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1.
EBioMedicine ; 79: 104000, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35490552

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions. METHODS: Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432). FINDINGS: Each trait MS was significantly associated with its corresponding phenotype in GS (ßrange=0.089-1.457) and in ALSPAC (ßrange=0.078-2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (ßrange=0.053-0.145). After accounting for relevant lifestyle factors, MS for educational attainment (ß=0.094) and alcohol consumption (MSp-value<0.01-0.5; ßrange=-0.069-0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes. INTERPRETATION: We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominal<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort (NALSPAC=565; NGS=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes. FUNDING: Wellcome Trust.

2.
Nat Commun ; 13(1): 2408, 2022 May 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
3.
Atherosclerosis ; 348: 44-50, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35452865

RESUMO

BACKGROUND AND AIMS: We aimed to determine associations of plasma amyloid-ß40 (Aß40) with subclinical atherosclerosis and risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. METHODS: Between 2002 and 2005, plasma Aß40 was measured by single molecule array (SiMoA®) in 3879 participants of the population-based Rotterdam Study (mean age: 71 years, 61% female). Subclinical atherosclerosis was quantified as computed tomography-assessed calcification volumes. We determined the association of Aß40 with calcification volumes and clinical ASCVD event risk, and repeated the analyses for ASCVD in a replication cohort of 1467 individuals. RESULTS: Higher levels of Aß40 were associated with increased volumes of calcification in the coronary arteries and to a lesser extent extracranial carotid arteries, independent of traditional cardiovascular risk factors. Of all 3879 participants, 748 developed ASCVD during a median 9.7 years of follow-up. In age- and sex-adjusted models, higher Aß40 predisposed to a minor increase in ASCVD risk (HR [95%CI]: 1.11[1.02-1.21] per 1-SD increase in Aß40), driven by coronary heart disease (HR: 1.17[1.05-1.29]) rather than stroke (HR: 1.04[0.93-1.16]). However, excess risk of clinical outcomes was largely explained by baseline differences in cardiovascular risk factors and attenuated after further adjustment (for ASCVD- HR: 1.05[0.96-1.15] and for CHD- HR: 1.08[0.96-1.20]). Results were similar in the replication cohort, with highest risk estimates for CHD (HR: 1.24[1.04-1.48]) in age- and sex-adjusted models, attenuated after adjustment for cardiovascular risk factors (HR: 1.15[0.96-1.39]). CONCLUSIONS: In this population-based study, higher plasma amyloid-ß40 is associated with subclinical atherosclerosis, but not risk of first-ever ASCVD after accounting for traditional cardiovascular risk factors.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Doença das Coronárias , Idoso , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Vasos Coronários , Feminino , Humanos , Masculino , Medição de Risco , Fatores de Risco
4.
Commun Biol ; 5(1): 336, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396452

RESUMO

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.


Assuntos
Doença de Alzheimer , Tauopatias , Afro-Americanos/genética , Doença de Alzheimer/genética , Exoma , Estudo de Associação Genômica Ampla , Humanos
5.
Anal Chem ; 94(14): 5493-5503, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35360896

RESUMO

Integration of multiple datasets can greatly enhance bioanalytical studies, for example, by increasing power to discover and validate biomarkers. In liquid chromatography-mass spectrometry (LC-MS) metabolomics, it is especially hard to combine untargeted datasets since the majority of metabolomic features are not annotated and thus cannot be matched by chemical identity. Typically, the information available for each feature is retention time (RT), mass-to-charge ratio (m/z), and feature intensity (FI). Pairs of features from the same metabolite in separate datasets can exhibit small but significant differences, making matching very challenging. Current methods to address this issue are too simple or rely on assumptions that cannot be met in all cases. We present a method to find feature correspondence between two similar LC-MS metabolomics experiments or batches using only the features' RT, m/z, and FI. We demonstrate the method on both real and synthetic datasets, using six orthogonal validation strategies to gauge the matching quality. In our main example, 4953 features were uniquely matched, of which 585 (96.8%) of 604 manually annotated features were correct. In a second example, 2324 features could be uniquely matched, with 79 (90.8%) out of 87 annotated features correctly matched. Most of the missed annotated matches are between features that behave very differently from modeled inter-dataset shifts of RT, MZ, and FI. In a third example with simulated data with 4755 features per dataset, 99.6% of the matches were correct. Finally, the results of matching three other dataset pairs using our method are compared with a published alternative method, metabCombiner, showing the advantages of our approach. The method can be applied using M2S (Match 2 Sets), a free, open-source MATLAB toolbox, available at https://github.com/rjdossan/M2S.


