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1.
Am J Hum Genet ; 105(4): 763-772, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564439

RESUMO

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

2.
Int J Mol Sci ; 20(17)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480455

RESUMO

African American women are affected by earlier onset of age-associated health deteriorations and obesity disproportionally, but little is known about the mechanism linking body mass index (BMI) and biological aging among this population. DNA methylation age acceleration (DNAm AA), measuring the difference between DNA methylation age and chronological age, is a novel biomarker of the biological aging process, and predicts aging-related disease outcomes. The present study estimated cross-tissue DNA methylation age acceleration using saliva samples from 232 African American mothers. Cross-sectional regression analyses were performed to assess the association of BMI with DNAm AA. The average chronological age and DNA methylation age were 31.67 years, and 28.79 years, respectively. After adjusting for smoking, hypertension diagnosis history, and socioeconomic factors (education, marital status, household income), a 1 kg/m2 increase in BMI is associated with 0.14 years increment of DNAm AA (95% CI: (0.08, 0.21)). The conclusion: in African American women, high BMI is independently associated with saliva-based DNA methylation age acceleration, after adjusting for smoking, hypertension, and socioeconomic status. This finding supports that high BMI accelerates biological aging, and plays a key role in age-related disease outcomes among African American women.

3.
Nat Med ; 25(8): 1274-1279, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31285632

RESUMO

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.

4.
Circulation ; 140(12): 1031-1040, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

5.
Neurobiol Dis ; 129: 159-168, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31112762

RESUMO

The dystonias are a group of disorders characterized by excessive contraction of muscles leading to abnormal involuntary movements. The clinical manifestations are very heterogeneous, with numerous distinct syndromes. The etiologies for dystonia are also heterogeneous with idiopathic, acquired, and inherited forms. Technological advances in genetics over the past two decades have led to a rapid growth in the number of genes associated with dystonia. These genes encode proteins with very diverse biological functions. This review focusses on genes that have contributed to understanding shared biological pathways relevant to specific subgroups of dystonia syndromes. Although many potential shared biological pathways have been proposed, the ones addressed here include defects in dopamine signaling, mitochondrial dysfunction and energy maintenance, toxic accumulation of heavy metals in the brain, and calcium channels and abnormal calcium homeostasis. Elucidation of these and other shared pathways is important for understanding the biological basis for dystonia and for designing novel experimental therapeutics that have the broadest potential for multiple types of dystonia.

6.
Psychoneuroendocrinology ; 106: 122-128, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30978531

RESUMO

Leukocyte telomere length (LTL) may be sensitive to psychosocial stressors such as discrimination. An inclusive examination of experiences of discrimination on LTL across racial/ethnic and sex groups is currently lacking. Baseline data were obtained from 369 White and African American patients with coronary artery disease (CAD) in the Mental Stress Ischemia Mechanisms and Prognosis Study. LTL was measured from peripheral blood leukocytes by quantitative polymerase chain reaction and calculated in kilobase pairs. Discrimination was measured using the 10-item Everyday Discrimination Scale (EDS). Responses were rated using 4-point Likert scales ranging from never = 1 to often = 4 and summed. Regression models were stratified by race/ethnicity and sex to estimate associations between discrimination and LTL. Each 10-unit increase in experiences of everyday discrimination was associated with an average of .20 fewer kilobase pairs (or 200 base pairs) among both African American women (ß = -0.19; 95% CI: -0.35, -0.04; p-value: 0.02) and White women (ß = -0.19; 95% CI: -0.37, -0.01; p-value: 0.04), after adjusting for basic demographic factors. Results were similar after further adjusting for behavioral, disease, and psychosocial risk factors (depression and stress). There were no significant associations between experiences of everyday discrimination and LTL for White men or African American men. Overall, experiences of discrimination were associated with shorter LTL among women and not in men. Discrimination may be a potential source of stress associated with shorter LTL among women with CAD. Future studies should explore longitudinal associations between everyday experiences of discrimination and telomere length and also with adverse cardiovascular outcomes.

