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1.
Epigenetics ; 12(10): 897-908, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29099281

RESUMO

Genome-wide association studies in the fields of reproductive medicine and endocrinology are yielding robust genetic variants associated with disease. Integrated genomic, transcriptomic, and epigenomic molecular profiling studies are common methodologies used to understand the biologic pathways perturbed by these variants. However, molecular profiling resources do not include the tissue most relevant to many female reproductive traits, the endometrium, while the parameters influencing variability of results from its molecular profiling are unclear. We investigated the sources of DNA methylation and RNA expression profile variability in endometrium (n = 135), endometriotic disease tissue (endometriosis), and subcutaneous abdominal fat samples from 24 women, quantifying between-individual, within-tissue (cellular heterogeneity), and technical variation. DNA samples (n = 96) were analyzed using Illumina HumanMethlylation450 BeadChip arrays; RNA samples (n = 39) were analyzed using H12-expression arrays. Variance-component analyses showed that, for the top 10-50% variable DNA methylation/RNA expression sites, between-individual variation far exceeded within-tissue and technical variation. Menstrual-phase accounted for most variability in methylation/expression patterns in endometrium (Pm = 7.8 × 10-3, Pe = 8.4 × 10-5) but not in fat and endometriotic tissue; age was significantly associated with DNA methylation profile of endometrium (Pm = 9 × 10-5) and endometriotic disease tissue (Pm = 2.4 × 10-5); and smoking was significantly associated with DNA methylation in adipose tissue (Pm = 1.8 × 10-3). Hierarchical cluster analysis showed significantly different methylation signatures between endometrium and endometriotic tissue enriched for WNT signaling, angiogenesis, cadherin signaling, and gonadotropin-releasing-hormone-receptor pathways. Differential DNA methylation/expression analyses suggested detection of a limited number of sites with large fold changes (FC > 4), but power calculations accounting for different sources of variability showed that for robust detection >500 tissue samples are required. These results enable appropriate study design for large-scale expression and methylation tissue-based profiling relevant to many reproductive and endocrine traits.


Assuntos
Metilação de DNA/genética , Doenças do Sistema Endócrino/genética , Endometriose/genética , Reprodução/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Fatores Etários , Ilhas de CpG/genética , Doenças do Sistema Endócrino/patologia , Endometriose/patologia , Endométrio/metabolismo , Endométrio/patologia , Epigênese Genética , Feminino , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , RNA Mensageiro/genética
2.
Nat Genet ; 49(1): 125-130, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27918534

RESUMO

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.


Assuntos
Adipócitos/citologia , Distribuição da Gordura Corporal , Diferenciação Celular , Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Adipócitos/metabolismo , Animais , Estudos de Coortes , Grupos Étnicos/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Fenótipo
3.
Nature ; 541(7635): 81-86, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28002404

RESUMO

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.


Assuntos
Adiposidade/genética , Índice de Massa Corporal , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Epigenômica , Estudo de Associação Genômica Ampla , Obesidade/genética , Tecido Adiposo/metabolismo , Grupo com Ancestrais do Continente Asiático/genética , Sangue/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Índia/etnologia , Masculino , Obesidade/sangue , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações , Sobrepeso/genética
5.
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
6.
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
7.
Clin Epigenetics ; 8: 2, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26759613

RESUMO

BACKGROUND: Alterations in endometrial DNA methylation profile have been proposed as one potential mechanism initiating the development of endometriosis. However, the normal endometrial methylome is influenced by the cyclic hormonal changes, and the menstrual cycle phase-dependent epigenetic signature should be considered when studying endometrial disorders. So far, no studies have been performed to evaluate the menstrual cycle influences and endometriosis-specific endometrial methylation pattern at the same time. RESULTS: Infinium HumanMethylation 450K BeadChip arrays were used to explore DNA methylation profiles of endometrial tissues from various menstrual cycle phases from 31 patients with endometriosis and 24 healthy women. The DNA methylation profile of patients and controls was highly similar and only 28 differentially methylated regions (DMRs) between patients and controls were found. However, the overall magnitude of the methylation differences between patients and controls was rather small (Δß ranging from -0.01 to -0.16 and from 0.01 to 0.08, respectively, for hypo- and hypermethylated CpGs). Unsupervised hierarchical clustering of the methylation data divided endometrial samples based on the menstrual cycle phase rather than diseased/non-diseased status. Further analysis revealed a number of menstrual cycle phase-specific epigenetic changes with largest changes occurring during the late-secretory and menstrual phases when substantial rearrangements of endometrial tissue take place. Comparison of cycle phase- and endometriosis-specific methylation profile changes revealed that 13 out of 28 endometriosis-specific DMRs were present in both datasets. CONCLUSIONS: The results of our study accentuate the importance of considering normal cyclic epigenetic changes in studies investigating endometrium-related disease-specific methylation patterns.


