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1.
Diabetes ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506343

RESUMO

Epigenetic changes may contribute substantially to risks of diseases of ageing. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based EPIC-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset to investigate the role of methylation in the aetiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM, and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1 and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs, and found one MVP, cg00574958 at CPT1A, with a possible direct causal role on T2DM. None of the implicated genes was previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

2.
Mol Metab ; 27S: S33-S41, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31500829

RESUMO

BACKGROUND: Obesity and type 2 diabetes (T2D) are major public health issues worldwide, and put a significant burden on the healthcare system. Genetic variants, along with traditional risk factors such as diet and physical activity, could account for up to approximately a quarter of disease risk. Epigenetic factors have demonstrated potential in accounting for additional phenotypic variation, along with providing insights into the causal relationship linking genetic variants to phenotypes. SCOPE OF REVIEW: In this review article, we discuss the epidemiological and functional insights into epigenetic disturbances in obesity and diabetes, along with future research directions and approaches, with a focus on DNA methylation. MAJOR CONCLUSIONS: Epigenetic mechanisms have been shown to contribute to obesity and T2D disease development, as well as potential differences in disease risks between ethnic populations. Technology to investigate epigenetic profiles in diseased individuals and tissues has advanced significantly in the last years, and suggests potential in application of epigenetic factors in clinical monitoring and as therapeutic options.

3.
Sci Rep ; 9(1): 10383, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316107

RESUMO

Whole genome bisulfite sequencing (WGBS), with its ability to interrogate methylation status at single CpG site resolution epigenome-wide, is a powerful technique for use in molecular experiments. Here, we aim to advance strategies for accurate and efficient WGBS for application in future large-scale epidemiological studies. We systematically compared the performance of three WGBS library preparation methods with low DNA input requirement (Swift Biosciences Accel-NGS, Illumina TruSeq and QIAGEN QIAseq) on two state-of-the-art sequencing platforms (Illumina NovaSeq and HiSeq X), and also assessed concordance between data generated by WGBS and methylation arrays. Swift achieved the highest proportion of CpG sites assayed and effective coverage at 26x (P < 0.001). TruSeq suffered from the highest proportion of PCR duplicates, while QIAseq failed to deliver across all quality metrics. There was little difference in performance between NovaSeq and HiSeq X, with the exception of higher read duplication rate on the NovaSeq (P < 0.05), likely attributable to the higher cluster densities on its flow cells. Systematic biases exist between WGBS and methylation arrays, with lower precision observed for WGBS across the range of depths investigated. To achieve a level of precision broadly comparable to the methylation array, a minimum coverage of 100x is recommended.

4.
Eur Heart J ; 40(34): 2883-2896, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31102408

RESUMO

AIMS: To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). METHODS AND RESULTS: We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05). CONCLUSION: Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.

5.
PLoS One ; 14(5): e0216354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31063476

RESUMO

BACKGROUND: Insulin resistance and related metabolic disturbances are major risk factors for the higher T2D risk and associated morbidity and mortality amongst South Asians. The contribution of physical activity to the increased prevalence of insulin resistance and related disturbances amongst South Asians is unknown. METHODS: We recruited 902 South Asian and European men and women, aged 35-85 years from the ongoing LOLIPOP study. Clinical characterisation comprised standardised questionnaire and measurement of height, weight, waist and hip circumference and blood pressure. Fasting bloods were taken for assessment of glucose, insulin, lipids and HbA1c. Physical activity was quantified using a validated accelerometer, Actigraph GT3X+, worn for 7 days. Univariate and multivariate approaches were used to investigate the relationship between ethnicity, physical activity, insulin resistance and related metabolic disturbances. RESULTS: Total physical activity was ~31% (P = 0.01) lower amongst South Asians compared to Europeans (Mean MET.minutes [SD]: 1505.2 [52] vs. 2050.9 [86.6], P<0.001). After adjusting for age and sex, total physical activity had a negative association with HOMA-IR (B [SE]: -0.18 [0.08], P = 0.04) and fasting glucose levels (B[SE]: -0.11 [0.04], P = 0.02). There was no association between physical activity and other glycemic and lipid parameters. Total physical activity per week contributed towards the differences in insulin resistance and associated metabolic disturbances between South Asians and Europeans. CONCLUSION: Lower levels of physical activity may contribute to the increased insulin resistance in South Asians compared to Europeans. Our results suggest that lifestyle modification through increased physical activity may help to improve glucose metabolism and reduce the burden of excess T2D and related complications amongst South Asians.

