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1.
Nat Commun ; 10(1): 3346, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.

2.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29030403

RESUMO

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Antiporters/genética , Moléculas de Adesão Celular Neuronais/genética , Bases de Dados Factuais , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas dos Microfilamentos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Retorno de Linfócitos/genética
4.
Expert Rev Mol Diagn ; 17(10): 905-915, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28816567

RESUMO

INTRODUCTION: Genome-wide association meta-analysis have now identified more than 150 loci where common variants (SNPs) are significantly associated with coronary heart disease (CHD) and CHD end points. Areas covered: The authors review publications from their own laboratory and published recently where identified CHD risk SNPs are used in combination, and 'scaled' by their effect size, to create a 'weighted' Genetic risk Score (GRS), which, in combination with an individual's classical CHD risk factors, can be used to identify those at overall low, intermediate and high future risk. Those at highest risk can be offered life-style and therapeutic options to reduce their risk and those at intermediate levels can be monitored. Expert commentary: The authors discuss the selection of the best variants to be included in the GRS, and the potential utility of such scores in different clinical settings. The limitations of the current data sets and the way forward in the next 5 years is discussed.


Assuntos
Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Estudos de Associação Genética/métodos , Testes Genéticos , Estudo de Associação Genômica Ampla/métodos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Leupeptinas , Adesão à Medicação , Polimorfismo de Nucleotídeo Único , Guias de Prática Clínica como Assunto , Prevenção Primária/métodos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Reino Unido/epidemiologia
5.
BioData Min ; 10: 25, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28770004

RESUMO

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

6.
Clin Chem Lab Med ; 55(10): 1605-1613, 2017 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-28586300

RESUMO

BACKGROUND: Risk prediction algorithms for coronary heart disease (CHD) are recommended for clinical use. However, their predictive ability remains modest and the inclusion of genetic risk may improve their performance. METHODS: QRISK2 was used to assess CHD risk using conventional risk factors (CRFs). The performance of a 19 single nucleotide polymorphism (SNP) gene score (GS) for CHD including variants identified by genome-wide association study and candidate gene studies (weighted using the results from the CARDIoGRAMplusC4D meta-analysis) was assessed using the second Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284 cases). To improve the GS, five SNPs with weak evidence of an association with CHD were removed and replaced with seven robustly associated SNPs - giving a 21-SNP GS. RESULTS: The weighted 19 SNP GS was associated with lipid traits (p<0.05) and CHD after adjustment for CRFs, (OR=1.31 per standard deviation, p=0.03). Addition of the 19 SNP GS to QRISK2 showed improved discrimination (area under the receiver operator characteristic curve 0.68 vs. 0.70 p=0.02), a positive net reclassification index (0.07, p=0.04) compared to QRISK2 alone and maintained good calibration (p=0.17). The 21-SNP GS was also associated with CHD after adjustment for CRFs (OR=1.39 per standard deviation, 1.42×10-3), but the combined QRISK2 plus GS score was poorly calibrated (p=0.03) and showed no improvement in discrimination (p=0.55) or reclassification (p=0.10) compared to QRISK2 alone. CONCLUSIONS: The 19-SNP GS is robustly associated with CHD and showed potential clinical utility in the UK population.


Assuntos
Algoritmos , Doença das Coronárias/genética , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único , Alelos , Área Sob a Curva , Doença das Coronárias/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Curva ROC , Fatores de Risco , Reino Unido
7.
Curr Opin Lipidol ; 28(2): 99-103, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28092275

RESUMO

PURPOSE OF REVIEW: Metabolomics directly measure substrates and products of biological processes and pathways. Based on instrumentation and throughput advances, the use of metabolomics has only recently become feasible at the population level. This has led to an intense interest in using the new information in combination with genomics, and other omics technologies, to give biological context to the rapidly accumulating associations between genes and diseases or their risk factors. RECENT FINDINGS: The use of metabolomics-genomic associations for the metabolic characterization of genes of interest has confirmed known pathways and permitted the identification of new ones. These include the unknown metabolite X12063 linking statins to myopathies, the role of glycerophospholipids in cholesterol metabolism, the structure of lipoprotein (a), the lipoprotein lipase-independent effect of Apolipoprotein C-III coding and the role of branched chain amino acids in the antagonistic coregulation of levels of HDLs and triglyceride. SUMMARY: The findings reviewed illustrate the importance of integrating metabolomics and genomics for the greater understanding of biological mechanisms. The limitations of the current approaches are also discussed together with approaches that will be required to make the most of the current multiomics data available.


