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1.
Arthritis Rheumatol ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36662418

RESUMO

OBJECTIVES: To examine the genetic architecture of cam morphology, using alpha angle (AA) as a proxy measure, we conducted an AA genome wide association study (GWAS), followed by Mendelian randomisation (MR) to evaluate its causal relationship with hip osteoarthritis (HOA). METHODS: Observational analyses examined associations between AA derived from hip DXA scans in UK Biobank (UKB), and radiographic HOA (rHOA) and subsequent total hip replacement (THR). Afterwards, an AA GWAS meta-analysis was performed (n=44,214), using AA previously derived in the Rotterdam Study (RS). Linkage disequilibrium score regression assessed the genetic correlation between AA and HOA. Genetic associations with P<5x10-8 instrumented AA for two-sample MR. RESULTS: DXA-derived AA showed expected associations between AA and rHOA (OR 1.63 [95% CI 1.58-1.67]) and THR (HR 1.45 [1.33-1.59]) in UKB. The heritability of AA was 10% and AA had a moderate genetic correlation with HOA (rg =0.26 [0.10-0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on HOA risk (inverse variance weighted (IVW): OR=1.84 [1.14-2.96], P 0.01). In contrast, genetic predisposition for HOA had stronger evidence of a causal effect on increased AA (IVW: ß=0.09 [0.04-0.13], P 4.58 x 10-05 ). CONCLUSIONS: Expected observational associations between AA and related clinical outcomes provided face-validity for the DXA-derived AA measures. Evidence of bidirectional associations between AA and HOA, particularly in the reverse direction, suggests that hip shape modelling secondary to a genetic predisposition to HOA contributes to the well-established relationship between HOA and cam morphology in older adults.

2.
Nat Commun ; 13(1): 7128, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36473852

RESUMO

Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut microbiome is a novel area of interest. Here we investigate the relation of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from the Rotterdam Study cohort and validate these findings in the Amsterdam HELIUS cohort in 1,539 subjects. We identify association of thirteen microbial taxa, including genera Eggerthella, Subdoligranulum, Coprococcus, Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002, UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup, and family Ruminococcaceae with depressive symptoms. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests that the gut microbiome composition may play a key role in depression.

3.
Artigo em Inglês | MEDLINE | ID: mdl-36495186

RESUMO

OBJECTIVES: Previous systematic reviews focused on the evidence of common risk factors for knee osteoarthritis (KOA); however, the effect and strength of association between risk factors and KOA might be different between the two sexes. The aim of the present systematic review was to determine the current evidence on sex differences in the association between risk factors and KOA and their prevalence. METHODS: We searched the following electronic bibliographic databases: MEDLINE (PubMed), EMBASE and Web of Science. A methodological quality assessment was conducted independently by two researchers according to an adapted version of the standardized set of criteria known as the Newcastle-Ottawa Quality Assessment Scale (NOS). The NOS, a star system, was converted to three categories of quality. RESULTS: In total, 27 studies reported sex-specific risk estimates on several risk factors for KOA. Out of the 22 longitudinal cohort studies (except one nested case-control), 12 were of good quality and 10 were of fair quality. The 5 cross-sectional studies consisted of one good, three fair and one of poor quality. There was an indication of sex differences in risk factors leading to higher risk of KOA: high BMI, alcohol consumption, atherosclerosis, high vitamin E levels in women and high physical activity, soft drink consumption and abdominal obesity in men. Knee injury, high blood pressure and low step rate seem to affect both women and men. CONCLUSION: More good quality studies are needed to assess sex differences in risk factors for KOA, especially for symptomatic/clinical OA.

