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BACKGROUND: The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been proposed, but no study has linked this epigenetic variance with regrowth potential and the clinical heterogeneity of nonfunctioning pituitary adenomas. This study aimed to investigate whether DNA methylation profiling can be useful as a clinical prognostic marker. METHODS: A DNA methylation analysis by Illumina's MethylationEPIC array was performed on 54 pituitary macroadenomas from patients who underwent transsphenoidal surgery during 2007-2017. Twelve patients were excluded due to an incomplete postoperative follow-up, degenerated biobank-stored tissue, or low DNA methylation quality. For the quantitative measurement of the tumor regrowth rate, we conducted a 3D volumetric analysis of tumor remnant volume via annual magnetic resonance imaging. A linear mixed effects model was used to examine whether different DNA methylation clusters had different regrowth patterns. RESULTS: The DNA methylation profiling of 42 tissue samples showed robust DNA methylation clusters, comparable with previous findings. The subgroup of 33 nonfunctioning pituitary adenomas of an SF1-lineage showed five subclusters with an approximately unbiased score of 86%. There were no overall statistically significant differences when comparing hazard ratios for regrowth of 100%, 50%, or 0%. Despite this, plots of correlated survival estimates suggested higher regrowth rates for some clusters. The mixed effects model of accumulated regrowth similarly showed tendencies toward an association between specific DNA methylation clusters and regrowth potential. CONCLUSION: The DNA methylation profiling of nonfunctioning pituitary adenomas may potentially identify adenomas with increased growth and recurrence potential. Larger validation studies are needed to confirm the findings from this explorative pilot study.
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Body mass results from a complex interplay between genetics and environment. Previous studies of the genetic contribution to body mass have excluded repetitive regions due to the technical limitations of platforms used for population scale studies. Here we apply genome-wide approaches, identifying an association between adult body mass and the copy number (CN) of 47S-ribosomal DNA (rDNA). rDNA codes for the 18 S, 5.8 S and 28 S ribosomal RNA (rRNA) components of the ribosome. In mammals, there are hundreds of copies of these genes. Inter-individual variation in the rDNA CN has not previously been associated with a mammalian phenotype. Here, we show that rDNA CN variation associates with post-pubertal growth rate in rats and body mass index in adult humans. rDNA CN is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This aligns with the observation that the association emerges by early adulthood.
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Índice de Masa Corporal , Variaciones en el Número de Copia de ADN , ADN Ribosómico , Animales , Humanos , ADN Ribosómico/genética , Masculino , Ratas , Femenino , Adulto , Mamíferos/genética , ARN Ribosómico/genética , ARN Ribosómico/metabolismoRESUMEN
Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10-8; rs880179, p = 4.83 × 10-8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10-5 < p < 7.35 × 10-3), of which two were replicated (p < 3.10 × 10-3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.
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Epistasis Genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Anciano , Femenino , Persona de Mediana Edad , Semántica , Anciano de 80 o más Años , Redes Reguladoras de Genes , GenotipoRESUMEN
BACKGROUND: Current clinical markers overestimate the recurrence risk in many lymph node negative (LNN) breast cancer (BC) patients such that a majority of these low-risk patients unnecessarily receive systemic treatments. We tested if differential microRNA expression in primary tumors allows reliable identification of indolent LNN BC patients to provide an improved classification tool for overtreatment reduction in this patient group. METHODS: We collected freshly frozen primary tumors of 80 LNN BC patients with recurrence and 80 recurrence-free patients (mean follow-up: 20.9 years). The study comprises solely systemically untreated patients to exclude that administered treatments confound the metastasis status. Samples were pairwise matched for clinical-pathological characteristics to minimize dependence of current markers. Patients were classified into risk-subgroups according to the differential microRNA expression of their tumors via classification model building with cross-validation using seven classification methods and a voting scheme. The methodology was validated using available data of two independent cohorts (n = 123, n = 339). RESULTS: Of the 80 indolent patients (who would all likely receive systemic treatments today) our ultralow-risk classifier correctly identified 37 while keeping a sensitivity of 100% in the recurrence group. Multivariable logistic regression analysis confirmed independence of voting results from current clinical markers. Application of the method in two validation cohorts confirmed successful classification of ultralow-risk BC patients with significantly prolonged recurrence-free survival. CONCLUSION: Profiles of differential microRNAs expression can identify LNN BC patients who could spare systemic treatments demanded by currently applied classifications. However, further validation studies are required for clinical implementation of the applied methodology.