6.
EBioMedicine ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30442561

RESUMO

BACKGROUND: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. METHODS: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). FINDINGS: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10-8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. INTERPRETATION: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.

7.
BMC Bioinformatics ; 19(1): 299, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30097004

RESUMO

BACKGROUND: The knowledge of miRNAs regulating the expression of sets of mRNAs has led to novel insights into numerous and diverse cellular mechanisms. While a single miRNA may regulate many genes, one gene can be regulated by multiple miRNAs, presenting a complex relationship to model for accurate predictions. RESULTS: Here, we introduce miREM, a program that couples an expectation-maximization (EM) algorithm to the common approach of hypergeometric probability (HP), which improves the prediction and prioritization of miRNAs from gene-sets of interest. miREM has been made available through a web-server ( https://bioinfo-csi.nus.edu.sg/mirem2/ ) that can be accessed through an intuitive graphical user interface. The program incorporates a large compendium of human/mouse miRNA-target prediction databases to enhance prediction. Users may upload their genes of interest in various formats as an input and select whether to consider non-conserved miRNAs, amongst filtering options. Results are reported in a rich graphical interface that allows users to: (i) prioritize predicted miRNAs through a scatterplot of HP p-values and EM scores; (ii) visualize the predicted miRNAs and corresponding genes through a heatmap; and (iii) identify and filter homologous or duplicated predictions by clustering them according to their seed sequences. CONCLUSION: We tested miREM using RNAseq datasets from two single "spiked" knock-in miRNA experiments and two double knock-out miRNA experiments. miREM predicted these manipulated miRNAs as having high EM scores from the gene set signatures (i.e. top predictions for single knock-in and double knock-out miRNA experiments). Finally, we have demonstrated that miREM predictions are either similar or better than results provided by existing programs.

8.
Front Aging Neurosci ; 10: 195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30042673

RESUMO

Introduction: This study is a parallel-arm randomized controlled trial evaluating choral singing's efficacy and underlying mechanisms in preventing cognitive decline in at-risk older participants. Methods: Three-hundred and sixty community-dwelling, non-demented older participants are recruited for a 2-year intervention. Inclusion criteria are self-reported cognitive complaints, early cognitive impairment based on neuropsychological test scores or multiple risk factors of dementia. Participants are randomized to either weekly choral singing sessions or general health education. The primary outcome is cognitive performance, measured by a composite cognitive test score (CCTS). Secondary outcomes include depression, anxiety and neuropsychiatric symptoms; perceived stress; sleep quality and severity of dementia symptoms. Underlying mechanisms are examined using blood- and urine-based biomarkers and neuroimaging. Results: Screening began in July 2016. The first group of participants (n = 93) have been recruited. Intervention and control treatments are ongoing and will end in December 2019. Discussion: An evidence-based singing intervention for dementia prevention holds potential for healthcare savings and societal welfare. Trial Registration: NCT02919748, IRB Approval Number: NUS 2508.

