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1.
Blood ; 136(26): 3062-3069, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33367543

RESUMO

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.

2.
Nature ; 586(7831): 763-768, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33057201

RESUMO

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

3.
Arterioscler Thromb Vasc Biol ; 40(11): 2756-2763, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32878478

RESUMO

OBJECTIVE: Venous thromboembolism (VTE) is a common disease that has a genetic basis. Lifestyle factors contribute to risk, but it is unknown whether healthy lifestyle can mitigate the genetic risk. We studied whether greater adherence to the American Heart Association's cardiovascular health metric, Life's Simple 7 (LS7), is associated with lower incidence of VTE in individuals across categories of a genetic risk score (GRS) for VTE. Approach AND RESULTS: We followed 9026 White participants from the ARIC (Atherosclerosis Risk in Communities) Study, a prospective cohort enrolled in 1987 to 1989 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories. There were 466 incident VTE events over 22.8 years. Participants with an optimal LS7 score had a lower incidence of VTE (3.9%) than those with inadequate LS7 (5.7%). Compared with the high GRS and inadequate LS7 group (hazard ratio=1), those with high GRS and optimal LS7 indeed had a reduced hazard ratio of VTE: 0.65 (95% CI, 0.48-0.89). The group with low GRS and optimal LS7 had the lowest hazard ratio of VTE (0.39 [95% CI, 0.25-0.61]). Of the LS7 components, in all GRS groups, the factor most strongly protective for VTE was normal weight. CONCLUSIONS: Among people at low or high genetic risk for VTE, healthier lifestyle factors, particularly normal weight, were associated with a lower incidence of VTE. Further studies should determine the impact of lifestyle changes among patients at high genetic risk of VTE, such as in thrombophilic families.

4.
Arterioscler Thromb Vasc Biol ; : ATVBAHA119313847, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32847391

RESUMO

BACKGROUND: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. OBJECTIVE: To evaluate the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23-1.62], P=6.0×10-7, VWF: odds ratio, 1.28 [95% CI, 1.07-1.52], P=0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF. CONCLUSIONS: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.

5.
Nat Commun ; 11(1): 3479, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661250

RESUMO

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/metabolismo , Ativação Plaquetária/fisiologia , Trombose/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Masculino , Espectrometria de Massas , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Agregação Plaquetária/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Trombose/genética
6.
Blood ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32722807

RESUMO

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied two-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects, and their clinical applications.

7.
Ann Am Thorac Soc ; 17(5): 589-595, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31899652

RESUMO

Rationale: Decreasing medication overuse represents an opportunity to avoid harm and costs in the era of value-based purchasing. Studies of inhaled corticosteroids (ICS) overuse in chronic obstructive pulmonary disease (COPD) have examined prevalent use. Understanding initiation of low-value ICS among complex patients with COPD may help shape deadoption efforts.Objectives: Examine ICS initiation among a cohort with low exacerbation risk COPD and test for associations with markers of patient and health system complexity.Methods: Between 2012 and 2016, we identified veterans with COPD from 21 centers. Our primary outcome was first prescription of ICS. We used the care assessment needs (CAN) score to assess patient-level complexity as the primary exposure. We used a time-to-event model with time-varying exposures over 1-year follow-up. We tested for effect modification using selected measures of health system complexity.Results: We identified 8,497 patients with COPD without an indication for ICS and did not have baseline use (inception cohort). Follow-up time was four quarters. Patient complexity by a continuous CAN score was associated with new dispensing of ICS (hazard ratio = 1.17 per 10-unit change; 95% confidence interval = 1.13-1.21). This association demonstrated a dose-response when examining quartiles of CAN score. Markers of health system complexity did not modify the association between patient complexity and first use of low-value ICS.Conclusions: Patient complexity may represent a symptom burden that clinicians are attempting to mitigate by initiating ICS. Lack of effect modification by health system complexity may reflect the paucity of structural support and low prioritization for COPD care.

