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1.
Bioinformatics ; 35(14): i233-i241, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31510689

RESUMO

MOTIVATION: With the wide availability of whole-genome genotype data, there is an increasing need for conducting genetic genealogical searches efficiently. Computationally, this task amounts to identifying shared DNA segments between a query individual and a very large panel containing millions of haplotypes. The celebrated Positional Burrows-Wheeler Transform (PBWT) data structure is a pre-computed index of the panel that enables constant time matching at each position between one haplotype and an arbitrarily large panel. However, the existing algorithm (Durbin's Algorithm 5) can only identify set-maximal matches, the longest matches ending at any location in a panel, while in real genealogical search scenarios, multiple 'good enough' matches are desired. RESULTS: In this work, we developed two algorithmic extensions of Durbin's Algorithm 5, that can find all L-long matches, matches longer than or equal to a given length L, between a query and a panel. In the first algorithm, PBWT-Query, we introduce 'virtual insertion' of the query into the PBWT matrix of the panel, and then scanning up and down for the PBWT match blocks with length greater than L. In our second algorithm, L-PBWT-Query, we further speed up PBWT-Query by introducing additional data structures that allow us to avoid iterating through blocks of incomplete matches. The efficiency of PBWT-Query and L-PBWT-Query is demonstrated using the simulated data and the UK Biobank data. Our results show that our proposed algorithms can detect related individuals for a given query efficiently in very large cohorts which enables a fast on-line query search. AVAILABILITY AND IMPLEMENTATION: genome.ucf.edu/pbwt-query. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

2.
J Am Coll Nutr ; : 1-7, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498715

RESUMO

Objective: To investigate gut microbial composition in Latino infants in relation to breastfeeding, obesity, and antibiotic exposure. Method: We analyzed the gut microbiome in 6-month-old Latino infants from an ongoing urban mother-child cohort. Alpha and beta diversity were assessed in relation to infants' early dietary exposure and anthropometrics including obesity. Results: Infants exclusively breastfed at 4 to 6 weeks had lower alpha diversity and less bacterial abundance compared with those who did not. Breastfeeding status at 4 to 6 weeks and 6 months of age accounted for differences in alpha and beta diversity. Infants who were obese at 6 months of age had higher levels of alpha diversity compared with non-obese infants. Conclusions: Early exclusive breastfeeding and obesity impacts microbial diversity by 6 months of age in Latino infants, a group at high risk for future obesity.

3.
Mol Genet Genomic Med ; 7(10): e00788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407531

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates. RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

4.
Genome Biol ; 20(1): 143, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345249

RESUMO

While genetic relatedness, usually manifested as segments identical by descent (IBD), is ubiquitous in modern large biobanks, current IBD detection methods are not efficient at such a scale. Here, we describe an efficient method, RaPID, for detecting IBD segments in a panel with phased haplotypes. RaPID achieves a time and space complexity linear to the input size and the number of reported IBDs. With simulation, we showed that RaPID is orders of magnitude faster than existing method while offering competitive power and accuracy. In UK Biobank, RaPID identified 3,335,807 IBDs with a lenght ≥ 10 cM among 223,507 male X chromosomes in 11 min.


Assuntos
Técnicas de Genotipagem/métodos , Linhagem , Bancos de Espécimes Biológicos , Cromossomos Humanos X , Estudos de Coortes , Simulação por Computador , Haplótipos , Humanos , Masculino
5.
BMC Bioinformatics ; 20(Suppl 11): 279, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31167638

RESUMO

BACKGROUND: Recent advances in whole-genome sequencing and SNP array technology have led to the generation of a large amount of genotype data. Large volumes of genotype data will require faster and more efficient methods for storing and searching the data. Positional Burrows-Wheeler Transform (PBWT) provides an appropriate data structure for bi-allelic data. With the increasing sample sizes, more multi-allelic sites are expected to be observed. Hence, there is a necessity to handle multi-allelic genotype data. RESULTS: In this paper, we introduce a multi-allelic version of the Positional Burrows-Wheeler Transform (mPBWT) based on the bi-allelic version for compression and searching. The time-complexity for constructing the data structure and searching within a panel containing t-allelic sites increases by a factor of t. CONCLUSION: Considering the small value for the possible alleles t, the time increase for the multi-allelic PBWT will be negligible and comparable to the bi-allelic version of PBWT.


