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2.
Nat Genet ; 51(3): 481-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804560

RESUMO

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.


Assuntos
Predisposição Genética para Doença/genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
3.
Bioinformatics ; 33(17): 2784-2786, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28472345

RESUMO

Summary: We developed the STOPGAP (Systematic Target OPportunity assessment by Genetic Association Predictions) database, an extensive catalog of human genetic associations mapped to effector gene candidates. STOPGAP draws on a variety of publicly available GWAS associations, linkage disequilibrium (LD) measures, functional genomic and variant annotation sources. Algorithms were developed to merge the association data, partition associations into non-overlapping LD clusters, map variants to genes and produce a variant-to-gene score used to rank the relative confidence among potential effector genes. This database can be used for a multitude of investigations into the genes and genetic mechanisms underlying inter-individual variation in human traits, as well as supporting drug discovery applications. Availability and implementation: Shell, R, Perl and Python scripts and STOPGAP R data files (version 2.5.1 at publication) are available at https://github.com/StatGenPRD/STOPGAP . Some of the most useful STOPGAP fields can be queried through an R Shiny web application at http://stopgapwebapp.com . Contact: matthew.r.nelson@gsk.com. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Bases de Dados Factuais , Estudos de Associação Genética/métodos , Variação Genética , Desequilíbrio de Ligação , Algoritmos , Humanos , Análise de Sequência de DNA/métodos
4.
J Allergy Clin Immunol ; 139(3): 797-803.e7, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27523435

RESUMO

BACKGROUND: Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability. OBJECTIVE: We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma. METHODS: Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate-treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies. The primary end point analyzed was change in trough FEV1 (ΔFEV1) from baseline to 8 to 12 weeks of treatment. RESULTS: More than 9.8 million common genetic variants (minor allele frequency ≥ 1%) were analyzed to test for association with ΔFEV1. No genetic variant met the prespecified threshold for statistical significance. CONCLUSIONS: This study provides no evidence to confirm previously reported associations between candidate genetic variants and ICS response (ΔFEV1) in patients with asthma. In addition, no variant satisfied the criterion for genome-wide significance in our study. Common genetic variants are therefore unlikely to prove useful as predictive biomarkers of ICS response in patients with asthma.


Assuntos
Corticosteroides/uso terapêutico , Androstadienos/uso terapêutico , Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Adulto , Asma/fisiopatologia , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
Pharmacogenomics ; 17(5): 459-62, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27023328

RESUMO

AIM: Pyrexia is a common adverse event (AE) on dabrafenib treatment (monotherapy or combination with trametinib). Since germline SNPs and HLA alleles are implicated in drug-induced AEs, this study investigated their association with pyrexia. PATIENTS & METHODS: 1006 melanoma subjects from five dabrafenib-trametinib clinical studies underwent genotyping for genome-wide SNPs, which enabled imputation of 150 HLA alleles. SNP/HLA allele frequencies were compared between pyrexia cases (n = 218) and controls (n = 361) out of the 1006 subjects by meta-analysis. RESULTS: This analysis had adequate power to detect association of common SNPs or HLA alleles with moderate to large effects on pyrexia (odds ratio >6), but no significant association was found. CONCLUSION: The study suggests that common genetic variation or HLA polymorphisms do not contribute substantially to dabrafenib-induced pyrexia.


Assuntos
Antineoplásicos/efeitos adversos , Febre/induzido quimicamente , Antígenos HLA/genética , Imidazóis/efeitos adversos , Melanoma/tratamento farmacológico , Oximas/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos de Casos e Controles , Febre/genética , Estudos de Associação Genética , Humanos , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética
6.
J Clin Pharmacol ; 53(10): 1078-90, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23934621

RESUMO

The mu-opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu-opioid antagonists have had limited success as anti-addiction treatments. GSK1521498 is a selective and potent mu-opioid antagonist being developed for the treatment of overeating and substance addictions. In this study, 28 healthy participants were administered single doses of GSK1521498 20 mg, ethanol 0.5 g/kg body weight, or both in combination, in a double blind placebo controlled four-way crossover design. The primary objective was to determine the risk of significant adverse pharmacodynamic and pharmacokinetic (PK) interactions. The effects of GSK1521498 on hedonic and consummatory responses to alcohol and the attentional processing of alcohol-related stimuli, and their modulation by the OPRM1 A118G polymorphism were also explored. GSK1521498 20 mg was well tolerated alone and in combination with ethanol. There were mild transient effects of GSK1521498 on alertness and mood that were greater when it was combined with ethanol. These effects were not of clinical significance. There were no effects of GSK1521498 on reaction time, hedonic or consummatory responses. These findings provide encouraging safety and PK data to support continued development of GSK1521498 for the treatment of alcohol addiction.