8.
Clin Gastroenterol Hepatol ; 18(4): 954-962.e6, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31394284

RESUMO

BACKGROUND & AIMS: Military veterans have been reported to have higher odds of hepatitis B virus (HBV) exposure after adjustment for demographic factors, family income, and birthplace. It is not clear whether military-related exposures are associated with risk of HBV exposure in veterans. METHODS: A random sample of veterans receiving care from 1998 through 2000 in the national Veterans' Health Administration system completed a risk factor survey and underwent phlebotomy analysis (N = 1146). Stored serum samples were reanalyzed to determine prevalence of HBV exposure (core antibody positive), infection (surface antigen or DNA positive), and immunity (surface antibody positive, surface antigen negative, and core antibody negative). Associations between military-related risk factors and HBV exposure were assessed using logistic regression. RESULTS: The prevalence values for infection, exposure, and immunity were 0.7% (95% CI, 0.3-1.5), 13.6% (95% CI, 11.5-16.1), and 6.2% (95% CI, 4.7-8.2), respectively. Evidence of HBV exposure was highest among respondents with traditional risk factors (such as drug use or high-risk sexual practices). More than half the individuals with HBV exposure (53%) reported no history of traditional risk factors; of these, 59.5% reported a history of combat exposure. After adjustment for demographic and traditional risk factors, service in a combat zone (adjusted odds ratio, 1.56; 95% CI, 1.01-2.41) and being wounded in combat (adjusted odds ratio, 1.79; 95% CI, 1.04-3.08) were associated independently with exposure to HBV. CONCLUSIONS: In an analysis of US military veterans, we found the prevalence of exposure to HBV to be highest among veterans with traditional risk factors but also independently related to military combat or being wounded in combat. Studies are needed to determine whether veterans with combat exposure before the era of universal vaccination should be screened for HBV exposure.

9.
Nat Genet ; 51(11): 1574-1579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Doenças Vasculares/genética , Tromboembolia Venosa/genética , Idoso , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Fatores de Risco , Reino Unido/epidemiologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/patologia
10.
Ann Am Thorac Soc ; 16(8): e1-e16, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31368802

RESUMO

Since 2001, more than 2.7 million U.S. military personnel have been deployed in support of operations in Southwest Asia and Afghanistan. Land-based personnel experienced elevated exposures to particulate matter and other inhalational exposures from multiple sources, including desert dust, burn pit combustion, and other industrial, mobile, or military sources. A workshop conducted at the 2018 American Thoracic Society International Conference had the goals of: 1) identifying key studies assessing postdeployment respiratory health, 2) describing emerging research, and 3) highlighting knowledge gaps. The workshop reviewed epidemiologic studies that demonstrated more frequent encounters for respiratory symptoms postdeployment compared with nondeployers and for airway disease, predominantly asthma, as well as case series describing postdeployment dyspnea, asthma, and a range of other respiratory tract findings. On the basis of particulate matter effects in other populations, it also is possible that deployers experienced reductions in pulmonary function as a result of such exposure. The workshop also gave particular attention to constrictive bronchiolitis, which has been reported in lung biopsies of selected deployers. Workshop participants had heterogeneous views regarding the definition and frequency of constrictive bronchiolitis and other small airway pathologic findings in deployed populations. The workshop concluded that the relationship of airway disease, including constrictive bronchiolitis, to exposures experienced during deployment remains to be better defined. Future clinical and epidemiologic research efforts should address better characterization of deployment exposures; carry out longitudinal assessment of potentially related adverse health conditions, including lung function and other physiologic changes; and use rigorous histologic, exposure, and clinical characterization of patients with respiratory tract abnormalities.


Assuntos
Campanha Afegã de 2001- , Guerra do Iraque 2003-2011 , Militares , Doenças Respiratórias/epidemiologia , Asma/epidemiologia , Bronquite/epidemiologia , Intervalos de Confiança , Tosse/epidemiologia , Dispneia/epidemiologia , Feminino , Humanos , Pulmão/patologia , Masculino , Oriente Médio , Material Particulado/efeitos adversos , Sociedades Médicas , Estados Unidos/epidemiologia
12.
Spine (Phila Pa 1976) ; 44(17): 1220-1227, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30985567

