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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.
Am J Hum Genet ; 105(4): 763-772, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564439

RESUMO

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

3.
J Am Med Inform Assoc ; 26(10): 1083-1090, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31529123

RESUMO

OBJECTIVE: Pleiotropy, where 1 genetic locus affects multiple phenotypes, can offer significant insights in understanding the complex genotype-phenotype relationship. Although individual genotype-phenotype associations have been thoroughly explored, seemingly unrelated phenotypes can be connected genetically through common pleiotropic loci or genes. However, current analyses of pleiotropy have been challenged by both methodologic limitations and a lack of available suitable data sources. MATERIALS AND METHODS: In this study, we propose to utilize a new regression framework, reduced rank regression, to simultaneously analyze multiple phenotypes and genotypes to detect pleiotropic effects. We used a large-scale biobank linked electronic health record data from the Penn Medicine BioBank to select 5 cardiovascular diseases (hypertension, cardiac dysrhythmias, ischemic heart disease, congestive heart failure, and heart valve disorders) and 5 mental disorders (mood disorders; anxiety, phobic and dissociative disorders; alcohol-related disorders; neurological disorders; and delirium dementia) to validate our framework. RESULTS: Compared with existing methods, reduced rank regression showed a higher power to distinguish known associated single-nucleotide polymorphisms from random single-nucleotide polymorphisms. In addition, genome-wide gene-based investigation of pleiotropy showed that reduced rank regression was able to identify candidate genetic variants with novel pleiotropic effects compared to existing methods. CONCLUSION: The proposed regression framework offers a new approach to account for the phenotype and genotype correlations when identifying pleiotropic effects. By jointly modeling multiple phenotypes and genotypes together, the method has the potential to distinguish confounding from causal genotype and phenotype associations.

4.
Genet Med ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31383942

RESUMO

PURPOSE: "Genome-first" approaches, in which genetic sequencing is agnostically linked to associated phenotypes, can enhance our understanding of rare variants' contributions to disease. Loss-of-function variants in LMNA cause a range of rare diseases, including cardiomyopathy. METHODS: We leveraged exome sequencing from 11,451 unselected individuals in the Penn Medicine Biobank to associate rare variants in LMNA with diverse electronic health record (EHR)-derived phenotypes. We used Rare Exome Variant Ensemble Learner (REVEL) to annotate rare missense variants, clustered predicted deleterious and loss-of-function variants into a "gene burden" (N = 72 individuals), and performed a phenome-wide association study (PheWAS). Major findings were replicated in DiscovEHR. RESULTS: The LMNA gene burden was significantly associated with primary cardiomyopathy (p = 1.78E-11) and cardiac conduction disorders (p = 5.27E-07). Most patients had not been clinically diagnosed with LMNA cardiomyopathy. We also noted an association with chronic kidney disease (p = 1.13E-06). Regression analyses on echocardiography and serum labs revealed that LMNA variant carriers had dilated cardiomyopathy and primary renal disease. CONCLUSION: Pathogenic LMNA variants are an underdiagnosed cause of cardiomyopathy. We also find that LMNA loss of function may be a primary cause of renal disease. Finally, we show the value of aggregating rare, annotated variants into a gene burden and using PheWAS to identify novel ontologies for pleiotropic human genes.

5.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

6.
Blood ; 134(19): 1645-1657, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

7.
Circulation ; 140(12): 1031-1040, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

8.
Circulation ; 140(6): 449-458, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31280589

RESUMO

BACKGROUND: The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation in a large cohort of veterans to determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease. METHODS: Participants in the Veterans Aging Cohort Study were recruited from April 1, 2003 through December 31, 2014. We excluded participants with known prior lower limb amputation. Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors. RESULTS: Among 125 674 veterans without evidence of prior amputation at baseline, the rate of incident amputation over a median of 9.3 years of follow-up was 1.16 per 1000 person-years, yielding a total of 1185 amputations. In time-updated multivariable-adjusted analyses, compared with those without peripheral artery disease or microvascular disease, microvascular disease alone was associated with a 3.7-fold (95% CI, 3.0-4.6) increased risk of amputation; peripheral artery disease alone conferred a 13.9-fold (95% CI, 11.3-17.1) elevated risk of amputation; and the combination of peripheral artery disease and microvascular disease was associated with a 22.7-fold (95% CI, 18.3-28.1) increased risk of amputation. CONCLUSIONS: Independent of traditional risk factors, the presence of microvascular disease increases the risk of amputation alone and synergistically increases risk in patients with peripheral artery disease. Further research is needed to understand the mechanisms by which this occurs.

9.
Nat Med ; 25(8): 1274-1279, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285632

RESUMO

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.