Assuntos
Algoritmos , Alelos , Compressão de Dados , Genes , Haplótipos/genética , Humanos , Fatores de Tempo
6.
J Am Med Inform Assoc ; 26(11): 1263-1271, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31197365

RESUMO

OBJECTIVE: HIV infection risk can be estimated based on not only individual features but also social network information. However, there have been insufficient studies using n machine learning methods that can maximize the utility of such information. Leveraging a state-of-the-art network topology modeling method, graph convolutional networks (GCN), our main objective was to include network information for the task of detecting previously unknown HIV infections. MATERIALS AND METHODS: We used multiple social network data (peer referral, social, sex partners, and affiliation with social and health venues) that include 378 young men who had sex with men in Houston, TX, collected between 2014 and 2016. Due to the limited sample size, an ensemble approach was engaged by integrating GCN for modeling information flow and statistical machine learning methods, including random forest and logistic regression, to efficiently model sparse features in individual nodes. RESULTS: Modeling network information using GCN effectively increased the prediction of HIV status in the social network. The ensemble approach achieved 96.6% on accuracy and 94.6% on F1 measure, which outperformed the baseline methods (GCN, logistic regression, and random forest: 79.0%, 90.5%, 94.4% on accuracy, respectively; and 57.7%, 80.2%, 90.4% on F1). In the networks with missing HIV status, the ensemble also produced promising results. CONCLUSION: Network context is a necessary component in modeling infectious disease transmissions such as HIV. GCN, when combined with traditional machine learning approaches, achieved promising performance in detecting previously unknown HIV infections, which may provide a useful tool for combatting the HIV epidemic.

7.
BMC Med Inform Decis Mak ; 19(Suppl 2): 58, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30961579

RESUMO

BACKGROUND: Learning distributional representation of clinical concepts (e.g., diseases, drugs, and labs) is an important research area of deep learning in the medical domain. However, many existing relevant methods do not consider temporal dependencies along the longitudinal sequence of a patient's records, which may lead to incorrect selection of contexts. METHODS: To address this issue, we extended three popular concept embedding learning methods: word2vec, positive pointwise mutual information (PPMI) and FastText, to consider time-sensitive information. We then trained them on a large electronic health records (EHR) database containing about 50 million patients to generate concept embeddings and evaluated them for both intrinsic evaluations focusing on concept similarity measure and an extrinsic evaluation to assess the use of generated concept embeddings in the task of predicting disease onset. RESULTS: Our experiments show that embeddings learned from information within one visit (time window zero) improve performance on the concept similarity measure and the FastText algorithm usually had better performance than the other two algorithms. For the predictive modeling task, the optimal result was achieved by word2vec embeddings with a 30-day sliding window. CONCLUSIONS: Considering time constraints are important in training clinical concept embeddings. We expect they can benefit a series of downstream applications.

8.
BMC Med Genomics ; 12(Suppl 1): 26, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704471

RESUMO

BACKGROUND: Cardiovascular disease, diabetes, and kidney disease are among the leading causes of death and disability worldwide. However, knowledge of genetic determinants of those diseases in African Americans remains limited. RESULTS: In our study, associations between 4956 GWAS catalog reported SNPs and 67 traits were examined among 7726 African Americans from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is focused on identifying factors that increase stroke risk. The prevalent and incident phenotypes studied included inflammation, kidney traits, cardiovascular traits and cognition. Our results validated 29 known associations, of which eight associations were reported for the first time in African Americans. CONCLUSION: Our cross-racial validation of GWAS findings provide additional evidence for the important roles of these loci in the disease process and may help identify genes especially important for future functional validation.