9.
Anal Chem ; 90(15): 9025-9032, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-29992805

RESUMO

Raman spectroscopy in combination with appropriate sample preparation strategies, for example, enrichment of bacteria on metal surfaces, has been proven to be a promising approach for rapidly diagnosing infectious diseases. Unfortunately, the fabrication of the required chip substrates is usually very challenging due to the lack of feasible instruments that can be used for quality control in the surface modification process. The intrinsically weak Raman signal of the biomolecules, employed for the enrichment of the micro-organisms on the chip surface, does not allow for monitoring of the successful immobilization by means of a Raman spectroscopic approach. Within this contribution, we demonstrate how a simple modification of a plain aluminum surface enables enhancement (or a decrease, if desired) of the Raman signal of molecules deposited on that surface. The manipulation of the Raman signal strength is achieved via exploiting interference effects that occur, if the highly reflective aluminum surface is modified with thin layers of transparent dielectrics like aluminum oxide. The thicknesses of these layers were determined by theoretical considerations and calculations. For the first time, it is shown that the interference effects can be used for the detection of biomolecules as well by investigating the siderophore ferrioxamine B. The observed degree of enhancement was approximately 1 order of magnitude. Moreover, the employed aluminum/aluminum oxide layers have been thoroughly characterized using atomic force and scanning electron microscopy as well as X-ray reflectometry and UV-Vis measurements.

10.
PLoS One ; 12(10): e0186200, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29036176

RESUMO

BACKGROUND AND AIMS: Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population. METHODS: This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants. RESULTS: Two SNPs in NAT2 (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30-44.70), 0.10 (0.03-0.33) and 9.98 (3.32-33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027). CONCLUSIONS: We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.


Assuntos
Antituberculosos/toxicidade , Arilamina N-Acetiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Isoniazida/toxicidade , Antituberculosos/uso terapêutico , Biomarcadores Farmacológicos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Singapura , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose/genética
12.
JAMA Oncol ; 3(11): 1538-1545, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28715540

RESUMO

Importance: Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective: To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants: This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions: Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures: Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results: In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10-8), including a novel DPYD variant (rs75267292; P = 1.57 × 10-10), and variants in the MACF1 (rs183324967, P = 4.80 × 10-11; rs148221738, P = 5.73 × 10-10) and SPRY2 (rs117876855, P < 1.01 × 10-8; rs139544515, P = 1.30 × 10-8) genes involved in wound healing. Conclusions and Relevance: Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration: clinicaltrials.gov Identifier: NCT00486213.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Síndrome Mão-Pé/prevenção & controle , Neoplasias/tratamento farmacológico , Piridoxina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Distribuição de Qui-Quadrado , Di-Hidrouracila Desidrogenase (NADP)/genética , Método Duplo-Cego , Esquema de Medicação , Feminino , Ácido Fólico/sangue , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Síndrome Mão-Pé/sangue , Síndrome Mão-Pé/etnologia , Síndrome Mão-Pé/genética , Humanos , Incidência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/sangue , Neoplasias/etnologia , Razão de Chances , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Singapura/epidemiologia , Fatores de Tempo , Resultado do Tratamento
13.
J Am Soc Nephrol ; 28(8): 2311-2321, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28360221

RESUMO

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.


Assuntos
Loci Gênicos , Plasma/química , Simportadores de Sódio-Bicarbonato/genética , Sódio/análise , Fatores de Transcrição/genética , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/genética , Idoso , Grupos de Populações Continentais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar
14.
Stem Cell Reports ; 8(3): 619-633, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28238795

RESUMO

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Doença de Huntington/genética , Doença de Huntington/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fenótipo , Diferenciação Celular/genética , Linhagem Celular , Autorrenovação Celular/genética , Fenômenos Eletrofisiológicos/genética , Regulação da Expressão Gênica no Desenvolvimento , Marcação de Genes , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Neurônios/citologia , Neurônios/metabolismo , Fatores de Transcrição/genética
15.
Nat Genet ; 49(3): 403-415, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28135244

RESUMO

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.


Assuntos
Pressão Sanguínea/genética , Doenças Cardiovasculares/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Adulto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
16.
Nature ; 541(7635): 81-86, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28002404

RESUMO

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.