7.
Am J Cardiol ; 123(12): 1955-1961, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30979411

RESUMO

We have previously identified associations of 2 circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk in 1,919 blacks in the Atherosclerosis Risk in Communities cohort. We aimed to replicate these findings in an independent sample of 2,003 white and black Atherosclerosis Risk in Communities participants, and performed a new metabolomic analysis in the combined sample of 3,922 participants, followed between 1987 and 2013. Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by 1 standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95% CI 1.00, 1.21 and HR 1.13, 95% CI 1.04, 1.22, respectively). Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95% CI 0.92, 1.13). An analysis of 245 metabolites in the combined cohort identified 3 additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95% CI 1.10, 1.28), uridine (HR 0.86, 95% CI 0.79, 0.93) and acisoga (HR 1.17, 95% CI 1.09, 1.26). In conclusion, we replicated a prospective association among a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.

8.
Clin Infect Dis ; 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30893429

RESUMO

BACKGROUND: People living with human immunodeficiency virus (HIV) infection have higher risk for chronic kidney disease (CKD), defined by a reduced estimated glomerular filtration rate (eGFR). Previous studies have implicated epigenetic changes related to CKD; however, the mechanism of HIV-related CKD has not been thoroughly investigated. METHODS: We conducted an epigenome-wide association study of eGFR among 567 HIV-positive and 117 HIV-negative male participants in the Veterans Aging Cohort Study (VACS) to identify epigenetic signatures of kidney function. RESULTS: By surveying over 400,000 CpG sites measured from peripheral blood mononuclear cells, we identified 15 sites significantly associated with eGFR (false discovery rate q-value < 0.05) among HIV-positive participants. The most significant CpG sites, located at MAD1L1, TSNARE1/BAI1, and LTV1, were all negatively associated with eGFR (cg06329547: p-value 5.2510-9; cg23281907: p-value 1.3710-8; cg18368637: p-value 5.1710-8). We also replicated previously reported eGFR-associated CpG sites including cg17944885 (p-value of 2.510-5) located between ZNF788 and ZNF20 on chromosome 19 in the pooled population. CONCLUSION: Our study uncovered novel epigenetic associations with kidney function among people living with HIV and suggested potential epigenetic mechanisms linked with HIV-related CKD risk.

9.
Circ Genom Precis Med ; 12(4): e002471, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30897348

RESUMO

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

10.
Circ Genom Precis Med ; 12(4): e002470, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30896328

RESUMO

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

11.
Epigenetics ; 14(4): 383-391, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30915882

RESUMO

INTRODUCTION: Cigarette smoking has been associated with adverse health outcomes for mothers and children and is a major contributor to heart disease. Although cigarette smoking is known to affect the epigenome, few studies have been done in African American populations. In this study, we investigated the association between cigarette smoking and DNA methylation (DNAm) among African Americans from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN), and the Genetic Epidemiology Network of Arteriopathy (GENOA). METHODS: The InterGEN study aims to examine the effects of genetic and psychological factors on blood pressure among African American women and their children. Current cigarette smoking was assessed at baseline. DNAm of saliva was assessed using the 850K EPIC Illumina BeadChip for Epigenome-Wide Association analyses. A replication study was conducted among 1100 participants in the GENOA study using the same BeadChip. RESULTS: After controlling for age, body mass index, population structure and cell composition, 26 epigenome-wide significant sites (FDR q < 0.05) were identified, including the AHRR and PHF14 genes associated with atherosclerosis and lung disease, respectively. Six novel CpG sites were discovered in the InterGEN sample and replicated in the GENOA sample. Genes mapped include RARA, FSIP1, ALPP, PIK3R5, KIAA0087, and MGAT3, which were largely associated with cancer development. CONCLUSION: We observed significant epigenetic associations between smoking and disease-associated genes (e.g., cardiovascular disease, lung cancer). Six novel CpG sites were identified and replicated across saliva and blood samples.

