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1.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
2.
J Hum Genet ; 63(4): 431-446, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29382920

RESUMO

Genome-wide association studies (GWAS) have identified many susceptibility loci for cardiometabolic disorders. Most of the associated variants reside in non-coding regions of the genome including long non-coding RNAs (lncRNAs), which are thought to play critical roles in diverse biological processes. Here, we leveraged data from the available GWAS meta-analyses on lipid and obesity-related traits, blood pressure, type 2 diabetes, and coronary artery disease and identified 179 associated single-nucleotide polymorphisms (SNPs) in 102 lncRNAs (p-value < 2.3 × 10-7). Of these, 55 SNPs, either the lead SNP or in strong linkage disequilibrium with the lead SNP in the related loci, were selected for further investigations. Our in silico predictions and functional annotations of the SNPs as well as expression and DNA methylation analysis of their lncRNAs demonstrated several lncRNAs that fulfilled predefined criteria for being potential functional targets. In particular, we found evidence suggesting that LOC157273 (at 8p23.1) is involved in regulating serum lipid-cholesterol. Our results showed that rs4841132 in the second exon and cg17371580 in the promoter region of LOC157273 are associated with lipids; the lncRNA is expressed in liver and associates with the expression of its nearby coding gene, PPP1R3B. Collectively, we highlight a number of loci associated with cardiometabolic disorders for which the association may act through lncRNAs.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Cardiopatias/genética , Doenças Metabólicas/genética , RNA Longo não Codificante/genética , Biologia Computacional/métodos , Metilação de DNA , Epigênese Genética , Epistasia Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , MicroRNAs/genética , Anotação de Sequência Molecular , Conformação de Ácido Nucleico , Interferência de RNA , RNA Longo não Codificante/química
3.
Aging Cell ; 16(4): 672-682, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28401650

RESUMO

We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up.


Assuntos
Caenorhabditis elegans/genética , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Longevidade/genética , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/antagonistas & inibidores , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Hidrolases/antagonistas & inibidores , Hidrolases/genética , Hidrolases/metabolismo , Anotação de Sequência Molecular , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/genética , Proteínas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Tetraspaninas/antagonistas & inibidores , Tetraspaninas/genética , Tetraspaninas/metabolismo
4.
Genome Biol ; 17(1): 255, 2016 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-27955697

RESUMO

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.


Assuntos
Proteína C-Reativa/genética , Epigênese Genética , Inflamação/genética , Locos de Características Quantitativas/genética , Afro-Americanos , Ilhas de CpG/genética , Metilação de DNA/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Inflamação/sangue , Masculino , Motivos de Nucleotídeos/genética
5.
Aging (Albany NY) ; 8(9): 1844-1865, 2016 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-27690265

RESUMO

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.


Assuntos
Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Envelhecimento/genética , Grupos de Populações Continentais , Epigênese Genética , Feminino , Humanos , Modelos Logísticos , Masculino , Mortalidade , Fatores de Risco , Análise de Sobrevida , Subpopulações de Linfócitos T
6.
Oncotarget ; 7(44): 71353-71361, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27655681

RESUMO

Genome-wide alterations in RNA expression profiles are age-associated. Yet the rate and temporal pattern of those alterations are poorly understood. We investigated temporal changes in RNA expression profiles in blood from population-based studies using a quadratic regression model. Comparative analysis between two independent studies was carried out after sample-weighting that downsized differences in sample distribution over age between the datasets. We show that age-associated expression profiles are clustered into two major inclinations and transcriptional alternations occur predominantly from the seventh decade onwards. The age-associated genes in blood are enriched in functional groups of the translational machinery and the immune system. The results are highly consistent between the two population-based studies indicating that our analysis overcomes potential confounders in population-based studies. We suggest that the critical age when major transcriptional alterations occur could help understanding aging and disease risk during adulthood.


Assuntos
RNA/sangue , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Transcrição Genética
7.
Diabetes ; 65(12): 3794-3804, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27625022

RESUMO

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis.


