL), antibodies against oxLDL [OLAB], conjugated dienes [CD], baseline conjugated dienes [BCD]-LDL and total antioxidant capacity [TAOC]) and incident disease in up to 966 age-matched individuals. RESULTS: In total, we found 66 cytosine-guanine (CpG) sites associated with one or more oxidative stress markers (false discovery rate [FDR] <0.05). These sites were enriched in regulatory regions of the genome. Genes annotated to CpG sites showed enrichment in annotation clusters relating to phospho-metabolism and proteins with pleckstrin domains. We investigated the contribution of oxidative stress-associated CpGs to development of cardiometabolic disease. Methylation variation at CpGs in the 3'-UTR of HIST1H4D (cg08170869; histone cluster 1, H4d) and in the body of DVL1 (cg03465880; dishevelled-1) were associated with incident T2D events during 10 years of follow-up (all permutation p-values <0.01), indicating a role of epigenetic regulation in oxidative stress processes leading to development or progression of diabetes. Methylation QTL (meQTL) analysis showed significant associations with genetic sequence variants in cis at 28 (42%) of oxidative stress phenotype-associated sites (FDR < 0.05). Integrating cis-meQTLs with genotype-phenotype associations indicated that genetic effects on oxidative stress phenotype at one locus (cg07547695; BCL2L11) may be mediated through DNA methylation. CONCLUSIONS: In conclusion, we report novel associations of DNA methylation with oxidative stress, some of which also show evidence of a relation with T2D incidence.


Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Metilação de DNA , Estresse Oxidativo/genética , Biomarcadores/metabolismo , Ilhas de CpG/genética , Glutationa/metabolismo , Homocisteína/metabolismo , Humanos
7.
J Lipid Res ; 57(12): 2176-2184, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27729386

RESUMO

Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a ∼410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPARγ, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids.


Assuntos
Antígenos CD36/genética , Remanescentes de Quilomícrons/sangue , Lipoproteínas LDL/sangue , Adulto , Ilhas de CpG , Metilação de DNA , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Triglicerídeos/sangue
8.
Nat Commun ; 7: 10494, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833098

RESUMO

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.


Assuntos
Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Leptina/sangue , Leptina/metabolismo , Tecido Adiposo/metabolismo , Animais , Técnicas de Silenciamento de Genes , Leptina/genética , Masculino , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Técnicas de Cultura de Tecidos
9.
Nat Commun ; 7: 10495, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833246

RESUMO

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.


Assuntos
Adiposidade/genética , Predisposição Genética para Doença , Cardiopatias/genética , Locos de Características Quantitativas/genética , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos
10.
Hum Mol Genet ; 25(4): 817-27, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26681806

RESUMO

Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA , Fator 15 de Diferenciação de Crescimento/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Ilhas de CpG , DNA/sangue , DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade
12.
Nat Commun ; 6: 7211, 2015 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-26021296

RESUMO

Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.


Assuntos
Tecido Adiposo/metabolismo , Antígenos CD36/genética , HDL-Colesterol/sangue , Metilação de DNA , Epigênese Genética , Triglicerídeos/sangue , Antígenos CD36/metabolismo , HDL-Colesterol/genética , Ilhas de CpG , Elementos Facilitadores Genéticos , Genômica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Triglicerídeos/genética
13.
Hum Mol Genet ; 24(15): 4464-79, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25935004

RESUMO

Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.


Assuntos
Aterosclerose/genética , Metilação de DNA/genética , Epigênese Genética/genética , Obesidade/genética , Afro-Americanos/genética , Idoso , Aterosclerose/patologia , Índice de Massa Corporal , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/patologia , Circunferência da Cintura/genética
14.
Nature ; 518(7538): 197-206, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25673413

RESUMO

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.


Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Obesidade/genética , Obesidade/metabolismo , Adipogenia/genética , Adiposidade/genética , Fatores Etários , Grupos de Populações Continentais/genética , Metabolismo Energético/genética , Europa (Continente)/etnologia , Feminino , Predisposição Genética para Doença/genética , Ácido Glutâmico/metabolismo , Humanos , Insulina/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sinapses/metabolismo
15.
Circ Cardiovasc Genet ; 8(2): 334-42, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25583993

RESUMO

BACKGROUND: Epigenetic mechanisms might be involved in the regulation of interindividual lipid level variability and thus may contribute to the cardiovascular risk profile. The aim of this study was to investigate the association between genome-wide DNA methylation and blood lipid levels high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and total cholesterol. Observed DNA methylation changes were also further analyzed to examine their relationship with previous hospitalized myocardial infarction. METHODS AND RESULTS: Genome-wide DNA methylation patterns were determined in whole blood samples of 1776 subjects of the Cooperative Health Research in the Region of Augsburg F4 cohort using the Infinium HumanMethylation450 BeadChip (Illumina). Ten novel lipid-related CpG sites annotated to various genes including ABCG1, MIR33B/SREBF1, and TNIP1 were identified. CpG cg06500161, located in ABCG1, was associated in opposite directions with both high-density lipoprotein cholesterol (ß coefficient=-0.049; P=8.26E-17) and triglyceride levels (ß=0.070; P=1.21E-27). Eight associations were confirmed by replication in the Cooperative Health Research in the Region of Augsburg F3 study (n=499) and in the Invecchiare in Chianti, Aging in the Chianti Area study (n=472). Associations between triglyceride levels and SREBF1 and ABCG1 were also found in adipose tissue of the Multiple Tissue Human Expression Resource cohort (n=634). Expression analysis revealed an association between ABCG1 methylation and lipid levels that might be partly mediated by ABCG1 expression. DNA methylation of ABCG1 might also play a role in previous hospitalized myocardial infarction (odds ratio, 1.15; 95% confidence interval=1.06-1.25). CONCLUSIONS: Epigenetic modifications of the newly identified loci might regulate disturbed blood lipid levels and thus contribute to the development of complex lipid-related diseases.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Metilação de DNA/genética , Epigênese Genética , Lipídeos/sangue , Infarto do Miocárdio , Proteína de Ligação a Elemento Regulador de Esterol 1 , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Loci Gênicos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
16.
Hum Mol Genet ; 24(4): 1185-99, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25296917

RESUMO

Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.


Assuntos
Endometriose/etiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Obesidade/complicações , Obesidade/genética , Locos de Características Quantitativas , Característica Quantitativa Herdável , Adiposidade/genética , Adulto , Alelos , Cromossomos Humanos Par 7 , Endometriose/diagnóstico , Endometriose/metabolismo , Feminino , Humanos , Razão de Chances , Transdução de Sinais
17.
PLoS Genet ; 10(12): e1004801, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25502724

RESUMO

Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.


Assuntos
Biomarcadores/sangue , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Idoso , Proteína C-Reativa/metabolismo , Doença das Coronárias/genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Incidência , Modelos Lineares , Estudos Longitudinais , Lisofosfatidilcolinas/sangue , Masculino , Metabolômica , Pessoa de Meia-Idade , Monoglicerídeos/sangue , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Esfingomielinas/sangue , Suécia
18.
Diabetes ; 63(3): 1154-65, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24306210

RESUMO

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10(-5)) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10(-4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10(-6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016-0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r(2) = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10(-3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.


Assuntos
Resistência à Insulina , Músculo Esquelético/enzimologia , Fosfofrutoquinase-1 Muscular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopeptidases/genética , Proteínas de Transporte de Cátions/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Transportador 8 de Zinco
19.
Am J Hum Genet ; 93(5): 876-90, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24183450

RESUMO

Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(2)median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.


Assuntos
Tecido Adiposo , Metilação de DNA , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Índice de Massa Corporal , Mapeamento Cromossômico , Epigenômica , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano , Humanos , Hibridização Genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Locos de Características Quantitativas , Análise de Sequência de DNA , Sulfitos/metabolismo , Gêmeos/genética
20.
Genome Biol ; 14(7): R75, 2013 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-23889843

RESUMO

BACKGROUND: Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age. RESULTS: Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues. CONCLUSIONS: Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.


Assuntos
Tecido Adiposo/metabolismo , Envelhecimento/sangue , Envelhecimento/genética , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Pele/metabolismo , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Transcrição Genética
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