Assuntos
Genômica/métodos , Metabolômica/métodos , Apolipoproteína C-III/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Lipase Lipoproteica/metabolismo
8.
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
9.
Hum Genet ; 136(2): 165-178, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27848076

RESUMO

Genetic loci explain only 25-30 % of the heritability observed in plasma lipid traits. Epistasis, or gene-gene interactions may contribute to a portion of this missing heritability. Using the genetic data from five NHLBI cohorts of 24,837 individuals, we combined the use of the quantitative multifactor dimensionality reduction (QMDR) algorithm with two SNP-filtering methods to exhaustively search for SNP-SNP interactions that are associated with HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG). SNPs were filtered either on the strength of their independent effects (main effect filter) or the prior knowledge supporting a given interaction (Biofilter). After the main effect filter, QMDR identified 20 SNP-SNP models associated with HDL-C, 6 associated with LDL-C, 3 associated with TC, and 10 associated with TG (permutation P value <0.05). With the use of Biofilter, we identified 2 SNP-SNP models associated with HDL-C, 3 associated with LDL-C, 1 associated with TC and 8 associated with TG (permutation P value <0.05). In an independent dataset of 7502 individuals from the eMERGE network, we replicated 14 of the interactions identified after main effect filtering: 11 for HDL-C, 1 for LDL-C and 2 for TG. We also replicated 23 of the interactions found to be associated with TG after applying Biofilter. Prior knowledge supports the possible role of these interactions in the genetic etiology of lipid traits. This study also presents a computationally efficient pipeline for analyzing data from large genotyping arrays and detecting SNP-SNP interactions that are not primarily driven by strong main effects.


Assuntos
Doenças Cardiovasculares/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Epistasia Genética , Fenótipo , Triglicerídeos/sangue , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Estudos de Coortes , Feminino , Loci Gênicos , Marcadores Genéticos , Genoma Humano , Técnicas de Genotipagem , Humanos , Modelos Lineares , Desequilíbrio de Ligação , Masculino , Redução Dimensional com Múltiplos Fatores , Polimorfismo de Nucleotídeo Único
10.
Int J Epidemiol ; 45(5): 1539-1550, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27892411

RESUMO

BACKGROUND: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults. METHODS: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15-75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI). RESULTS: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood. CONCLUSIONS: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.


Assuntos
Aminoácidos/sangue , Suscetibilidade a Doenças/sangue , Ácidos Graxos/sangue , Recém-Nascido de Baixo Peso/sangue , Lipoproteínas/sangue , Adiposidade , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Suscetibilidade a Doenças/metabolismo , Feminino , Finlândia , Idade Gestacional , Ensaios de Triagem em Larga Escala , Humanos , Recém-Nascido de Baixo Peso/metabolismo , Recém-Nascido , Masculino , Metabolômica , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido , Adulto Jovem
11.
Nat Genet ; 48(10): 1162-70, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618448

RESUMO

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Exoma , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único
12.
Nat Genet ; 48(10): 1151-1161, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618447

RESUMO

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Hipertensão/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos
13.
J Am Coll Cardiol ; 68(9): 934-45, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27561768

RESUMO

BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.


Assuntos
Doenças Cardiovasculares/genética , Cistatina C/genética , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Cistatina C/sangue , Genótipo , Saúde Global , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
14.
Cardiovasc Diabetol ; 15(1): 115, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27549350

RESUMO

AIMS: An intergenic locus on chromosome 1 (lead SNP rs10911021) was previously associated with coronary heart disease (CHD) in type 2 diabetes (T2D). Using data from the UCLEB consortium we investigated the relationship between rs10911021 and CHD in T2D, whether rs10911021 was associated with levels of amino acids involved in the γ-glutamyl cycle or any conventional risk factors (CRFs) for CHD in the T2D participants. METHODS: Four UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform. RESULTS: The expected direction of effect between rs10911021 and CHD in T2D was observed (1377 no CHD/160 CHD; minor allele OR 0.80, 95 % CI 0.60-1.06) although this was not statistically significant (p = 0.13). No association between rs10911021 and CHD was seen in non-T2D participants (11218 no CHD/1274 CHD; minor allele OR 1.00 95 % CIs 0.92-1.10). In T2D participants, while no associations were observed between rs10911021 and the nine amino acids measured, rs10911021 was associated with HDL-cholesterol (p = 0.0005) but the minor "protective" allele was associated with lower levels (-0.034 mmol/l per allele). Focusing more closely on the HDL-cholesterol subclasses measured, we observed that rs10911021 was associated with six large HDL particle measures in T2D (all p < 0.001). No significant associations were seen in non-T2D subjects. CONCLUSIONS: Our findings are consistent with a true association between rs10911021 and CHD in T2D. The protective minor allele was associated with lower HDL-cholesterol and reductions in HDL particle traits. Our results indicate a complex relationship between rs10911021 and CHD in T2D.