Assuntos
Glicemia/metabolismo , Jejum/sangue , Insulina/sangue , Transcriptoma/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética
8.
F1000Res ; 5: 109, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27134727

RESUMO

OBJECTIVE: To identify molecular biomarkers for early knee osteoarthritis (OA), we examined whether joint effusion in the knee associated with different gene expression levels in the circulation. MATERIALS AND METHODS: Joint effusion grades measured with magnetic resonance (MR) imaging and gene expression levels in blood were determined in women of the Rotterdam Study (N=135) and GARP (N=98). Associations were examined using linear regression analyses, adjusted for age, fasting status, RNA quality, technical batch effects, blood cell counts, and BMI. To investigate enriched pathways and protein-protein interactions, we used the DAVID and STRING webtools. RESULTS: In a meta-analysis, we identified 257 probes mapping to 189 unique genes in blood that were nominally significantly associated with joint effusion grades in the knee. Several compelling genes were identified such as C1orf38 and NFATC1. Significantly enriched biological pathways were: response to stress, gene expression, negative regulation of intracellular signal transduction, and antigen processing and presentation of exogenous pathways. CONCLUSION: Meta-analyses and subsequent enriched biological pathways resulted in interesting candidate genes associated with joint effusion that require further characterization. Associations were not transcriptome-wide significant most likely due to limited power. Additional studies are required to replicate our findings in more samples, which will greatly help in understanding the pathophysiology of OA and its relation to inflammation, and may result in biomarkers urgently needed to diagnose OA at an early stage.

9.
Am J Hum Genet ; 98(4): 680-96, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27040690

RESUMO

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.


Assuntos
Metilação de DNA , Epigênese Genética , Fumar/efeitos adversos , Asma/etiologia , Asma/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Fenda Labial/etiologia , Fenda Labial/genética , Fissura Palatina/etiologia , Fissura Palatina/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Gravidez
10.
Nat Commun ; 7: 10577, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26861414

RESUMO

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.


Assuntos
Metilação de DNA , Epigênese Genética , Ácido Fólico/sangue , Regulação da Expressão Gênica no Desenvolvimento , Adulto , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Recém-Nascido , Calicreínas/genética , Proteínas com Homeodomínio LIM/genética , Transportadores de Ácidos Monocarboxílicos/genética , Periferinas/genética , Gravidez , Serina Endopeptidases/genética , Fatores de Transcrição/genética
11.
Diabetologia ; 59(5): 998-1006, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26825526

RESUMO

AIMS/HYPOTHESIS: Tobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes. METHODS: We annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The discovery study consisted of 630 individuals (Bonferroni-corrected p = 1.4 × 10(-5)), and we sought replication in an independent sample of 674 individuals. The replicated sites were tested for association with nearby genetic variants and gene expression and fasting glucose and insulin levels. RESULTS: We annotated 3,620 CpG sites to the genes identified in the GWAS on type 2 diabetes. Comparing current smokers to never smokers, we found 12 differentially methylated CpG sites, of which five replicated: cg23161492 within ANPEP (p = 1.3 × 10(-12)); cg26963277 (p = 1.2 × 10(-9)), cg01744331 (p = 8.0 × 10(-6)) and cg16556677 (p = 1.2 × 10(-5)) within KCNQ1 and cg03450842 (p = 3.1 × 10(-8)) within ZMIZ1. The effect of smoking on DNA methylation at the replicated CpG sites attenuated after smoking cessation. Increased DNA methylation at cg23161492 was associated with decreased gene expression levels of ANPEP (p = 8.9 × 10(-5)). rs231356-T, which was associated with hypomethylation of cg26963277 (KCNQ1), was associated with a higher odds of diabetes (OR 1.06, p = 1.3 × 10(-5)). Additionally, hypomethylation of cg26963277 was associated with lower fasting insulin levels (p = 0.04). CONCLUSIONS/INTERPRETATION: Tobacco smoking is associated with differential DNA methylation of the diabetes risk genes ANPEP, KCNQ1 and ZMIZ1. Our study highlights potential biological mechanisms connecting tobacco smoking to excess risk of type 2 diabetes.