4.
BMJ Open ; 12(11): e064779, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36375984

RESUMO

INTRODUCTION: The incidence of degenerative disorders, including osteoarthritis (OA), increases rapidly in women after menopause. However, the influence of the menopause is still insufficiently investigated due to the slowness of menopausal transition. In this study, a novel human model is used in which it is expected that menopausal-related changes will occur faster. This is the Females discontinuing Oral Contraceptives Use at Menopausal age model. The ultimate aim is to link these changes to OA and other degenerative disorders, including cardiovascular diseases, diabetes, osteoporosis and tendinopathies. METHODS AND ANALYSIS: This is a pilot observational prospective cohort study with 2 years of follow-up. Fifty women aged 50-60 who use oral contraceptive (OC) and have the intention to stop are included. Measurements are performed once before stopping OC, and four times thereafter at 6 weeks, 6 months, 1 year and 2 years. At every time point, a questionnaire is filled in and a sample of blood is drawn. At the first and final time points, a physical examination, hand radiographs and a MRI scan of one knee are performed. The primary OA outcome is progression of the MRI Osteoarthritis Knee Score. Secondary OA outcomes are the development of clinical knee and hand OA, development of knee OA according to the MRI definition, and progression of radiographic features for hand OA. Principal component analysis will be used to assess which changes occur after stopping OC. Univariate and multivariate generalised estimating equation models will be used to test for associations between these components and OA. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam (MEC-2019-0592). All participants must give informed consent before data collection. Results will be disseminated in national and international journals. TRIAL REGISTRATION NUMBER: NL70796.078.19.


Assuntos
Osteoartrite do Joelho , Feminino , Humanos , Articulação do Joelho , Menopausa , Estudos Observacionais como Assunto , Osteoartrite do Joelho/diagnóstico por imagem , Estudos Prospectivos , Radiografia , Pessoa de Meia-Idade
5.
Artigo em Inglês | MEDLINE | ID: mdl-35924962

RESUMO

OBJECTIVES: The aim of this study was to identify biomarkers for radiographic osteoarthritis severity and progression acting within the inflammation and metabolic pathways. METHODS: For 3,517 Rotterdam Study participants, 184 plasma protein levels were measured using Olink inflammation and cardiometabolic panels. We studied associations with severity and progression of knee, hip, hand osteoarthritis, and a composite overall OA burden-score by multivariable regression models, adjusting for age, sex, cell counts and BMI. RESULTS: We found 18 significantly associated proteins for overall osteoarthritis burden, of which 5 stayed significant after multiple testing correction: circulating Cartilage acidic protein 1 (CRTAC1), Cartilage oligomeric matrix protein (COMP), Thrombospondin 4 (THBS4), Interleukin 18 receptor 1 (IL18R1) and Tumor necrosis factor ligand superfamily member 14 (TNFSF14). These proteins were also associated with progression of knee OA, with the exception of IL18R1. The strongest association was found for the level of CRTAC1 with 1 SD increase in protein level resulting in an increase of 0.09 (95%CI : 0.06-0.12) in overall osteoarthritis KLsum-score (p= 2.9x10-8), in the model adjusted for age, sex, BMI and cell counts. This association was also present with severity of osteoarthritis in all three joints, progression of knee osteoarthritis and was independent of BMI. We observed a stronger association for CRTAC1 with osteoarthritis than for the well-known osteoarthritis-biomarker COMP. CONCLUSION: We identified several compelling biomarkers reflecting overall osteoarthritis burden and increased risk for osteoarthritis progression. CRTAC1 was the most compelling and robust biomarker for osteoarthritis severity and progression. Such a biomarker may be used for disease monitoring.

6.
Arthritis Rheumatol ; 74(9): 1488-1496, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35644035

RESUMO

OBJECTIVE: Polygenic risk scores (PRS) allow risk stratification using common single-nucleotide polymorphisms (SNPs), and clinical applications are currently explored for several diseases. This study was undertaken to assess the risk of hip and knee osteoarthritis (OA) using PRS. METHODS: We analyzed 12,732 individuals from a population-based cohort from the Rotterdam Study (n = 11,496), a clinical cohort (Cohort Hip and Cohort Knee [CHECK] study; n = 908), and a high-risk cohort of overweight women (Prevention of Knee OA in Overweight Females [PROOF] study; n = 328), for the association of the PRS with prevalence/incidence of radiographic OA, of clinical OA, and of total hip replacement (THR) or total knee replacement (TKR). The hip PRS and knee PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent genome-wide association study meta-analysis. Standardized PRS (with Z transformation) were used in all analyses. RESULTS: We found a stronger association of the PRS for clinically defined OA compared to radiographic OA phenotypes, and we observed the highest PRS risk stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident THR (95% confidence interval [95% CI] 1.1-1.5) and 1.6 (95% CI 1.3-1.9) for incident TKR in the Rotterdam Study. The knee PRS was associated with incident clinical knee OA in the CHECK study (OR 1.3 [95% CI 1.1-1.5]), but not for the PROOF study (OR 1.2 [95% CI 0.8-1.7]). The OR for OA increased gradually across the PRS distribution, up to 2.1 (95% CI 1.4-3.2) for individuals with the 10% highest PRS compared to the middle 50% of the PRS distribution. CONCLUSION: Our findings validated the association of PRS across OA definitions. Since OA is becoming frequent and primary prevention is not commonly applicable, PRS-based risk assessment could play a role in OA prevention. However, the utility of PRS is dependent on the setting. Further studies are needed to test the integration of genetic risk assessment in diverse health care settings.