Assuntos
Adiposidade/genética , Índice de Massa Corporal , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Epigenômica , Estudo de Associação Genômica Ampla , Obesidade/genética , Tecido Adiposo/metabolismo , Grupo com Ancestrais do Continente Asiático/genética , Sangue/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Índia/etnologia , Masculino , Obesidade/sangue , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações , Sobrepeso/genética
17.
J Proteome Res ; 15(12): 4188-4194, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27628670

RESUMO

Large-scale metabolomics studies involving thousands of samples present multiple challenges in data analysis, particularly when an untargeted platform is used. Studies with multiple cohorts and analysis platforms exacerbate existing problems such as peak alignment and normalization. Therefore, there is a need for robust processing pipelines that can ensure reliable data for statistical analysis. The COMBI-BIO project incorporates serum from ∼8000 individuals, in three cohorts, profiled by six assays in two phases using both 1H NMR and UPLC-MS. Here we present the COMBI-BIO NMR analysis pipeline and demonstrate its fitness for purpose using representative quality control (QC) samples. NMR spectra were first aligned and normalized. After eliminating interfering signals, outliers identified using Hotelling's T2 were removed and a cohort/phase adjustment was applied, resulting in two NMR data sets (CPMG and NOESY). Alignment of the NMR data was shown to increase the correlation-based alignment quality measure from 0.319 to 0.391 for CPMG and from 0.536 to 0.586 for NOESY, showing that the improvement was present across both large and small peaks. End-to-end quality assessment of the pipeline was achieved using Hotelling's T2 distributions. For CPMG spectra, the interquartile range decreased from 1.425 in raw QC data to 0.679 in processed spectra, while the corresponding change for NOESY spectra was from 0.795 to 0.636, indicating an improvement in precision following processing. PCA indicated that gross phase and cohort differences were no longer present. These results illustrate that the pipeline produces robust and reproducible data, successfully addressing the methodological challenges of this large multifaceted study.


Assuntos
Interpretação Estatística de Dados , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Humanos , Metabolômica/instrumentação , Metabolômica/estatística & dados numéricos , Epidemiologia Molecular , Espectroscopia de Prótons por Ressonância Magnética/normas , Espectroscopia de Prótons por Ressonância Magnética/estatística & dados numéricos , Controle de Qualidade , Reprodutibilidade dos Testes , Fluxo de Trabalho
18.
Sci Rep ; 6: 27826, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27296624

RESUMO

The FDA-approved starting dosage of capecitabine is 1,250 mg/m(2), and market research indicates that U.S. physicians routinely prescribe 1,000 mg/m(2). Retrospective analyses however report reduced toxicity and efficacy in a subset of patients with the 3R/3R genotype of the thymidylate synthase gene enhancer region (TSER). This study sought to develop TSER genotype-specific guidelines for capecitabine dosing. Capecitabine was dose-escalated in advanced and/or metastatic cancer patients with TSER 3R/3R (Group A; N = 18) or 2R/2R + 2R/3R (Group B; N = 5) from 1,250 to 1,625 mg/m(2) b.i.d., every 2 weeks on/1 week off for up to 8 cycles. Parent and metabolites pharmacokinetics, adverse events, and tumour response were assessed. The maximum tolerated and recommended doses in 3R/3R patients are 1,625 mg/m(2) and 1,500 mg/m(2). At 1,500 mg/m(2), one in nine 3R/3R patients experienced a dose-limiting toxicity. Dosing guidelines for 2R/2R + 2R/3R remain undetermined due to poor accrual. The results indicate that 3R/3R patients may be amenable to 1,500 mg/m(2) b.i.d. on an intermittent schedule, and is the first to prospectively validate the utility of TSER pharmacogenetic-testing before capecitabine treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Elementos Facilitadores Genéticos/genética , Genótipo , Timidilato Sintase/genética , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Protocolos Clínicos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Testes Farmacogenômicos , Polimorfismo Genético
19.
PLoS One ; 11(5): e0155478, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27195708

RESUMO

South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.


Assuntos
Variação Genética , Obesidade Abdominal/etnologia , Obesidade Abdominal/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNA
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