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Biomarcadores de Tumor , Neoplasias de la Mama , MicroARNs , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , MicroARNs/genética , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Anciano , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Adulto , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Medición de Riesgo/métodos , Metástasis de la Neoplasia , PronósticoRESUMEN
Preserving cognitive function with age or super-aging greatly contributes to successful aging. Super-aging nonagenarians born in Denmark in either year 1905 or 1915 were classified as Cognitively High-Performing Oldest Old individuals with a five item cognitive composite score, equivalent to or better than mean middle-aged subjects. Cognitively high-performers were more physically active and had a better physical performance on e.g., Activity of Daily Living (p-value < 0.01), gait speed (p-value < 0.01) and grip strength (p-value < 0.05) compared with age-matched peers. Cognitive high-performing was also linked to lower depression symptomatology. When comparing super-agers with semi super-agers classified by Mini Mental State Examination > 27, super-agers were still more physically active and had a better physical performance (p-value < 0.05). Results suggests that physical activity is a lifestyle factor strongly associated with both semi and full cognitive super-aging.
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Actividades Cotidianas , Cognición , Destreza Motora , Humanos , Dinamarca , Masculino , Femenino , Anciano de 80 o más Años , Cognición/fisiología , Destreza Motora/fisiología , Ejercicio Físico/psicología , Fuerza de la Mano/fisiología , Estudios de Cohortes , Envejecimiento/fisiología , Envejecimiento/psicología , Estilo de VidaRESUMEN
Carotid intima-media thickness (CIMT) is a surrogate indicator for atherosclerosis and has been shown to predict cardiovascular risk in multiple large studies. Identification of molecular markers for carotid atheroma plaque formation can be critical for early intervention and prevention of atherosclerosis. This study performed transcription factor (TF) network analysis of global gene expression data focusing on two TF genes, ZNF385D and HAND2, whose polymorphisms have been recently reported to show association with CIMT. Genome-wide gene expression data were measured from pieces of carotid endarterectomy collected from 34 hypertensive patients (atheroma plaque of stages IV and above according to the Stary classification) each paired with one sample of distant macroscopically intact tissue (stages I and II). Transcriptional regulation networks or the regulons were reconstructed for ZNF385D (5644 target genes) and HAND2 (781 target genes) using network inference. Their association with the progression of carotid atheroma was examined using gene-set enrichment analysis with extremely high statistical significance for regulons of both ZNF385D and HAND2 (p < 6.95 × 10-7) suggesting the involvement of expression quantitative loci (eQTL). Functional annotation of the regulon genes found heavy involvement in the immune system's response to inflammation and infection in the development of atherosclerosis. Detailed examination of the regulation and correlation patterns suggests that activities of the two TF genes could have high clinical and interventional impacts on impairing carotid atheroma plaque formation and preventing carotid atherosclerosis.
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Aterosclerosis , Enfermedades de las Arterias Carótidas , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/genética , Factores de Transcripción/genética , Grosor Intima-Media Carotídeo , Factores de Riesgo , Enfermedades de las Arterias Carótidas/genética , Regulación de la Expresión GénicaRESUMEN
It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.
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The correlation of early life adversity with adulthood psychopathology has already been revealed by epidemiological studies. To find the biological mechanisms underlying the cross-talk between prenatal adversity and mental health, molecular genetic studies have been performed using animal models of prenatal undernutrition and stress, reporting altered expression of serotonin receptors which modulate the release of many neurotransmitters that regulate a broad range of physiological functions including psychopathology. Unfortunately, no such study has been possible on humans due to ethical reasons. Using the Chinese Famine of 1959-1961 as a natural experiment, we investigated DNA methylation patterns in genes of the serotonin receptor signaling pathway in the whole blood of adults born during the famine. A significant pattern of reduced DNA methylation was observed in sex combined samples (p value, 0.022). In a sex-stratified analysis, the pattern was only significant in females (p-value, 0.019) but not in males. We further tested the DNA methylation patterns specifically in HTR1A, HTR2A and the X-linked HTR2C and found reduced DNA methylation in females for HTR2A (p-value 0.033) and HTR2C (p-value 0.014) but not in males. Overall, this study reveals altered epigenetic regulation of the serotonin receptor signaling pathway in association with prenatal adversity in humans providing novel epigenetic evidence in support of neurodevelopmental origin of psychiatric disorders.