9.
BMC Genomics ; 20(Suppl 1): 82, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712510

RESUMO

BACKGROUND: Existing functional description of genes are categorical, discrete, and mostly through manual process. In this work, we explore the idea of gene embedding, distributed representation of genes, in the spirit of word embedding. RESULTS: From a pure data-driven fashion, we trained a 200-dimension vector representation of all human genes, using gene co-expression patterns in 984 data sets from the GEO databases. These vectors capture functional relatedness of genes in terms of recovering known pathways - the average inner product (similarity) of genes within a pathway is 1.52X greater than that of random genes. Using t-SNE, we produced a gene co-expression map that shows local concentrations of tissue specific genes. We also illustrated the usefulness of the embedded gene vectors, laden with rich information on gene co-expression patterns, in tasks such as gene-gene interaction prediction. CONCLUSIONS: We proposed a machine learning method that utilizes transcriptome-wide gene co-expression to generate a distributed representation of genes. We further demonstrated the utility of our distribution by predicting gene-gene interaction based solely on gene names. The distributed representation of genes could be useful for more bioinformatics applications.


Assuntos
Biologia Computacional/métodos , Software , Algoritmos , Biologia Computacional/normas , Epistasia Genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Curva ROC , Transcriptoma , Interface Usuário-Computador
10.
BMC Genomics ; 20(Suppl 1): 80, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712512

RESUMO

The sixth International Conference on Intelligent Biology and Medicine (ICIBM) took place in Los Angeles, California, USA on June 10-12, 2018. This conference featured eleven regular scientific sessions, four tutorials, one poster session, four keynote talks, and four eminent scholar talks. The scientific program covered a wide range of topics from bench to bedside, including 3D Genome Organization, reconstruction of large scale evolution of genomes and gene functions, artificial intelligence in biological and biomedical fields, and precision medicine. Both method development and application in genomic research continued to be a main component in the conference, including studies on genetic variants, regulation of transcription, genetic-epigenetic interaction at both single cell and tissue level and artificial intelligence. Here, we write a summary of the conference and also briefly introduce the four high quality papers selected to be published in BMC Genomics that cover novel methodology development or innovative data analysis.


Assuntos
Inteligência Artificial , Biologia , Medicina , Biologia/métodos , Humanos , Medicina/métodos
11.
BMC Med Genomics ; 12(Suppl 1): 20, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704510

RESUMO

During June 10-12, 2018, the International Conference on Intelligent Biology and Medicine (ICIBM 2018) was held in Los Angeles, California, USA. The conference included 11 scientific sessions, four tutorials, one poster session, four keynote talks and four eminent scholar talks that covered a wide range of topics ranging from 3D genome structure analysis and visualization, next generation sequencing analysis, computational drug discovery, medical informatics, cancer genomics to systems biology. While medical genomics has always been a main theme in ICIBM, this year we for the first time organized the BMC Medical Genomics Supplement for ICIBM. Here, we describe 15 ICIBM papers selected for publishing in BMC Medical Genomics.

12.
BMC Syst Biol ; 12(Suppl 8): 125, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577731

RESUMO

Between June 10-12, 2018, the International Conference on Intelligent Biology and Medicine (ICIBM 2018) was held in Los Angeles, California, USA. The conference included 11 scientific sessions, four tutorials, one poster session, four keynote talks and four eminent scholar talks that covered a wide range of topics in 3D genome structure analysis and visualization, next generation sequencing analysis, computational drug discovery, medical informatics, cancer genomics and systems biology. Systems biology has been a main theme in ICIBM 2018, with exciting advances presented in many areas of systems biology, covering various different data types such as gene regulation, circular RNAs expression, single-cell RNA-Seq, inter-chromosomal interactions, metabolomics, proteomics and phosphoproteomics. Here, we describe ten high quality papers to be published in BMC Systems Biology.


Assuntos
Internacionalidade , Medicina , Biologia de Sistemas
13.
BMC Bioinformatics ; 19(Suppl 17): 492, 2018 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-30591012

RESUMO

The 2018 International Conference on Intelligent Biology and Medicine (ICIBM 2018) was held on June 10-12, 2018, in Los Angeles, California, USA. The conference consisted of a total of eleven scientific sessions, four tutorials, one poster session, four keynote talks and four eminent scholar talks, which covered a wild range of aspects of bioinformatics, medical informatics, systems biology and intelligent computing. Here, we summarize nine research articles selected for publishing in BMC Bioinformatics.