Assuntos
Estudo de Associação Genômica Ampla , Doença Arterial Periférica/genética , Idoso , LDL-Colesterol/genética , Fator V/genética , Inibidores do Fator Xa/uso terapêutico , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Receptores de LDL/genética , Veteranos
10.
JAMA Netw Open ; 2(6): e195345, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173123

RESUMO

Importance: Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population. Objectives: To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions. Design, Setting, and Participants: This cross-sectional study included veterans who used national VHA pharmacy services from October 1, 2011, to September 30, 2017. Data analyses began April 26, 2018, and were completed February 6, 2019. Exposures: Receipt of level A drugs based on VHA pharmacy dispensing records. Main Outcomes and Measures: Projected prevalence of actionable pharmacogenetic variants among VHA pharmacy users based on variant frequencies from the 1000 Genomes Project and veteran demographic characteristics; incident number of level A prescriptions, and proportion of new level A drug recipients projected to carry an actionable pharmacogenetic variant. Results: During the study, 7 769 359 veterans (mean [SD] age, 58.1 [17.8] years; 7 021 504 [90.4%] men) used VHA pharmacy services. It was projected that 99% of VHA pharmacy users would carry at least 1 actionable pharmacogenetic variant. Among VHA pharmacy users, 4 259 153 (54.8%) received at least 1 level A drug with 1 188 124 (15.3%) receiving 2 drugs, and 912 189 (11.7%) receiving 3 or more drugs. The most common incident prescriptions during the study were tramadol (923 671 new recipients), simvastatin (533 928 new recipients), citalopram (266 952 new recipients), and warfarin (205 177 new recipients). Gene-drug interactions projected to have substantial clinical impacts in the VHA population include the interaction of SLCO1B1 with simvastatin (1 988 956 veterans [25.6%]), CYP2D6 with tramadol (318 544 veterans [4.1%]), and CYP2C9 or VKORC1 with warfarin (7 163 349 veterans [92.2%]). Conclusions and Relevance: Clinically important pharmacogenetic variants are highly prevalent in the VHA population. Almost all veterans would carry an actionable variant, and more than half of the population had been exposed to a drug affected by these variants. These results suggest that pharmacogenetic testing has the potential to affect pharmacotherapy decisions for commonly prescribed outpatient medications for many veterans.

11.
Circulation ; 140(1): 42-54, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31216868

RESUMO

BACKGROUND: Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of the impact of TTNtvs in different clinical contexts, and the evaluation of modifiers such as genetic ancestry, has not been performed. METHODS: We reviewed whole exome sequence data for >71 000 individuals (61 040 from the Geisinger MyCode Community Health Initiative (2007 to present) and 10 273 from the PennMedicine BioBank (2013 to present) to identify anyone with TTNtvs. We further selected individuals with TTNtvs in exons highly expressed in the heart (proportion spliced in [PSI] >0.9). Using linked electronic health records, we evaluated associations of TTNtvs with diagnoses and quantitative echocardiographic measures, including subanalyses for individuals with and without DCM diagnoses. We also reviewed data from the Jackson Heart Study to validate specific analyses for individuals of African ancestry. RESULTS: Identified with a TTNtv in a highly expressed exon (hiPSI) were 1.2% individuals in PennMedicine BioBank and 0.6% at Geisinger. The presence of a hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (odds ratio [95% CI]: 18.7 [9.1-39.4] {PennMedicine BioBank} and 10.8 [7.0-16.0] {Geisinger}). hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, despite a high DCM prevalence (odds ratio, 1.8 [0.2-13.7]; P=0.57). Among 244 individuals of European ancestry with DCM in PennMedicine BioBank, hiPSI TTNtv carriers had lower left ventricular ejection fraction (ß=-12%, P=3×10-7), and increased left ventricular diameter (ß=0.65 cm, P=9×10-3). In the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (odds ratio, 2.4 [1.6-3.6]) and heart failure (odds ratio, 3.8 [2.4-6.0]), and lower left ventricular ejection fraction (ß=-3.4%, P=1×10-7). CONCLUSIONS: Individuals of European ancestry with hiPSI TTNtv have an abnormal cardiac phenotype characterized by lower left ventricular ejection fraction, irrespective of the clinical manifestation of cardiomyopathy. Associations with arrhythmias, including atrial fibrillation, were observed even when controlling for cardiomyopathy diagnosis. In contrast, no association between hiPSI TTNtvs and DCM was discerned among individuals of African ancestry. Given these findings, clinical identification of hiPSI TTNtv carriers may alter clinical management strategies.