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Metilación de ADN , Efectos Tardíos de la Exposición Prenatal , Masculino , Embarazo , Femenino , Animales , Humanos , Adulto , Hambruna , Epigénesis Genética , Transducción de Señal/genética , Receptores de Serotonina/genética , Efectos Tardíos de la Exposición Prenatal/genéticaRESUMEN
BACKGROUND: Elevated fasting plasma glucose (FPG) levels can increase morbidity and mortality even when it is below the diagnostic threshold of type 2 diabetes mellitus (T2DM). We conducted a genome-wide DNA methylation analysis to detect DNA methylation (DNAm) variants potentially related to FPG in Chinese monozygotic twins. METHODS: Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing (RRBS), yielding 551,447 raw CpGs. Association between DNAm of single CpG and FPG was tested using a generalized estimation equation. Differentially methylated regions (DMRs) were identified using comb-P approach. ICE FALCON method was utilized to perform the causal inference. Candidate CpGs were quantified and validated using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data from twins. RESULTS: The mean age of 52 twin pairs was 52 years (SD: 7). The relationship between DNAm of 142 CpGs and FPG reached the genome-wide significance level. Thirty-two DMRs within 24 genes were identified, including TLCD1, MRPS31P5, CASZ1, and CXADRP3. The causal relationship of top CpGs mapped to TLCD1, MZF1, PTPRN2, SLC6A18, ASTN2, IQCA1, GRIN1, and PDE2A genes with FPG were further identified using ICE FALCON method. Pathways potentially related to FPG were also identified, such as phospholipid-hydroperoxide glutathione peroxidase activity and mitogen-activated protein kinase p38 binding. Three CpGs mapped to SLC6A18 gene were validated in a community population, with a hypermethylated direction in diabetic patients. The expression levels of 18 genes (including SLC6A18 and TLCD1) were positively correlated with FPG levels. CONCLUSIONS: We detect many DNAm variants that may be associated with FPG in whole blood, particularly the loci within SLC6A18 gene. Our findings provide important reference for the epigenetic regulation of elevated FPG levels and diabetes.
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Background: Prognostic models of glioma have been the focus of many studies. However, most of them are based on Western populations. Additionally, because of the complexity of healthcare data in China, it is important to select a suitable model based on existing clinical data. This study aimed to develop and independently validate a nomogram for predicting the overall survival (OS) with newly diagnosed grade II/III astrocytoma after surgery. Methods: Data of 472 patients with astrocytoma (grades II-III) were collected from Qilu Hospital as training cohort while data of 250 participants from Linyi People's Hospital were collected as validation cohort. Cox proportional hazards model was used to construct the nomogram and individually predicted 1-, 3-, and 5-year survival probabilities. Calibration ability, and discrimination ability were analyzed in both training and validation cohort. Results: Overall survival was negatively associated with histopathology, age, subtotal resection, multiple tumors, lower KPS and midline tumors. Internal validation and external validation showed good discrimination (The C-index for 1-, 3-, and 5-year survival were 0.791, 0.748, 0.733 in internal validation and 0.754, 0.735, 0.730 in external validation, respectively). The calibration curves showed good agreement between the predicted and actual 1-, 3-, and 5-year OS rates. Conclusion: This is the first nomogram study that integrates common clinicopathological factors to provide an individual probabilistic prognosis prediction for Chinese Han patients with astrocytoma (grades II-III). This model can serve as an easy-to-use tool to advise patients and establish optimized surveillance approaches after surgery. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-023-00223-0.
