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1.
Nat Genet ; 51(11): 1574-1579, 2019 Nov.
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.

2.
Ann Am Thorac Soc ; 16(8): e1-e16, 2019 Aug.
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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31394284

RESUMO

BACKGROUND & AIMS: Military veterans were 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.

5.
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
6.
Am J Physiol Renal Physiol ; 316(6): F1114-F1123, 2019 Jun 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.

8.
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
9.
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 , Estudos de Coortes , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , 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
10.
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
11.
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
12.
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.

13.
PLoS Genet ; 14(9): e1007601, 2018 Sep.
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).

14.
BMC Med Res Methodol ; 18(1): 88, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157766

RESUMO

BACKGROUND: Research participant recruitment is often fraught with obstacles. Poor response rates can reduce statistical power, threaten both internal and external validity, and increase study costs and duration. Military personnel are socialized to a specific set of laws, norms, traditions, and values; their willingness to participate in research may differ from civilians. The aims of this study were to better understand the views of United States (US) Veterans who served in Operation Enduring Freedom (OEF)/ Operation Iraqi Freedom (OIF) on research and motivators for participating in research to inform recruitment for a planned observational study of respiratory health in OEF/OIF Veterans. METHODS: We conducted 10 focus groups in a purposive sample of OEF/OIF Veterans (n = 89) in five US cities in 2015. Key topics included: reasons for participating or declining to participate in health-related research, logistics around study recruitment and conduct, compensation, written materials, and information sharing preferences for study results. Two authors independently coded the data using template analysis. RESULTS: Participants identified three criteria that motivated a decision to participate in health-related research: 1) adequate compensation, 2) desire to help other Veterans, and 3) significance and relevance of the research topic. For many, both sufficient compensation and a sense that the study would help other Veterans were critical. The importance of transparency arose as a key theme; Veterans communicated that vague language about study aims or procedures engendered distrust. Lastly, participants expressed a desire for studies to communicate results of their specific health tests, as well as overall study findings, back to research participants. CONCLUSIONS: OEF/OIF Veterans described trust, transparent communication, and respect as essential characteristics of research in which they would be willing to participate. Additional studies are needed to determine whether our results generalize to other US Veterans; nevertheless, our results highlight precepts that have been reported as important for recruitment in other populations. Researchers may benefit from using community-engaged research methods to seek feedback on recruitment materials and strategies prior to initiating research. For costly studies targeting a large sample (i.e. in the thousands), it may be important to test a variety of recruitment strategies.

15.
PLoS One ; 13(6): e0199194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29933385

RESUMO

PURPOSE: Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP. MATERIALS AND METHODS: Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively. RESULTS: Of the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49-0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48-0.69). After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70-1.13) or any CaP (HR 0.90; 95% CI 0.81-1.01). No association between cumulative testosterone dose or formulation and CaP was observed. CONCLUSIONS: Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.

17.
Circ Genom Precis Med ; 11(3): e001901, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29540468

RESUMO

BACKGROUND: Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations. METHODS AND RESULTS: We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, P=1×10-41). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (R2=1.0) linkage disequilibrium with rs9912468 within intron 2 of PRKCA. We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The PRKCA enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations. CONCLUSIONS: These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.

18.
J Gen Intern Med ; 33(2): 155-165, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29181788

RESUMO

BACKGROUND: For patients with type 2 diabetes and chronic kidney disease (CKD), high-quality evidence about the relative benefits and harms of oral glucose-lowering drugs is limited. OBJECTIVE: To evaluate whether mortality risk differs after the initiation of monotherapy with either metformin or a sulfonylurea in Veterans with type 2 diabetes and CKD. DESIGN: Observational, national cohort study in the Veterans Health Administration (VHA). PARTICIPANTS: Veterans who received care from the VHA for at least 1 year prior to initiating monotherapy treatment for type 2 diabetes with either metformin or a sulfonylurea between 2004 and 2009. MAIN MEASURES: Metformin and sulfonylurea use was assessed from VHA electronic pharmacy records. The CKD-EPI equation was used to estimate glomerular filtration rate (eGFR). The outcome of death from January 1, 2004, through December 31, 2009, was assessed from VHA Vital Status files. KEY RESULTS: Among 175,296 new users of metformin or a sulfonylurea monotherapy, 5121 deaths were observed. In primary analyses adjusted for all measured potential confounding factors, metformin monotherapy was associated with a lower mortality hazard ratio (HR) compared with sulfonylurea monotherapy across all ranges of eGFR evaluated (HR ranging from 0.59 to 0.80). A secondary analysis of mortality risk differences favored metformin across all eGFR ranges; the greatest risk difference was observed in the eGFR category 30-44 mL/min/1.73m2 (12.1 fewer deaths/1000 person-years, 95% CI 5.2-19.0). CONCLUSIONS: Initiation of metformin versus a sulfonylurea among individuals with type 2 diabetes and CKD was associated with a substantial reduction in mortality, in terms of both relative and absolute risk reduction. The largest absolute risk reduction was observed among individuals with moderately-severely reduced eGFR (30-44 mL/min/1.73m2).

20.
Ann Am Thorac Soc ; 14(9): 1443-1449, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28708421

RESUMO

RATIONALE: Short-term follow-up in the Fluid and Catheter Treatment Trial (FACTT) suggested differential mortality by race with conservative fluid management, but no significant interaction. OBJECTIVE: In a post hoc analysis of FACTT including 1-year follow-up, we sought to estimate long-term mortality by race and test for an interaction between fluids and race. METHODS: We performed a post hoc analysis of FACTT and the Economic Analysis of Pulmonary Artery Catheters (EAPAC) study (which included 655 of the 1,000 FACTT patients with near-complete 1-year follow up). We fit a multistate Markov model to estimate 1-year mortality for all non-Hispanic black and white randomized FACTT subjects. The model estimated the distribution of time from randomization to hospital discharge or hospital death (available on all patients) and estimated the distribution of time from hospital discharge to death using data on patients after hospital discharge for patients in EAPAC. The 1-year mortality was found by combining these estimates. RESULTS: Non-Hispanic black (n = 217, 25%) or white identified subjects (n = 641, 75%) were included. There was a significant interaction between race and fluid treatment (P = 0.012). One-year mortality was lower for black subjects assigned to conservative fluids (38 vs. 54%; mean mortality difference, 16%; 95% confidence interval, 2-30%; P = 0.027 between conservative and liberal). Conversely, 1-year mortality for white subjects was 35% versus 30% for conservative versus liberal arms (mean mortality difference, -4.8%; 95% confidence interval, -13% to 3%; P = 0.23). CONCLUSIONS: In our cohort, conservative fluid management may have improved 1-year mortality for non-Hispanic black patients with ARDS. However, we found no long-term benefit of conservative fluid management in white subjects.


Assuntos
Hidratação , Síndrome do Desconforto Respiratório do Adulto/etnologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/terapia , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Tempo de Internação , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , National Heart, Lung, and Blood Institute (U.S.) , Fatores de Tempo , Estados Unidos
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