RESUMO

STUDY DESIGN: A longitudinal cotwin control study of the Vietnam Era Twin Registry. OBJECTIVE: The aim of this study was to examine the association of post-traumatic stress disorder (PTSD) symptoms with incident chronic back pain (CBP), while controlling for genetic factors and early family environment. SUMMARY OF BACKGROUND DATA: It is unknown whether PTSD symptoms are associated with an increased incidence of CBP. METHODS: In 2010 to 2012, a baseline survey was undertaken as part of a large-scale study of PTSD. Study participants completed the PTSD Symptom Checklist (PCL) and a self-report measure of CBP. In 2015 to 2017, a follow-up survey was sent to all 171 monozygotic (MZ) twin pairs (342 individuals) where both cotwins had no history of CBP at baseline, but only one cotwin in the pair met criteria for having current PTSD symptoms (one twin with PCL <30 and the cotwin with PCL ≥30). No other inclusion/exclusion criteria were applied. CBP at 5-year follow-up was defined as back pain of duration ≥3 months in the low back or mid/upper back. Covariates included age, race, education, income, Veterans Affairs health care use, disability compensation, smoking, body mass index, and depression. Statistical analysis estimated the cumulative incidence of CBP according to baseline PTSD symptoms. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated in matched-pair cotwin control analyses adjusting for familial factors. RESULTS: Among 227 males completing 5-year follow-up, including 91 MZ twin pairs, the mean age was 62 years. Five-year incidence of CBP in those without and with baseline PTSD symptoms was 40% and 60%, respectively. Baseline PTSD symptoms were significantly associated with incident CBP in crude and multivariable-adjusted within-pair analyses (RR 1.6, 95% CI 1.2-2.1; P = 0.002). CONCLUSION: PTSD symptoms were associated with an increased incidence of CBP, without confounding by genetic factors or early family environment. PTSD symptoms may be a modifiable risk factor for prevention of CBP. LEVEL OF EVIDENCE: 3.


Assuntos
Dor nas Costas , Dor Crônica , Transtornos de Estresse Pós-Traumáticos , Gêmeos Monozigóticos/estatística & dados numéricos , Veteranos/estatística & dados numéricos , Dor nas Costas/complicações , Dor nas Costas/epidemiologia , Dor Crônica/complicações , Dor Crônica/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/epidemiologia
13.
Am J Physiol Renal Physiol ; 316(6): F1114-F1123, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30908934

RESUMO

Little is known about the population genetics of water balance. A recent meta-genome-wide association study on plasma sodium concentration identified novel loci of high biological plausibility, yet heritability of the phenotype has never been convincingly shown in European ancestry. The present study linked the Vietnam Era Twin Registry with the Department of Veterans Affairs VistA patient care clinical database. Participants (n = 2,370, 59.6% monozygotic twins and 40.4% dizygotic twins) had a median of seven (interquartile range: 3-14) plasma sodium determinations between October 1999 and March 2017. Heritability of the mean plasma sodium concentration among all twins was 0.41 (95% confidence interval: 0.35-0.46) and 0.49 (95% confidence interval: 0.43-0.54) after exclusion of 514 twins with only a single plasma sodium determination. Heritability among Caucasian (n = 1,958) and African-American (n = 268) twins was 0.41 (95% confidence interval: 0.34-0.47) and 0.36 (95% confidence interval: 0.17-0.52), respectively. Exclusion of data from twins who had been prescribed medications known to impact systemic water balance had no effect. The ability of the present study to newly detect substantial heritability across multiple racial groups was potentially a function of the cohort size and relatedness, exclusion of sodium determinations confounded by elevated plasma glucose and/or reduced glomerular filtration rate, transformation of plasma sodium for the independent osmotic effect of plasma glucose, and use of multiple laboratory determinations per individual over a period of years. Individual-level plasma sodium concentration exhibited longitudinal stability (i.e., individuality); the degree to which individual-level means differed from the population mean was substantial, irrespective of the number of determinations. In aggregate, these data establish the heritability of plasma sodium concentration in European ancestry and corroborate its individuality.


Assuntos
Heterogeneidade Genética , Hereditariedade , Sódio/sangue , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Veteranos , Equilíbrio Hidroeletrolítico/genética , Afro-Americanos/genética , Variação Biológica Individual , Bases de Dados Factuais , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estados Unidos
15.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
16.
Am J Hum Genet ; 104(2): 260-274, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639324

RESUMO

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.