Assuntos
Metilação de DNA , Endometriose/metabolismo , Endométrio/metabolismo , Epigênese Genética , Ciclo Menstrual/metabolismo , Adulto , Estudos de Casos e Controles , Endometriose/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Ciclo Menstrual/genética , Análise de Sequência com Séries de Oligonucleotídeos
8.
Curr Diab Rep ; 15(10): 83, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26363598

RESUMO

Obesity and type 2 diabetes (T2D) are common and complex metabolic diseases, which are caused by an interchange between environmental and genetic factors. Recently, a number of large-scale genome-wide association studies (GWAS) have improved our knowledge of the genetic architecture and biological mechanisms of these diseases. Currently, more than ~250 genetic loci have been found for monogenic, syndromic, or common forms of T2D and/or obesity-related traits. In this review, we discuss the implications of these GWAS for obesity and T2D, and investigate the overlap of loci for obesity-related traits and T2D, highlighting potential mechanisms that affect T2D susceptibility.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Obesidade/genética , Adiponectina/genética , Animais , Diabetes Mellitus Tipo 2/etiologia , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Obesidade/complicações
9.
Nat Genet ; 47(11): 1282-1293, 2015 11.
Artigo em Inglês | MEDLINE | ID: mdl-26390057

RESUMO

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.


Assuntos
Pressão Sanguínea/genética , Metilação de DNA , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Fatores de Risco
10.
Lancet Diabetes Endocrinol ; 3(7): 526-534, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26095709

RESUMO

BACKGROUND: Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. METHODS: We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. FINDINGS: 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34)). INTERPRETATION: DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. FUNDING: The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.


Assuntos
Metilação de DNA , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Epigênese Genética , Grupo com Ancestrais do Continente Europeu , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
11.
Genome Biol ; 16: 37, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25853392

RESUMO

DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis of genome-wide DNA methylation data remains to be determined. We developed a comprehensive analysis pipeline for epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWAS using permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identification of methylation quantitative trait loci for hypothesis driven follow-up experiments.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Ilhas de CpG/genética , Genoma Humano , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Locos de Características Quantitativas/genética , Software
12.
Nature ; 518(7538): 187-196, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25673412

RESUMO

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.


Assuntos
Tecido Adiposo/metabolismo , Distribuição da Gordura Corporal , Estudo de Associação Genômica Ampla , Insulina/metabolismo , Locos de Características Quantitativas/genética , Adipócitos/metabolismo , Adipogenia/genética , Fatores Etários , Índice de Massa Corporal , Grupos de Populações Continentais/genética , Epigênese Genética , Europa (Continente)/etnologia , Feminino , Genoma Humano/genética , Humanos , Resistência à Insulina/genética , Masculino , Modelos Biológicos , Neovascularização Fisiológica/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Caracteres Sexuais , Transcrição Genética/genética , Relação Cintura-Quadril
13.
Cell Metab ; 21(1): 138-49, 2015 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-25565211

RESUMO

Using a functional approach to investigate the epigenetics of type 2 diabetes (T2D), we combine three lines of evidence-diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence-to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change are conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk.


Assuntos
Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Células Cultivadas , Metilação de DNA , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Regulação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
14.
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
15.
PLoS One ; 8(2): e55923, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23431366

RESUMO

Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.


Assuntos
Metilação de DNA , Locos de Características Quantitativas , Gordura Subcutânea Abdominal/metabolismo , Adulto , Idoso , Estudos de Coortes , Ilhas de CpG , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma
16.
PLoS Genet ; 5(6): e1000508, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19557161

RESUMO

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.


Assuntos
Adiposidade , Distribuição da Gordura Corporal , Estudo de Associação Genômica Ampla , Lisofosfolipase/genética , Obesidade/genética , Oxirredutases/genética , Fator de Transcrição AP-2/genética , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Metionina Sulfóxido Redutases , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único , Circunferência da Cintura , Relação Cintura-Quadril
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