Assuntos
Artroplastia de Quadril , Osteoartrite do Quadril , Osteoartrite do Joelho , Artroplastia de Quadril/efeitos adversos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/epidemiologia , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/epidemiologia , Osteoartrite do Joelho/genética , Sobrepeso/complicações , Medição de Risco , Fatores de Risco
7.
Aging Cell ; 21(6): e13608, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35546478

RESUMO

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.


Assuntos
Doenças Cardiovasculares , Neoplasias , Biomarcadores , Doenças Cardiovasculares/genética , Metilação de DNA/genética , Epigênese Genética , Epigenômica , Humanos , Masculino , Neoplasias/genética
8.
Nat Commun ; 13(1): 2408, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504910

RESUMO

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.


Assuntos
Metilação de DNA , Inflamação , Proteína C-Reativa/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Humanos , Inflamação/genética , Motivos de Nucleotídeos
9.
Eur J Clin Invest ; 52(8): e13784, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35347712

RESUMO

BACKGROUND: Congenital cardiac outflow defects (COD) are the largest group of congenital heart defects, with ventricular septal defect (VSD) as the most prevalent phenotype. Increased maternal age, excessive oxidative stress and inflammation are involved in the pathophysiology of COD and enhance telomere length (TL) shortening. We investigated the association between periconception maternal TL and the risk of having a child with COD. METHODS: From a multicentre case-control trial, 306 case mothers of a child with COD and 424 control mothers of a child without a congenital malformation were selected. Relative TL was measured by qPCR. Multivariable logistic regression was used to compute crude and adjusted odds ratios, per standard deviation decrease, between maternal T/S ratio and COD and VSD risk. Adjustments were made for maternal age. Additional adjustments were made in a second model. RESULTS: Shorter maternal relative TL was significantly associated with an OR of 1.29 (95% CI 1.04-1.61), p = .02, for the risk of VSD in offspring, which remained significant after an adjustment for maternal age (adjOR 1.25(95% CI 1.01-1.55), p = .04). No association between maternal TL and the risk of overall COD in offspring was observed. CONCLUSION: Shorter maternal relative TL is associated with an approximately 1.3-OR for the risk, per SD in relative TL shortening, of VSD in the offspring. These findings need further confirmation in other studies on the predictive value of maternal TL.


Assuntos
Cardiopatias Congênitas , Comunicação Interventricular , Feminino , Comunicação Interventricular/genética , Humanos , Mães , Razão de Chances , Telômero/genética , Encurtamento do Telômero
10.
Rheumatology (Oxford) ; 61(2): 648-657, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33895803

RESUMO

OBJECTIVES: The aim of this study was to identify sex-specific prevalence and strength of risk factors for the incidence of radiographic knee OA (incRKOA). METHODS: Our study population consisted of 10 958 Rotterdam Study participants free of knee OA in one or both knees at baseline. One thousand and sixty-four participants developed RKOA after a median follow-up time of 9.6 years. We estimated the association between each available risk factor and incRKOA using sex stratified multivariate regression models with generalized estimating equations. Subsequently, we statistically tested sex differences between risk estimates and calculated the population attributable fractions (PAFs) for modifiable risk factors. RESULTS: The prevalence of the investigated risk factors was, in general, higher in women compared with men, except that alcohol intake and smoking were higher in men and high BMI showed equal prevalence. We found significantly different risk estimates between men and women: high level of physical activity [relative risk (RR) 1.76 (95% CI: 1.29-2.40)] or a Kellgren and Lawrence score 1 at baseline [RR 5.48 (95% CI: 4.51-6.65)] was higher in men. Among borderline significantly different risk estimates was BMI ≥27, associated with higher risk for incRKOA in women [RR 2.00 (95% CI: 1.74-2.31)]. The PAF for higher BMI was 25.6% in women and 19.3% in men. CONCLUSION: We found sex-specific differences in both presence and relative risk of several risk factors for incRKOA. Especially BMI, a modifiable risk factor, impacts women more strongly than men. These risk factors can be used in the development of personalized prevention strategies and in building sex-specific prediction tools to identify high risk profile patients.