Assuntos
Biologia Computacional , Internacionalidade , Medicina , Pesquisa Médica Translacional , Registros Eletrônicos de Saúde , Humanos , Células MCF-7 , Farmacogenética
14.
J Med Internet Res ; 20(7): e236, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29986843

RESUMO

BACKGROUND: Timely understanding of public perceptions allows public health agencies to provide up-to-date responses to health crises such as infectious diseases outbreaks. Social media such as Twitter provide an unprecedented way for the prompt assessment of the large-scale public response. OBJECTIVE: The aims of this study were to develop a scheme for a comprehensive public perception analysis of a measles outbreak based on Twitter data and demonstrate the superiority of the convolutional neural network (CNN) models (compared with conventional machine learning methods) on measles outbreak-related tweets classification tasks with a relatively small and highly unbalanced gold standard training set. METHODS: We first designed a comprehensive scheme for the analysis of public perception of measles based on tweets, including 3 dimensions: discussion themes, emotions expressed, and attitude toward vaccination. All 1,154,156 tweets containing the word "measles" posted between December 1, 2014, and April 30, 2015, were purchased and downloaded from DiscoverText.com. Two expert annotators curated a gold standard of 1151 tweets (approximately 0.1% of all tweets) based on the 3-dimensional scheme. Next, a tweet classification system based on the CNN framework was developed. We compared the performance of the CNN models to those of 4 conventional machine learning models and another neural network model. We also compared the impact of different word embeddings configurations for the CNN models: (1) Stanford GloVe embedding trained on billions of tweets in the general domain, (2) measles-specific embedding trained on our 1 million measles related tweets, and (3) a combination of the 2 embeddings. RESULTS: Cohen kappa intercoder reliability values for the annotation were: 0.78, 0.72, and 0.80 on the 3 dimensions, respectively. Class distributions within the gold standard were highly unbalanced for all dimensions. The CNN models performed better on all classification tasks than k-nearest neighbors, naïve Bayes, support vector machines, or random forest. Detailed comparison between support vector machines and the CNN models showed that the major contributor to the overall superiority of the CNN models is the improvement on recall, especially for classes with low occurrence. The CNN model with the 2 embedding combination led to better performance on discussion themes and emotions expressed (microaveraging F1 scores of 0.7811 and 0.8592, respectively), while the CNN model with Stanford embedding achieved best performance on attitude toward vaccination (microaveraging F1 score of 0.8642). CONCLUSIONS: The proposed scheme can successfully classify the public's opinions and emotions in multiple dimensions, which would facilitate the timely understanding of public perceptions during the outbreak of an infectious disease. Compared with conventional machine learning methods, our CNN models showed superiority on measles-related tweet classification tasks with a relatively small and highly unbalanced gold standard. With the success of these tasks, our proposed scheme and CNN-based tweets classification system is expected to be useful for the analysis of tweets about other infectious diseases such as influenza and Ebola.

15.
Am J Infect Control ; 46(12): 1375-1380, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29929837

RESUMO

BACKGROUND: The public increasingly uses social media not only to look for information about emerging infectious diseases (EIDs), but also to share opinions, emotions, and coping strategies. Identifying the frames used in social media discussion about EIDs will allow public health agencies to assess public opinions and sentiments. METHOD: This study examined how the public discussed measles during the measles outbreak in the United States during early 2015 that originated in Disneyland Park in Anaheim, CA, through a semantic network analysis of the content of around 1 million tweets using KH coder. RESULTS: Four frames were identified based on word frequencies and co-occurrence: news update, public health, vaccination, and political. The prominence of each individual frame changed over the corse of the pre-crisis, initial, maintenance, and resolution stages of the outbreak. CONCLUSIONS: This study proposed and tested a method for assessing the frames used in social media discussions about EIDs based on the creation, interpretation, and quantification of semantic networks. Public health agencies could use social media outlets, such as Twitter, to assess how the public makes sense of an EID outbreak and to create adaptive messages in communicating with the public during different stages of the crisis.