Assuntos
Etanol/administração & dosagem , Indanos/administração & dosagem , Triazóis/administração & dosagem , Adulto , Afeto/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Etanol/efeitos adversos , Etanol/farmacocinética , Humanos , Indanos/efeitos adversos , Indanos/farmacocinética , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/genética , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto Jovem
8.
Am J Hum Genet ; 92(4): 547-57, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23541341

RESUMO

Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Testes Genéticos/estatística & dados numéricos , Variação Genética/genética , Genótipo , Degeneração Macular/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Projetos de Pesquisa , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Humanos , Degeneração Macular/genética , Modelos Estatísticos , Infarto do Miocárdio/genética , Fenótipo , Fatores de Risco
9.
J Invest Dermatol ; 133(6): 1489-96, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23358095

RESUMO

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)

Assuntos
Alopecia/epidemiologia , Alopecia/genética , Proteínas Wnt/genética , Via de Sinalização Wnt/fisiologia , Adulto , Alopecia/etiologia , Alopecia/metabolismo , Colestanotriol 26-Mono-Oxigenase/genética , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Receptores Frizzled/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Proteína Wnt3/genética
10.
PLoS One ; 8(12): e83137, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24391740

RESUMO

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.


Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Rim/fisiologia , Hormônios Peptídicos/genética , Hormônios Peptídicos/fisiologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/fisiologia , Urotensinas/genética , Urotensinas/fisiologia , Adolescente , Adulto , Idoso , Animais , Estudos de Coortes , Evolução Molecular , Feminino , Expressão Gênica , Estudos de Associação Genética , Taxa de Filtração Glomerular/genética , Taxa de Filtração Glomerular/fisiologia , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Primatas/genética , Primatas/fisiologia , Adulto Jovem
11.
PLoS Genet ; 8(5): e1002746, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22693459

RESUMO

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10⁻9-1.01×10⁻¹²). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10⁻³). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.


Assuntos
Alopecia/genética , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Adulto , Idoso , Alelos , Fertilidade/genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
J Cereb Blood Flow Metab ; 32(1): 1-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22008728

RESUMO

[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 × 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.


Assuntos
Acetamidas/metabolismo , Polimorfismo de Nucleotídeo Único , Piridinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Adulto , Substituição de Aminoácidos/genética , Ligação Competitiva/genética , Plaquetas/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Isoquinolinas/metabolismo , Masculino , Tomografia por Emissão de Pósitrons , Ligação Proteica , Ensaio Radioligante , Trítio
13.
Int J Mol Epidemiol Genet ; 2(3): 261-85, 2011 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-21915365

RESUMO

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

14.
PLoS One ; 6(4): e18208, 2011 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-21490708

RESUMO

BACKGROUND: The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA2 in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted. METHODOLOGY/PRINCIPAL FINDINGS: PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA2 activity and CAD risk. CONCLUSIONS: Natural deficiency in Lp-PLA2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Doença da Artéria Coronariana/genética , Alelos , Grupo com Ancestrais do Continente Asiático , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , República da Coreia
15.
Hypertension ; 56(6): 1069-76, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21060006

RESUMO

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈ 50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P = 1.2 × 10⁻8). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4 × 10⁻6). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea/genética , Canais de Cloreto/genética , Hipertensão/epidemiologia , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Prevalência , Regiões Promotoras Genéticas , Reino Unido/epidemiologia , Adulto Jovem
16.
Arterioscler Thromb Vasc Biol ; 30(11): 2264-76, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20864672

RESUMO

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Doença da Artéria Coronariana/genética , Metabolismo dos Lipídeos/genética , Triglicerídeos/genética , Grupo com Ancestrais do Continente Asiático , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Grupo com Ancestrais do Continente Europeu , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue
17.
Nature ; 466(7307): 707-13, 2010 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-20686565

RESUMO

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Afro-Americanos/genética , Animais , Grupo com Ancestrais do Continente Asiático/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/terapia , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Fígado/metabolismo , Masculino , Camundongos , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Reprodutibilidade dos Testes , Triglicerídeos/sangue
18.
Eur J Hum Genet ; 18(12): 1344-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20717167

RESUMO

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Estudo de Associação Genômica Ampla , Redes e Vias Metabólicas/genética , Característica Quantitativa Herdável , Transdução de Sinais/genética , Adulto , Sequência de Bases , Feminino , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Reprodutibilidade dos Testes
19.
Nat Genet ; 42(2): 142-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20081857

RESUMO

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).


Assuntos
Variação Genética , Glucose/metabolismo , Insulina/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Adenilil Ciclases/genética , Índice de Massa Corporal , Dinamarca , Diabetes Mellitus Tipo 2/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Teste de Tolerância a Glucose , Humanos , Incretinas/genética , Masculino , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo
20.
Nat Genet ; 42(2): 105-16, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20081858

RESUMO

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.


Assuntos
Glicemia/genética , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Loci Gênicos/genética , Predisposição Genética para Doença , Homeostase/genética , Adolescente , Adulto , Alelos , Criança , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável , Reprodutibilidade dos Testes
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