Assuntos
HDL-Colesterol/sangue , Cromossomos Humanos Par 1 , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Idoso , Aminoácidos/sangue , Biomarcadores/sangue , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , DNA Intergênico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Regulação para Baixo , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Ensaios de Triagem em Larga Escala , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Tamanho da Partícula , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco
15.
Heart ; 102(20): 1640-7, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27365493

RESUMO

OBJECTIVE: We investigated discrimination and calibration of cardiovascular disease (CVD) risk scores when genotypic was added to phenotypic information. The potential of genetic information for those at intermediate risk by a phenotype-based risk score was assessed. METHODS: Data were from seven prospective studies including 11 851 individuals initially free of CVD or diabetes, with 1444 incident CVD events over 10 years' follow-up. We calculated a score from 53 CVD-related single nucleotide polymorphisms and an established CVD risk equation 'QRISK-2' comprising phenotypic measures. The area under the receiver operating characteristic curve (AUROC), detection rate for given false-positive rate (FPR) and net reclassification improvement (NRI) index were estimated for gene scores alone and in addition to the QRISK-2 CVD risk score. We also evaluated use of genetic information only for those at intermediate risk according to QRISK-2. RESULTS: The AUROC was 0.635 for QRISK-2 alone and 0.623 with addition of the gene score. The detection rate for 5% FPR improved from 11.9% to 12.0% when the gene score was added. For a 10-year CVD risk cut-off point of 10%, the NRI was 0.25% when the gene score was added to QRISK-2. Applying the genetic risk score only to those with QRISK-2 risk of 10%-<20% and prescribing statins where risk exceeded 20% suggested that genetic information could prevent one additional event for every 462 people screened. CONCLUSION: The gene score produced minimal incremental population-wide utility over phenotypic risk prediction of CVD. Tailored prediction using genetic information for those at intermediate risk may have clinical utility.


Assuntos
Doenças Cardiovasculares/genética , Perfilação da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Adulto , Área Sob a Curva , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Reações Falso-Positivas , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologia
16.
PLoS One ; 11(6): e0156914, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27280446

RESUMO

Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.


Assuntos
Sistema do Grupo Sanguíneo ABO/genética , Replicação do DNA/genética , Eritrócitos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Grupos Étnicos , Europa (Continente) , Estudo de Associação Genômica Ampla , Humanos
17.
Pharmacogenomics ; 17(6): 583-91, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27045730

RESUMO

AIM: To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. PATIENTS & METHODS: In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE. RESULTS: No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10(-4)). CONCLUSION: The GRS was associated with statin response, but the small effect size (˜2% of the average low-density lipoprotein cholesterol reduction) limits applicability.


Assuntos
LDL-Colesterol/sangue , LDL-Colesterol/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Apolipoproteínas E/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
18.
Circ Cardiovasc Genet ; 9(3): 231-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27114411

RESUMO

BACKGROUND: Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low-density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures. METHODS AND RESULTS: A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low-density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low-density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL. CONCLUSIONS: We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.


Assuntos
Apolipoproteína C-III/genética , Aterosclerose/genética , Dislipidemias/genética , Lipase Lipoproteica/metabolismo , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/prevenção & controle , Biomarcadores/sangue , Criança , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Feminino , Frequência do Gene , Genótipo , Ensaios de Triagem em Larga Escala , Humanos , Hipolipemiantes/uso terapêutico , Lipase Lipoproteica/genética , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Estudos Longitudinais , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , Oligonucleotídeos/uso terapêutico , Fenótipo , Triglicerídeos/sangue , Reino Unido
19.
Atherosclerosis ; 246: 193-201, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26800306

RESUMO

Genome-wide association studies have confirmed the involvement of non-coding angiopoietin-like 3 (ANGPTL3) gene variants with coronary artery disease, levels of low-density lipoprotein cholesterol (LDL-C), triglycerides and ANGPTL3 mRNA transcript. Extensive linkage disequilibrium at the locus, however, has hindered efforts to identify the potential functional variants. Using regulatory annotations from ENCODE, combined with functional in vivo assays such as allele-specific formaldehyde-assisted isolation of regulatory elements, statistical approaches including eQTL/lipid colocalisation, and traditional in vitro methodologies including electrophoretic mobility shift assay and luciferase reporter assays, variants affecting the ANGPTL3 regulome were examined. From 253 variants associated with ANGPTL3 mRNA expression, and/or lipid traits, 46 were located within liver regulatory elements and potentially functional. One variant, rs10889352, demonstrated allele-specific effects on DNA-protein interactions, reporter gene expression and chromatin accessibility, in line with effects on LDL-C levels and expression of ANGPTL3 mRNA. The ANGPTL3 gene lies within DOCK7, although the variant is within non-coding regions outside of ANGPTL3, within DOCK7, suggesting complex long-range regulatory effects on gene expression. This study illustrates the power of combining multiple genome-wide datasets with laboratory data to localise functional non-coding variation and provides a model for analysis of regulatory variants from GWAS.


Assuntos
Angiopoietinas/genética , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas , Polimorfismo de Nucleotídeo Único , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/metabolismo , Montagem e Desmontagem da Cromatina , Biologia Computacional , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células Hep G2 , Humanos , Fenótipo , Locos de Características Quantitativas , Fatores de Tempo , Transfecção
20.
Lancet Diabetes Endocrinol ; 4(4): 327-36, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26781229

RESUMO

BACKGROUND: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS: In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION: Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions. FUNDING: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.


Assuntos
Doença das Coronárias/sangue , Doença das Coronárias/etiologia , Análise da Randomização Mendeliana/métodos , Ácido Úrico/efeitos adversos , Ácido Úrico/sangue , Humanos , Metanálise como Assunto , Estudos Observacionais como Assunto , Fatores de Risco
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