Assuntos
Osteoartrite do Joelho/etiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Índice de Massa Corporal , Estudos de Casos e Controles , Exercício Físico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/epidemiologia , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos
11.
Hum Mol Genet ; 31(7): 1171-1182, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-34788810

RESUMO

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.


Assuntos
Aterosclerose , Espessura Intima-Media Carotídea , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco
12.
Clin Epigenetics ; 13(1): 198, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702360

RESUMO

BACKGROUND: Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. RESULTS: By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets. CONCLUSIONS: The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Biomarcadores/análise , Epigênese Genética/genética , Consumo de Bebidas Alcoólicas/genética , Área Sob a Curva , Biomarcadores/sangue , Metilação de DNA , Epigênese Genética/fisiologia , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Curva ROC , Reprodutibilidade dos Testes
13.
Eur J Hum Genet ; 29(11): 1611-1624, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34140649

RESUMO

Array technology to genotype single-nucleotide variants (SNVs) is widely used in genome-wide association studies (GWAS), clinical diagnostics, and linkage studies. Arrays have undergone a tremendous growth in both number and content over recent years making a comprehensive comparison all the more important. We have compared 28 genotyping arrays on their overall content, genome-wide coverage, imputation quality, presence of known GWAS loci, mtDNA variants and clinically relevant genes (i.e., American College of Medical Genetics (ACMG) actionable genes, pharmacogenetic genes, human leukocyte antigen (HLA) genes and SNV density). Our comparison shows that genome-wide coverage is highly correlated with the number of SNVs on the array but does not correlate with imputation quality, which is the main determinant of GWAS usability. Average imputation quality for all tested arrays was similar for European and African populations, indicating that this is not a good criterion for choosing a genotyping array. Rather, the additional content on the array, such as pharmacogenetics or HLA variants, should be the deciding factor. As the research question of a study will in large part determine which class of genes are of interest, there is not just one perfect array for all different research questions. This study can thus help as a guideline to determine which array best suits a study's requirements.


Assuntos
Testes Genéticos/normas , Técnicas de Genotipagem/normas , Análise de Sequência com Séries de Oligonucleotídeos/normas , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/normas , Técnicas de Genotipagem/métodos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Kit de Reagentes para Diagnóstico/normas , Sensibilidade e Especificidade
14.
Nat Commun ; 12(1): 2830, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990564

RESUMO

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.


Assuntos
Café/efeitos adversos , Metilação de DNA , Epigenoma , Chá/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Fatores de Risco
15.
Clin Epigenetics ; 13(1): 40, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622391

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. RESULTS: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). CONCLUSIONS: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.


Assuntos
Células Sanguíneas/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla/métodos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adulto , Idoso , Carnitina O-Palmitoiltransferase , Proteínas de Transporte , Estudos de Casos e Controles , Ilhas de CpG , Estudos Transversais , Metilação de DNA , Diabetes Mellitus Tipo 2/epidemiologia , Epigênese Genética , Epigenoma/genética , União Europeia/estatística & dados numéricos , Feminino , Histona Desacetilases , Humanos , Masculino , MicroRNAs , Pessoa de Meia-Idade , Prevalência , Proteínas Repressoras , Fatores de Risco
16.
BMC Med Genomics ; 14(1): 45, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568140

RESUMO

BACKGROUND: Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control. RESULTS: On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR) < 0.1, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls. Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect. Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes. By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls. APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0.007) and high CAC (FDR = 0.01) compared with controls. CONCLUSIONS: We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI.