Assuntos
Metabolômica , Biomarcadores/análise , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Metabolômica/métodos
6.
Neurology ; 98(17): e1729-e1737, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35232820

RESUMO

BACKGROUND AND OBJECTIVES: To unravel whether Alzheimer disease-related pathology or neurodegeneration plays a role in stroke etiology, we determined the effect of plasma levels ß-amyloid (Aß), total-tau, and neurofilament light chain (NfL) on risk of stroke and its subtypes. METHODS: Between 2002 and 2005, we measured plasma Aß40, Aß42, total-tau, and NfL in 4,661 stroke-free participants from the population-based Rotterdam Study. We used Cox proportional-hazards models to determine the association between these markers with incident stroke for the entire cohort, per stroke subtype, and by median age, sex, APOE ε4 carriership, and education. RESULTS: After a mean follow-up of 10.8 ± 3.3 years, 379 participants had a first-ever stroke. Log2 total-tau at baseline showed a nonlinear association with risk of any stroke and ischemic stroke: compared to the first (lowest) quartile, the adjusted hazard ratio (HR) for the highest quartile total-tau was 1.68 (95% CI 1.18-2.40) for any stroke. Log2 NfL was associated with an increased risk of any stroke (HR per 1-SD increase 1.27, 95% CI 1.12-1.44), ischemic stroke, and hemorrhagic stroke (HR 1.56, 95% CI 1.14-2.12). Log2 Aß40, Aß42, and Aß42/40 ratio levels were not associated with stroke risk. DISCUSSION: Participants with higher total-tau and NfL at baseline had a higher risk of stroke and several stroke subtypes. These findings support the role of markers of neurodegeneration in the etiology of stroke. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that higher plasma levels of total-tau and NfL are associated with an increased risk of subsequent stroke.


Assuntos
Doença de Alzheimer , AVC Isquêmico , Acidente Vascular Cerebral , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Biomarcadores , Humanos , Filamentos Intermediários/patologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia
7.
Hum Mol Genet ; 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35234888

RESUMO

Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of Abdominal Aortic Aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in ten cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects (PBIO) as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In GWAS on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, p-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (p-value = 8.19 × 10-4). In exome-array single-variant analysis (p-value threshold = 9 × 10-7), the lowest p-value was found for rs239259 located in SLC22A20 (beta = 0.007, p-value =1.2 × 10-5). In the gene-based analysis (p-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (p-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, p-value = 0.02), triglycerides (beta = -0.16, p-value = 0.008) and height (beta = 0.03, p-value<0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

8.
Nat Genet ; 54(2): 152-160, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35115687

RESUMO

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Alelos , Sistema Cardiovascular/metabolismo , Estudos de Casos e Controles , Sistema Nervoso Central/metabolismo , Loci Gênicos , Humanos , Enxaqueca com Aura/genética , Anotação de Sequência Molecular , Locos de Características Quantitativas
9.
Circulation ; 145(14): 1040-1052, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35050683

RESUMO

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.