Assuntos
Estudos de Associação Genética , Modelos Genéticos , Sequenciamento Completo do Genoma , Cromossomos Humanos Par 4/genética , Computação em Nuvem , Feminino , Fibrinogênio/análise , Fibrinogênio/genética , Genética Populacional , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisão , Projetos de Pesquisa , Fatores de Tempo , Estados Unidos
17.
Blood ; 133(9): 967-977, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30642921

RESUMO

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.


Assuntos
Isquemia Encefálica/etiologia , Fator VII/genética , Estudo de Associação Genômica Ampla , Proteínas de Membrana Transportadoras/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Proteínas Correpressoras , Estudos de Coortes , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Proteínas de Ligação a DNA , Fator VII/metabolismo , Feminino , Seguimentos , Loci Gênicos , Predisposição Genética para Doença , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Fenótipo , Prognóstico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/metabolismo , Tromboembolia Venosa/patologia
18.
JAMA ; 320(22): 2354-2364, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30535219

RESUMO

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3. Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.


Assuntos
Fibrilação Atrial/genética , Conectina/genética , Mutação com Perda de Função , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade
19.
BMC Musculoskelet Disord ; 19(1): 362, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30301474

RESUMO

BACKGROUND: Poor general health predicts the transition to chronic back pain (CBP), but the role of specific medical conditions in the development of CBP is unclear. The study aim was to examine the association of medical conditions with the development of CBP ("incident CBP"), while controlling for familial factors, including genetics. METHODS: This was a longitudinal co-twin control study conducted in a nationwide United States sample from the Vietnam Era Twin Registry. The study sample included 3045 males without back problems at baseline, including 662 complete twin pairs, who were followed for 11 years. Baseline surveys inquired about self-reported medical conditions (arthritis, diabetes, hypertension, and coronary artery disease [CAD]). A medical comorbidity score was calculated based on the presence and/or treatment of 8 medical conditions. Covariates included age, race, and education. At 11-year follow-up, participants reported ever having had CBP. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated when considering twins as individuals, and in matched-pair co-twin control analyses adjusting for familial/genetic factors. RESULTS: Mean age at baseline was 51 years and 17% of participants developed CBP over the 11-year follow-up. Arthritis was significantly associated with incident CBP in individual-level analysis (OR 1.8 [95% CI 1.4-2.2]), but not within-pair analysis (OR 0.9 [95% CI 0.4-1.9]. CAD (OR 1.6 [95% CI 1.0-2.3]), hypertension (OR 1.3 [95% CI 1.0-1.5]), and the medical comorbidity score (OR 1.2 [95%CI 1.1-2.2]) were significantly associated with incident CBP in individual-level analyses; associations in within-pair analyses were of comparable magnitude, but not statistically significant. Diabetes was not associated with incident CBP. CONCLUSIONS: Arthritis, hypertension, CAD, and medical comorbidity score were associated with incident CBP in the current study. However, the association between arthritis and incident CBP was confounded by familial factors. This suggests that prevention or treatment of arthritis is unlikely to be useful for CBP prevention. Our findings cannot exclude the possibility of causal associations between CAD, hypertension, and medical comorbidities and incident CBP.


Assuntos
Dor nas Costas/epidemiologia , Dor Crônica/epidemiologia , Fatores Etários , Artrite/diagnóstico , Artrite/epidemiologia , Dor nas Costas/diagnóstico , Dor Crônica/diagnóstico , Comorbidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Seguimentos , Nível de Saúde , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Estados Unidos/epidemiologia
20.
PLoS Genet ; 14(9): e1007601, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30261039

RESUMO

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10(-8). Suggestive (p<5×10(-7)) and genome-wide significant (p<5×10(-8)) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10(-10)). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10(-11)), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10(-19)). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10(-13)), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10(-10)). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).


Assuntos
Dor nas Costas/genética , Dor Crônica/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Fatores de Transcrição SOXD/genética , Biomarcadores Tumorais/genética , Receptor DCC/genética , Proteínas de Ligação a DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Íntrons/genética , Polimorfismo de Nucleotídeo Único
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