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BACKGROUND: Clinical trials have shown zoledronic acid as a potent bisphosphonate in preventing bone loss, but with varying potency between patients. Human osteoclasts ex vivo reportedly displayed a variable sensitivity to zoledronic acid > 200-fold, determined by the half-maximal inhibitory concentration (IC50), with cigarette smoking as one of the reported contributors to this variation. To reveal the molecular basis of the smoking-mediated variation on treatment sensitivity, we performed a DNA methylome profiling on whole blood cells from 34 healthy female blood donors. Multiple regression models were fitted to associate DNA methylation with ex vivo determined IC50 values, smoking, and their interaction adjusting for age and cell compositions. RESULTS: We identified 59 CpGs displaying genome-wide significance (p < 1e-08) with a false discovery rate (FDR) < 0.05 for the smoking-dependent association with IC50. Among them, 3 CpGs have p < 1e-08 and FDR < 2e-03. By comparing with genome-wide association studies, 15 significant CpGs were locally enriched (within < 50,000 bp) by SNPs associated with bone and body size measures. Furthermore, through a replication analysis using data from a published multi-omics association study on bone mineral density (BMD), we could validate that 29 out of the 59 CpGs were in close vicinity of genomic sites significantly associated with BMD. Gene Ontology (GO) analysis on genes linked to the 59 CpGs displaying smoking-dependent association with IC50, detected 18 significant GO terms including cation:cation antiporter activity, extracellular matrix conferring tensile strength, ligand-gated ion channel activity, etc. CONCLUSIONS: Our results suggest that smoking mediates individual sensitivity to zoledronic acid treatment through epigenetic regulation. Our novel findings could have important clinical implications since DNA methylation analysis may enable personalized zoledronic acid treatment.
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Metilación de ADN , Epigénesis Genética , Humanos , Femenino , Ácido Zoledrónico/farmacología , Estudio de Asociación del Genoma Completo/métodos , Epigenoma , Osteoclastos , Fumar/efectos adversos , Fumar/genética , Islas de CpGRESUMEN
BACKGROUND: Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively. METHODS: Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data. RESULTS: The median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms. CONCLUSION: We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.
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Presión Sanguínea , Metilación de ADN , Epigenoma , Hipertensión , Gemelos Monocigóticos , Humanos , Pueblos del Este de Asia , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Hipertensión/genética , Proteínas Asociadas a Microtúbulos , Proteínas Tirosina Quinasas , Proteínas Activadoras de ras GTPasa , Gemelos Monocigóticos/genéticaRESUMEN
Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (pâ¯<â¯5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to pâ¯=â¯1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.
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Glioblastoma , Gemelos Monocigóticos , Persona de Mediana Edad , Humanos , Estudio de Asociación del Genoma Completo , O(6)-Metilguanina-ADN Metiltransferasa/genética , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Expresión Génica , Dinamarca , Glioblastoma/genética , Glioblastoma/metabolismo , Metilación de ADN , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Metilasas de Modificación del ADN , Proteínas Supresoras de Tumor/genética , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismoRESUMEN
Current knowledge of Alzheimer's disease (AD) etiology and effective therapy remains limited. Thus, the identification of biomarkers is crucial to improve the detection and treatment of patients with AD. Using robust rank aggregation method to analyze the microarray data from Gene Expression Omnibus database, we identified 1138 differentially expressed genes in AD. We then explored 13 hub genes by weighted gene co-expression network analysis, least absolute shrinkage, and selection operator, and logistic regression in the training dataset. The detection model, which composed of CD163, CDC42SE1, CECR6, CSF1R, CYP27A1, EIF4E3, H2AFJ, IFIT2, IL10RA, KIAA1324, PSTPIP1, SLA, and TBC1D2 genes, along with APOE gene, showed that the area under the curve for detecting AD was 0.821 (95% confidence interval [CI] = 0.782-0.861) and the model was validated in ADNI dataset (area under the curve = 0.776; 95%CI = 0.686-0.865). Notably, the 13 genes in the model were highly enriched in immune function. These findings have implications for the detection and therapeutic target of AD.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Perfilación de la Expresión Génica , Análisis por Micromatrices , Bases de Datos Factuales , InmunidadRESUMEN
We sought to examine the associations of common WWC1 variants with Alzheimer's disease (AD) and vascular dementia (VaD) among rural-dwelling older adults in China. This population-based study used data from the baseline assessments (March -September 2018) of MIND-China. AD and VaD were diagnosed following the international criteria. Of the 5455 participants (age≥60 years, 57.27% women), 182 were diagnosed with AD and 88 with VaD. Logistic regression analysis suggested that WWC1 rs17070145 C allele (vs. T) was associated with multivariable-adjusted odds ratio of 1.23 (95% confidence interval 0.96-1.58) for AD, and that CC genotype (vs. TT) was associated with multivariable-adjusted odds ratio of 2.19(1.10-4.39) for VaD, but the association with VaD became non-significant when further adjusting for stroke history. Furthermore, exonic SNPs rs3822660 and rs3822659 were in strong linkage disequilibrium (LD) with rs17070145 (D' = 0.88). These results suggest that the strong LD between rs17070145 and 2 exonic SNPs may explain the association of WWC1 rs17070145 C allele with AD and that stroke may partly explain the association of WWC1 rs17070145 CC genotype with VaD.