12.
J Infect Dis ; 219(12): 1959-1962, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-30649532

RESUMO

Epigenetic modifications such as DNA methylation are associated with both human immunodeficiency virus (HIV) infection and type 2 diabetes mellitus (T2DM). We investigated epigenetic associations with T2DM according to HIV infection status and assessed interaction effects among 681 male participants of the Veterans Aging Cohort Study. Methylation at previously reported sites, cg1963031 (TXNIP), cg18181703 (SOCS3), and cg09152259 (PROC), was significantly associated with T2DM in HIV-infected individuals. We identified 3 novel associations with suggestive statistical significance: cg1231141 (ADAMTS2), cg19534769 (HGFAC), and cg13163919 (TLE3). Suggestive interaction with HIV infection status was found at cg17862404 (TSC22D1). The implicated genes are involved in inflammation, pancreatic ß-cell function, and T2DM pathogenesis.

13.
Nurs Res ; 68(2): 135-144, 2019 Mar/Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30570522

RESUMO

BACKGROUND: Age at menarche and age at natural menopause occur significantly earlier in African American women than in other ethnic groups. African American women also have twice the prevalence of cardiometabolic disorders related to the timing of these reproductive traits. OBJECTIVES: The objectives of this integrative review were to (a) summarize the genome-wide association studies of reproductive traits in African American women, (b) identify genes that overlap with reproductive traits and cardiometabolic risk factors in African American women, and (c) propose biological mechanisms explaining the link between reproductive traits and cardiometabolic risk factors. METHODS: PubMed was searched for genome-wide association studies of genes associated with reproductive traits in African American women. After extracting and summarizing the primary genes, we examined whether any of the associations with reproductive traits had also been identified with cardiometabolic risk factors in African American women. RESULTS: Seven studies met the inclusion criteria. Associations with both reproductive and cardiometabolic traits were reported in or near the following genes: FTO, SEC16B, TMEM18, APOE, PHACTR1, KCNQ1, LDLR, PIK3R1, and RORA. Biological pathways implicated include body weight regulation, vascular homeostasis, and lipid metabolism. DISCUSSION: A better understanding of the genetic basis of reproductive traits in African American women may provide insight into the biological mechanisms linking variation in these traits with increased risk for cardiometabolic disorders in this population.

14.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
16.
Nat Genet ; 50(11): 1514-1523, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30275531

RESUMO

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

17.
Nat Genet ; 50(10): 1412-1425, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

18.
JAMA Cardiol ; 3(9): 849-857, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090940

RESUMO

Importance: Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene-drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade. Objective: To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials. Design, Setting, and Participants: Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center. Exposures: IL6R SNPs (rs2228145; rs4129267). Main Outcomes and Measures: Phenotypes defined by International Classification of Diseases, Ninth Revision codes. Results: Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank. Conclusions and Relevance: In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

20.
Epigenomics ; 10(4): 379-393, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29528243

RESUMO

AIM: We conducted a joint metabolomic-epigenomic study to identify patterns of epigenetic associations with smoking-related metabolites. PATIENTS & METHODS: We performed an untargeted metabolome-wide association study of smoking and epigenome-wide association studies of smoking-related metabolites among 180 male twins. We examined the patterns of epigenetic association linked to smoking-related metabolites using hierarchical clustering. RESULTS: Among 12 annotated smoking-related metabolites identified from a metabolome-wide association study, we observed significant hypomethylation associated with increased level of N-acetylpyrrolidine, cotinine, 5-hydroxycotinine and nicotine and hypermethylation associated with increased level of 8-oxoguanine. Hierarchical clustering revealed common and unique epigenetic-metabolic associations related to smoking. CONCLUSION: Our study suggested that a joint metabolome-epigenome approach can reveal additional details in molecular responses to the environmental exposure to understand disease risk.

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