Assuntos
Metilação de DNA/genética , Diabetes Mellitus Tipo 2/genética , Fumar/efeitos adversos , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
12.
Hum Mol Genet ; 25(21): 4611-4623, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28158590

RESUMO

Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) <0.1, we identified 1270 differentially expressed genes in current vs. never smokers, and 39 genes in former vs. never smokers. Expression levels of 12 genes remained elevated up to 30 years after smoking cessation, suggesting that the molecular consequence of smoking may persist for decades. Gene ontology analysis revealed enrichment of smoking-related genes for activation of platelets and lymphocytes, immune response, and apoptosis. Many of the top smoking-related differentially expressed genes, including LRRN3 and GPR15, have DNA methylation loci in promoter regions that were recently reported to be hypomethylated among smokers. By linking differential gene expression with smoking-related disease phenotypes, we demonstrated that stroke and pulmonary function show enrichment for smoking-related gene expression signatures. Mediation analysis revealed the expression of several genes (e.g. ALAS2) to be putative mediators of the associations between smoking and inflammatory biomarkers (IL6 and C-reactive protein levels). Our transcriptomic study provides potential insights into the effects of cigarette smoking on gene expression in whole blood and their relations to smoking-related diseases. The results of such analyses may highlight attractive targets for treating or preventing smoking-related health effects.


Assuntos
Fumar Cigarros/genética , Expressão Gênica/efeitos dos fármacos , Adulto , Idoso , Fumar Cigarros/sangue , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fumar/genética , Transcriptoma/efeitos dos fármacos
13.
Pain Pract ; 16(7): 831-41, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26205731

RESUMO

OBJECTIVE: Chronic musculoskeletal pain is accompanied by central sensitization, which can be determined with quantitative sensory testing (QST). In this study, we aim to investigate whether central sensitization, as measured by thermal QST, is detectable in community-dwelling elderly individuals suffering from self-reported chronic pain and identify determinants influencing thermal QST measurement analyses and interpretation. METHODS: In 3,936 participants of the Rotterdam Study, cold and warmth sensitivity and heat pain thresholds were determined using the thermo-sensory analyzer TSA II (Medoc Advanced Medical Systems, Durham, NC, U.S.A.). Using Cox regression, associations were studied with chronic pain and potential determinants (body mass index [BMI], reaction speed, systolic and diastolic blood pressure, skin color, skin temperature, seasonal influence, depression, anxiety, atopic eczema, age at menarche, years since menopause, hormone replacement therapy (HRT) use during menopause, and reproductive lifespan). RESULTS: In addition to the effect of age and gender on thermal sensitivity, darker skin color and the presence of atopic eczema were associated with higher sensitivity for heat pain. Cold sensitivity and warmth sensitivity thresholds were both influenced by BMI, reaction speed, skin temperature, season, depression, dark skin color, years since menopause, and reproductive lifespan. The presence of chronic pain was associated with 0.2 degrees lower heat pain threshold in all participants, and 0.3 degrees lower in individuals with chronic pain in more than 2 sites. CONCLUSION: Higher sensitivity for heat pain, one feature of central sensitization, is present in community-dwelling elderly with chronic pain. Additional determinants should be considered when analyzing and interpreting QST measurements.


Assuntos
Dor Musculoesquelética/diagnóstico , Medição da Dor/métodos , Idoso , Dor Crônica , Feminino , Humanos , Masculino , Limiar da Dor/fisiologia
14.
Nat Commun ; 6: 8570, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26490707

RESUMO

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.


Assuntos
Envelhecimento/sangue , Transcriptoma , Biomarcadores/sangue , Metilação de DNA , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos
15.
Clin Epigenetics ; 7: 54, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26015811