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Enfermedad de Alzheimer , Demencia Vascular , Accidente Cerebrovascular , Humanos , Femenino , Anciano , Masculino , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico , Demencia Vascular/genética , Demencia Vascular/diagnóstico , Genotipo , Polimorfismo de Nucleótido Simple/genética , China/epidemiología , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
Obesity is an established risk factor for hyperuricemia, but the mechanisms are only partially understood. We examined whether BMI-related DNA methylation (DNAm) variation would mediate the association of BMI with serum uric acid (SUA). We first conducted an epigenome-wide association analysis (EWAS) in 64 monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediated effect of DNAm using mediation analysis. Ontology enrichments analysis was performed for CpGs using GREAT tool. The genes where the candidate CpG mediators mapped were validated using gene expression data. BMI was positively associated with log10 transformed SUA level (ß = 0.01, P < 0.001). The association between BMI and DNAm of 138 CpGs reached P < 1 × 10-4 level. Twenty BMI-related differentially methylated regions within MAP2K2, POU4F2, AGAP2, MRGPRE, ADM5, and NKX1-1 were found. Of the 138 CpGs, 4 within VENTX (involved in cellular responses to stress pathway), SMOC2 (enable calcium ion binding), and FSCN2 (a member of fascin protein family) mediated the association between BMI and SUA, with a mediating effect of 0.002-µmol/L lower log10 transformed SUA levels and a proportion of 18.89 %-24.92 % negative mediating effect. BMI × DNAm interactions on SUA were observed for 2 CpGs within VENTX. The gene expression level of VENTX was also negatively associated with SUA level. BMI-related DNAm variation may partially mediate the association of BMI with SUA.
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Metilación de ADN , Gemelos Monocigóticos , Humanos , Gemelos Monocigóticos/genética , Ácido Úrico , Índice de Masa Corporal , Calcio , ChinaRESUMEN
The lifespan of humans varies greatly between individuals. Here, we aimed to explore what biological roles miRNAs may have on old age mortality-variation. Circulating miRNAs were measured in plasma from 43 monozygotic twin pairs (73-95 years of age) and mortality analyses were applied using Cox regression survival analyses and linear regression analyses of lifespan. In general, nominally significant miRNAs were mainly upregulated with shorter lifespan, both in Cox analysis (72 % upregulated) and in linear regression analysis (81 % upregulated). A total of 29 miRNAs were associated to mortality at a nominal significance level (p < 0.05) in the survival analysis, but no miRNAs passed the FDR adjusted level of significance. Seven of the 29 miRNAs; hsa-miR-140-3p, hsa-miR-16-5p, hsa-miR-487b-3p, hsa-miR-19a-3p, hsa-let-7d-5p, hsa-miR-320a, hsa-miR-375, were nominally significant across two linear twin-paired analyses and the cox analysis. Pathway analyses of the 29 nominally significant miRNAs from the individual level analyses resulted in two nominally significant associated Reactome pathways (unadjusted p < 0.05); 'Negative regulation of FGFR signaling' and 'Neurotransmitter receptor binding and downstream transmission in the postsynaptic cell', and two significantly associated KEGG pathways; 'Linoleic acid metabolism' and 'Toxoplasmosis'. Additional pathway analyses and results of previous studies support that miRNAs linked to mortality at age 70 years or older play a role in lipid metabolism, tissues maintenance and morphology.
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MicroARN Circulante , MicroARNs , Humanos , Anciano , MicroARN Circulante/genética , MicroARN Circulante/metabolismo , Metabolismo de los Lípidos/genética , MicroARNs/genética , MicroARNs/metabolismo , Transducción de Señal , Perfilación de la Expresión GénicaAsunto(s)
Epigenómica , Caracteres Sexuales , Envejecimiento/genética , Islas de CpG , Metilación de ADN , Epigénesis Genética , Femenino , Humanos , MasculinoRESUMEN
We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.
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Cese del Hábito de Fumar , Gemelos Monocigóticos , Niño , Escolaridad , Humanos , Fumar/genética , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genéticaRESUMEN
BACKGROUND: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time. METHODS: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history. FINDINGS: The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions. INTERPRETATION: Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation. FUNDING: Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.