Assuntos
Diabetes Mellitus Tipo 2 , Substância Branca , Idoso , Encéfalo/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Metaboloma , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem
10.
Eur J Prev Cardiol ; 28(16): 1850-1857, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34583386

RESUMO

AIMS: Data on the lifetime risk of type 2 diabetes (T2D) incidence across different cardiovascular health (CVH) categories are scarce. Moreover, it remains unclear whether a genetic predisposition modifies this association. METHODS AND RESULTS: Using data from the prospective population-based Rotterdam Study, a CVH score (body mass index, blood pressure, total cholesterol, smoking status, diet, and physical activity) was calculated and further categorized at baseline. Genetic predisposition to T2D was assessed and divided into tertiles by creating a genetic risk score (GRS). We estimated the lifetime risk for T2D within different CVH and GRS categories. Among 5993 individuals free of T2D at baseline [mean (standard deviation) age, 69.1 (8.5) years; 58% female], 869 individuals developed T2D during follow-up. At age 55 years, the remaining lifetime risk of T2D was 22.6% (95% CI: 19.4-25.8) for ideal, 28.3% (25.8-30.8) for intermediate, and 32.6% (29.0-36.2) for poor CVH. After further stratification by GRS tertiles, the lifetime risk for T2D was still the lowest for ideal CVH in the lowest GRS tertiles [21.5% (13.7-29.3)], in the second GRS tertile [20.8% (15.9-25.8)], and in the highest tertile [23.5% (18.5-28.6)] when compared with poor and intermediate CVH. CONCLUSION: Our results highlight the importance of favourable CVH in preventing T2D among middle-aged individuals regardless of their genetic predisposition.


Assuntos
Doenças Cardiovasculares , Sistema Cardiovascular , Diabetes Mellitus Tipo 2 , Idoso , Pressão Sanguínea/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
11.
Clin Mol Hepatol ; 28(2): 183-195, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34839623

RESUMO

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic dysfunction. Among the multiple factors, genetic variation acts as important modifiers. Klotho, an enzyme encoded by the klotho (KL) gene in human, has been implicated in the pathogenesis of metabolic dysfunctions. However, the impact of variants in KL on NAFLD risk remains poorly understood. The aim of this study was to investigate the impact of KL rs495392 C>A polymorphism on the histological severity of NAFLD. METHODS: We evaluated the impact of the KL rs495392 polymorphism on liver histology in 531 Chinese with NAFLD and replicated that in the population-based Rotterdam Study cohort. The interactions between the rs495392, vitamin D, and patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism were also analyzed. RESULTS: Carriage of the rs495392 A allele had a protective effect on steatosis severity (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.42-0.89; P=0.010) in Chinese patients. After adjustment for potential confounders, the A allele remained significant with a protective effect (OR, 0.66; 95% CI, 0.45-0.98; P=0.040). The effect on hepatic steatosis was confirmed in the Rotterdam Study cohort. Additional analysis showed the association between serum vitamin D levels and NAFLD specifically in rs495392 A allele carriers, but not in non-carriers. Moreover, we found that the rs495392 A allele attenuated the detrimental impact of PNPLA3 rs738409 G allele on the risk of severe hepatic steatosis. CONCLUSION: The KL rs495392 polymorphism has a protective effect against hepatic steatosis in patients with NAFLD.


Assuntos
/genética , Hepatopatia Gordurosa não Alcoólica , Predisposição Genética para Doença , Humanos , Lipase/genética , Fígado/patologia , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Vitamina D/metabolismo
12.
Diabetes Care ; 45(1): 232-240, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34789503

RESUMO

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.


Assuntos
Diabetes Mellitus Tipo 2 , LDL-Colesterol , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Fatores de Risco
13.
Clin Gastroenterol Hepatol ; 20(3): e573-e582, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33618024