Assuntos
Doença da Artéria Coronariana , Humanos , Infarto do Miocárdio , RNA Longo não Codificante/genética , Análise de Sequência de RNA , Transcriptoma
17.
Rheumatology (Oxford) ; 60(7): 3409-3412, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33463692

RESUMO

OBJECTIVE: The role of vitamin D in OA is unclear and previous epidemiological studies have provided inconsistent results. We conducted a two-sample Mendelian randomization (MR) study to investigate the causal relationship between genetically determined serum vitamin D levels and hip/knee OA. METHODS: Six single-nucleotide polymorphisms (SNPs) associated with vitamin D levels in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits Consortium were selected as instrumental variables. Summary statistics of the SNPs effects on OA were derived from the Iceland and UK Biobank, comprising 23 877 knee OA cases, 17 151 hip OA cases and >562 000 controls. The control samples match the OA cases in age, sex and county of origin. RESULTS: The MR analyses showed no causal association between genetically determined vitamin D levels and knee OA [odds ratio (OR) 1.03 (95% CI 0.84, 1.26)] or hip OA [OR 1.06 (95% CI 0.83, 1.35)]. CONCLUSION: Genetic variations associated with low vitamin D serum levels are not associated with increased risk of hip or knee OA in community-dwelling older adults, suggesting that vitamin D levels are not causally linked to OA. It is therefore unlikely that vitamin D supplementation protects against hip or knee OA.


Assuntos
Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Vitamina D/análogos & derivados , Causalidade , Humanos , Análise da Randomização Mendeliana , Razão de Chances , Osteoartrite , Osteoartrite do Quadril/epidemiologia , Osteoartrite do Joelho/epidemiologia , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , Vitamina D/genética
18.
J Dev Orig Health Dis ; 12(1): 113-123, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32327008

RESUMO

Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues.


Assuntos
Epigênese Genética , Recém-Nascido/metabolismo , Epidemiologia Molecular/métodos , Especificidade de Órgãos/genética , Placenta/metabolismo , Adulto , Estudos de Casos e Controles , Ilhas de CpG/genética , Metilação de DNA , Desenvolvimento Embrionário/genética , Feminino , Sangue Fetal , Regulação da Expressão Gênica no Desenvolvimento , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Gravidez
19.
Eur Respir J ; 57(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33122337

RESUMO

Since chronic cough has common neurobiological mechanisms and pathophysiology with chronic pain, both clinical disorders might be interrelated. Hence, we examined the association between chronic cough and chronic pain in adult subjects in the Rotterdam Study, a large prospective population-based cohort study.Using a standardised questionnaire, chronic pain was defined as pain lasting up to 6 months and grouped into a frequency of weekly/monthly or daily pain. Chronic cough was described as daily coughing for at least 3 months duration. The longitudinal and cross-sectional associations were investigated bi-directionally.Of 7141 subjects in the study, 54% (n=3888) reported chronic pain at baseline. The co-prevalence of daily chronic pain and chronic cough was 4.4%. Chronic cough was more prevalent in subjects with daily and weekly/monthly chronic pain compared with those without chronic pain (13.8% and 10.3% versus 8.2%; p<0.001). After adjustment for potential confounders, prevalent chronic pain was significantly associated with incident chronic cough (OR 1.47, 95% CI 1.08-1.99). The association remained significant in subjects with daily chronic pain (OR 1.49, 95% CI 1.06-2.11) with a similar effect estimate, albeit non-significant in those with weekly/monthly chronic pain (OR 1.43, 95% CI 0.98-2.10). After adjustment for covariables, subjects with chronic cough had a significant risk of developing chronic pain (OR 1.63, 95% CI 1.02-2.62) compared with those without chronic cough.Chronic cough and chronic pain confer risk on each other among adult subjects, indicating that both conditions might share common risk factors and/or pathophysiologic mechanisms.


Assuntos
Dor Crônica , Tosse , Adulto , Doença Crônica , Estudos de Coortes , Estudos Transversais , Humanos , Estudos Prospectivos
20.
Clin Epigenetics ; 12(1): 157, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092652

RESUMO

BACKGROUND: Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. RESULTS: We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. CONCLUSIONS: Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.


Assuntos
Doenças Cardiovasculares/genética , Epigenômica/métodos , Fumar/efeitos adversos , Triglicerídeos/genética , Idoso , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Fumar/sangue , Fumar/genética , Transcriptoma
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