RESUMO

BACKGROUND: Tobacco smoking, a risk factor for coronary artery disease (CAD), is known to modify DNA methylation. We hypothesized that tobacco smoking modifies methylation of the genes identified for CAD by genome-wide association study (GWAS). RESULTS: We selected genomic regions based on 150 single-nucleotide polymorphisms (SNPs) identified in the largest GWAS on CAD. We investigated the association between current smoking and the CpG sites within and near these CAD-related genes. Methylation was measured with the Illumina Human Methylation 450K array in whole blood of 724 Caucasian subjects from the Rotterdam Study, a Dutch population based cohort study. A total of 3669 CpG sites within 169 CAD-related genes were studied for association with current compared to never smoking. Fifteen CpG sites were significantly associated after correction for multiple testing (Bonferroni-corrected p value <1.4 × 10(-5)). These sites were located in the genes TERT, SARS, GNGT2, SMG6, SKI, TOM1L2, SIPA1, MRAS, CDKN1A, LRRC2, FES and RPH3A. In 12 sites, current smoking was associated with a 1.2 to 2.4 % lower methylation compared to never smoking; and in three sites, it was associated with a 1.2 to 1.8 % higher methylation. The effect estimates were lower in 10 of the 15 CpG sites when comparing current to former smoking. One CpG site, cg05603985 (SKI), was found to be associated with expression of nearby CAD-related gene PRKCZ. CONCLUSIONS: Our study suggests an effect of tobacco smoking on DNA methylation of CAD-related genes and thus provides novel insights in the pathways that link tobacco smoking to risk of CAD.

16.
PLoS Genet ; 11(5): e1005223, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25955312

RESUMO

The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.


Assuntos
Linfócitos/citologia , Neutrófilos/citologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Linhagem Celular , Doença de Crohn/genética , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla/métodos , Humanos , Linfócitos/metabolismo , Neutrófilos/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Fenótipo , Análise de Componente Principal , Reprodutibilidade dos Testes
17.
PLoS Genet ; 11(3): e1005035, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25785607

RESUMO

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.


Assuntos
Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Hipertensão/genética , Transcriptoma/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/patologia , Polimorfismo de Nucleotídeo Único
18.
Nat Commun ; 6: 5897, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-25631608

RESUMO

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (ß=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (ß=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (ß=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (ß=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Exoma/genética , Jejum/sangue , Predisposição Genética para Doença , Variação Genética , Taxa de Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Grupo com Ancestrais do Continente Africano/genética , Diabetes Mellitus Tipo 2/sangue , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Loci Gênicos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Glucose-6-Fosfatase/genética , Humanos , Insulina/sangue , Polimorfismo de Nucleotídeo Único/genética
19.
Hum Mutat ; 35(12): 1524-31, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25256095

RESUMO

MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein-cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3, and GOSR2) through which these effects might be taking place. Using luciferase reporter assays, we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA-mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases.


Assuntos
Glicemia/metabolismo , Pressão Sanguínea/genética , Doença da Artéria Coronariana/genética , Homeostase/genética , Metabolismo dos Lipídeos , MicroRNAs/genética , Sequência de Bases , Primers do DNA , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo Genético , Locos de Características Quantitativas
20.
Arthritis Care Res (Hoboken) ; 66(9): 1337-43, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24623639

RESUMO

OBJECTIVE: Type 3 finger length pattern (longer fourth digit than second digit) is influenced by prenatal androgens and has been studied previously as a biomarker for sexually dimorphic traits. Because osteoarthritis (OA) and chronic pain are known to be sexually dimorphic traits, we evaluated the association between finger length pattern and OA and chronic joint pain. METHODS: This study was part of the Rotterdam Study, a prospective population-based cohort study. We examined 4,784 participants. Associations between type 3 finger length and radiologic knee, hip, and hand OA and chronic joint pain were analyzed using a logistic regression model. Our results for OA were combined with previously published data in a meta-analysis. RESULTS: Participants with type 3 finger length pattern had an odds ratio of 1.64 for hand OA (P = 1.06 × 10(-7)). No associations with radiologic knee or hip OA were observed in the Rotterdam Study. The meta-analysis of previously published data and our novel data showed a significant association between type 3 finger length pattern and clinical symptomatic knee OA, but no association was found with radiologic knee OA. In addition, within the Rotterdam Study, we observed an odds ratio of 1.41 for individuals having joint pain at multiple sites (P = 1.4 × 10(-3)). CONCLUSION: Type 3 finger length pattern, as an indicator of prenatal androgen exposure, was associated with having symptomatic knee OA, chronic pain, and hand OA. Therefore, it may be applicable as an easy measurable biomarker to identify susceptible subjects for these traits.


Assuntos
Artralgia/diagnóstico , Dor Crônica/diagnóstico , Dedos/anatomia & histologia , Osteoartrite do Quadril/diagnóstico , Osteoartrite do Joelho/diagnóstico , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
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