RESUMO

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new terminology updated from non-alcoholic fatty liver disease (NAFLD). In this study, we aim to estimate the global prevalence of MAFLD specifically in overweight and obese adults from the general population by performing a systematic review and meta-analysis through mining the existing epidemiological data on fatty liver disease. METHODS: We searched Medline, Embase, Web of Science, Cochrane and google scholar database from inception to November, 2020. DerSimonian-Laird random-effects model with Logit transformation was performed for data analysis. Sensitivity analysis and meta-regression were used to explore predictors of MAFLD prevalence in pooled statistics with high heterogeneity. RESULTS: We identified 116 relevant studies comprised of 2,667,052 participants in general population with an estimated global MAFLD prevalence as 50.7% (95% CI 46.9-54.4) among overweight/obese adults regardless of diagnostic techniques. Ultrasound was the most commonly used diagnostic technique generating prevalence rate of 51.3% (95% CI, 49.1-53.4). Male (59.0%; 95% CI, 52.0-65.6) had a significantly higher MAFLD prevalence than female (47.5%; 95% CI, 40.7-54.5). Interestingly, MAFLD prevalence rates are comparable based on classical NAFLD and non-NAFLD studies in general population. The pooled estimate prevalence of comorbidities such as type 2 diabetes and metabolic syndrome was 19.7% (95% CI, 12.8-29.0) and 57.5% (95% CI, 49.9-64.8), respectively. CONCLUSIONS: MAFLD has an astonishingly high prevalence rate in overweight and obese adults. This calls for attention and dedicated action from primary care physicians, specialists, health policy makers and the general public alike.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Sobrepeso/complicações , Sobrepeso/epidemiologia , Prevalência
14.
Diabetes Care ; 45(3): 674-683, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35085396

RESUMO

OBJECTIVE: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed ß-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS: Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.


Assuntos
Diabetes Mellitus Tipo 2 , Preparações Farmacêuticas , Alelos , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Loci Gênicos , Humanos , Obesidade/genética , Preparações Farmacêuticas/metabolismo
15.
Nat Commun ; 12(1): 7173, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887389

RESUMO

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.


Assuntos
Epigenoma , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/genética , Ácido Úrico/sangue , Sistema y+ de Transporte de Aminoácidos/genética , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Gota/sangue , Humanos , Masculino
16.
Nat Commun ; 12(1): 7174, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887417

RESUMO

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.


Assuntos
Metilação de DNA , Insuficiência Renal Crônica/genética , Adulto , Idoso , Ilhas de CpG , Feminino , Taxa de Filtração Glomerular , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Rim/metabolismo , Rim/fisiopatologia , Testes de Função Renal , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
BMC Med ; 19(1): 266, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34727949

RESUMO

BACKGROUND: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. METHODS: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. RESULTS: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). CONCLUSIONS: Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.


Assuntos
Doenças Cardiovasculares , Tireotropina , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Feminino , Humanos , Lipídeos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Tiroxina , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-34612501

RESUMO

BACKGROUND: Inflammatory processes have been implicated in the development of chronic kidney disease (CKD). We investigated the association of a large panel of inflammatory biomarkers reflecting aspects of immunity with kidney function and CKD incidence. METHODS: We used data from two independent population-based studies, KORA F4 (discovery, n = 1,110, mean age 70.3 years, 48.7% male) and ESTHER (replication, n = 1,672, mean age 61.9 years, 43.6% male). Serum levels of biomarkers were measured using proximity extension assay technology. The association of biomarkers with estimated glomerular filtration rate (eGFR) at baseline and with incident CKD was investigated using linear and logistic regression models adjusted for cardiorenal risk factors. Independent results from prospective analyses of both studies were pooled. The significance level was corrected for multiple testing by false-discovery rate (PFDR < 0.05.). RESULTS: In the KORA F4 discovery study, 52 out of 71 inflammatory biomarkers were inversely associated with eGFR estimated based on serum creatinine. Top biomarkers included CD40, TNFRSF9 and IL10RB. Forty-two of these 52 biomarkers were replicated in the ESTHER study. Nine of the 42 biomarkers were associated with incident CKD independently of cardiorenal risk factors in the meta-analysis of the KORA (n = 142, mean follow-up of 6.5 years) and ESTHER (n = 103, mean follow-up of 8 years) studies. Pathway analysis revealed the involvement of inflammatory and immunomodulatory processes reflecting cross-communication of innate and adaptive immune cells. CONCLUSIONS: Novel and known biomarkers of inflammation were reproducibly associated with kidney function. Future studies should investigate their clinical utility and underlying molecular mechanisms in independent cohorts.

19.
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
20.
Circulation ; 144(24): 1899-1911, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34587750

RESUMO

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P<0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; P<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.


Assuntos
Envelhecimento , Metilação de DNA , Epigênese Genética , Modelos Cardiovasculares , Modelos Genéticos , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Epigenômica , Feminino , Seguimentos , Humanos , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
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