16.
J Biomed Inform ; 84: 11-16, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29908902

RESUMO

Recently, recurrent neural networks (RNNs) have been applied in predicting disease onset risks with Electronic Health Record (EHR) data. While these models demonstrated promising results on relatively small data sets, the generalizability and transferability of those models and its applicability to different patient populations across hospitals have not been evaluated. In this study, we evaluated an RNN model, RETAIN, over Cerner Health Facts® EMR data, for heart failure onset risk prediction. Our data set included over 150,000 heart failure patients and over 1,000,000 controls from nearly 400 hospitals. Convincingly, RETAIN achieved an AUC of 82% in comparison to an AUC of 79% for logistic regression, demonstrating the power of more expressive deep learning models for EHR predictive modeling. The prediction performance fluctuated across different patient groups and varied from hospital to hospital. Also, we trained RETAIN models on individual hospitals and found that the model can be applied to other hospitals with only about 3.6% of reduction of AUC. Our results demonstrated the capability of RNN for predictive modeling with large and heterogeneous EHR data, and pave the road for future improvements.

17.
Pharmacogenomics J ; 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29855607

RESUMO

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

18.
Clin Epigenetics ; 10: 56, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713391

RESUMO

Background: Recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids. Methods: We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5'-Cytosine-phosphate-guanine-3' genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. We used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels as well as five fasting inflammatory markers plus adiponectin. Results: Both DNA methylation age estimates were highly correlated with chronological age (r > 0.90). We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated (r = 0.50). The regression models revealed that the Horvath age acceleration measure exhibited marginal associations with increased postprandial HDL (p = 0.05), increased postprandial total cholesterol (p = 0.06), and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα, p = 0.02). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL (p = 0.02) and positively associated with postprandial TG (p = 0.02), interleukin-6 (IL6, p = 0.007), C-reactive protein (C-reactive protein, p = 0.0001), and tumor necrosis factor alpha (TNFα, p = 0.0001). Overall, the observed effect sizes were small and the association of the Hannum residual with inflammatory markers was attenuated by adjustment for estimated T cell type percentages. Conclusions: Our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in Caucasian individuals of the GOLDN study. Future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.

19.
JAMA Cardiol ; 3(6): 463-472, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617535

RESUMO

Importance: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision. Objective: To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures: Circulating TNF-α concentration. Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (ß [SE] = -0.01 [0.003]; P = 7.36 × 10-8), cg08122652 (ß [SE] = -0.008 [0.002]; P = 2.24 × 10-7), and cg22930808(ß [SE] = -0.01 [0.002]; P = 6.92 × 10-8); NLRC5 at cg16411857 (ß [SE] = -0.01 [0.002]; P = 2.14 × 10-13) and cg07839457 (ß [SE] = -0.02 [0.003]; P = 6.31 × 10-10); or ABO, at cg13683939 (ß [SE] = 0.04 [0.008]; P = 1.42 × 10-7) and cg24267699 (ß [SE] = -0.009 [0.002]; P = 1.67 × 10-7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10-5). Conclusions and Relevance: We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.

20.
Clin Epigenetics ; 10: 49, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29643945

RESUMO

Background: The high prevalence of obesity among US adults has resulted in significant increases in associated metabolic disorders such as diabetes, dyslipidemia, and high blood pressure. Together, these disorders constitute metabolic syndrome, a clinically defined condition highly prevalent among African-Americans. Identifying epigenetic alterations associated with metabolic syndrome may provide additional information regarding etiology beyond current evidence from genome-wide association studies. Methods: Data on metabolic syndrome and DNA methylation was assessed on 614 African-Americans from the Hypertension Genetic Epidemiology Network (HyperGEN) study. Metabolic syndrome was defined using the joint harmonized criteria, and DNA methylation was assessed using the Illumina HumanMethylation450K Bead Chip assay on DNA extracted from buffy coat. Linear mixed effects regression models were used to examine the association between CpG methylation at > 450,000 CpG sites and metabolic syndrome adjusted for study covariates. Replication using DNA from a separate sample of 69 African-Americans, as well as meta-analysis combining both cohorts, was conducted. Results: Two differentially methylated CpG sites in the IGF2BP1 gene on chromosome 17 (cg06638433; p value = 3.10 × 10- 7) and the ABCG1 gene on chromosome 21 (cg06500161; p value = 2.60 × 10- 8) were identified. Results for the ABCG1 gene remained statistically significant in the replication dataset and meta-analysis. Conclusion: Metabolic syndrome was consistently associated with increased methylation in the ABCG1 gene in the discovery and replication datasets, a gene that encodes a protein in the ATP-binding cassette transporter family and is involved in intra- and extra-cellular signaling and lipid transport.

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