13.
J Vasc Surg Venous Lymphat Disord ; 7(3): 405-412, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30885629

RESUMO

OBJECTIVE: The aim of this study was to examine practice patterns of inferior vena cava (IVC) filter insertion and retrieval at a tertiary care institution. METHODS: A retrospective review of all IVC filter procedures performed at the University of Pennsylvania and entered into the Penn cohort of the Vascular Quality Initiative registry between January 2013 and September 2017 was performed. Data collected included demographics, venous thromboembolism risk factors, indications for filter placement, and presence and timing of retrieval. Trend analysis and multivariable logistic regression were performed to evaluate factors associated with failure to retrieve the filter. RESULTS: During the study period, 627 IVC filters were inserted. The mean age was 52.8 ± 16.9 years, and 49.3% were male; 39.2% were placed for a major indication, whereas 58.1% were placed for prophylaxis. There was a significant decline in overall frequency of filter placement during the period observed, with a 33% decrease from 2015 to 2016 and a 26% decrease from 2016 to 2017 (P < .001), with an overall retrieval rate of 44.9%. In contrast, there was a corresponding increase in filter retrieval, with a 20% increase in 2015 and a 68% increase in 2016 (P = .02). In evaluating trends separated by indication, there was a significant decline in prophylactic filter placement (P < .001) and a trend toward an increase in retrieval of prophylactic filters (P = .09). Whereas there was not a significant change in number of filter insertions for major indication (P = .06), filter retrievals for major indication filters increased (P = .01). Multivariable regression analysis revealed that longer time to follow-up (odds ratio [OR], 1.08; P < .001) and discharge to rehabilitation facility (OR, 6.14; P < .001) were predictive of failure to retrieve the filter. In contrast, filter placement at a later date within our study period (OR, 0.90; P < .001) and prophylactic indication for filter placement (OR, 0.36; P < .001) were protective from filter nonretrieval. CONCLUSIONS: These results show both a decline in overall IVC filter placement and an increase in overall IVC filter retrieval at our institution. These trends are predominantly due to a decrease in prophylactic filter placement as well as an overall increase in filter retrieval. Further study should be dedicated to increasing the retrieval rate in this population of patients.

15.
JAMA Oncol ; 5(4): 514-522, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30676620

RESUMO

Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. Design, Setting, and Participants: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. Main Outcomes and Measures: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. Results: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). Conclusions and Relevance: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

16.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
17.
Circ Genom Precis Med ; 11(11): e002352, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571185

RESUMO

BACKGROUND: Coronary artery disease (CAD) is influenced by genetic variation and traditional risk factors. Polygenic risk scores (PRS), which can be ascertained before the development of traditional risk factors, have been shown to identify individuals at elevated risk of CAD. Here, we demonstrate that a genome-wide PRS for CAD predicts all-cause mortality after accounting for not only traditional cardiovascular risk factors but also angiographic CAD itself. METHODS: Individuals who underwent coronary angiography and were enrolled in an institutional biobank were included; those with prior myocardial infarction or heart transplant were excluded. Using a pruning-and-thresholding approach, a genome-wide PRS comprised of 139 239 variants was calculated for 1503 participants who underwent coronary angiography and genotyping. Individuals were categorized into high PRS (hiPRS) and low-PRS control groups using the maximally selected rank statistic. Stratified analysis based on angiographic findings was also performed. The primary outcome was all-cause mortality following the index coronary angiogram. RESULTS: Individuals with hiPRS were younger than controls (66 years versus 69 years; P=2.1×10-5) but did not differ by sex, body mass index, or traditional risk-factor profiles. Individuals with hiPRS were at significantly increased risk of all-cause mortality after cardiac catheterization, adjusting for traditional risk factors and angiographic extent of CAD (hazard ratio, 1.6; 95% CI, 1.2-2.2; P=0.004). The strongest increase in risk of all-cause mortality conferred by hiPRS was seen among individuals without angiographic CAD (hazard ratio, 2.4; 95% CI, 1.1-5.5; P=0.04). In the overall cohort, adding hiPRS to traditional risk assessment improved prediction of 5-year all-cause mortality (area under the receiver-operating curve 0.70; 95% CI, 0.66-0.75 versus 0.66; 95% CI, 0.61-0.70; P=0.001). CONCLUSIONS: A genome-wide PRS improves risk stratification when added to traditional risk factors and coronary angiography. Individuals without angiographic CAD but with hiPRS remain at significantly elevated risk of mortality.


Assuntos
Cateterismo Cardíaco , Angiografia Coronária , Doença da Artéria Coronariana , Infarto do Miocárdio , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Medição de Risco , Fatores de Risco , Taxa de Sobrevida
18.
Nat Genet ; 50(11): 1514-1523, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30275531

RESUMO

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

19.
Ann Vasc Surg ; 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30217710

RESUMO

BACKGROUND: Length of stay (LOS) is a commonly used metric to optimize value in medical care. Although pathways have been developed for some procedures in vascular surgery to reduce LOS, they do not yet exist for thoracic endovascular aortic repair (TEVAR). The purpose of this study is to identify and define the risk factors for prolonged LOS in patients undergoing TEVAR to facilitate pathway development. METHODS: We included TEVAR patients in the National Surgical Quality Improvement Program database from 2005 to 2015. Prolonged LOS was defined as LOS > 75th percentile of the overall cohort (11 days). Because initial analysis revealed the distinct clinical differences between dissection and aneurysm patients, further analysis was stratified by aortic pathology. Student's t-test and Chi-square tests were used to compare demographic and perioperative variables between dissection and aneurysm patients, respectively. Multivariable logistic regression was used to evaluate the predictors for prolonged LOS. RESULTS: A total of 3,021 patients underwent TEVAR, with 858 patients (28.4%) undergoing TEVAR for dissection and 2,163 (71.6%) undergoing TEVAR for aneurysm. An initial analysis with logistic regression identified dissection indication (odds ratio [OR], 2.87; 95% confidence interval [CI], 1.1-7.3) as an independent predictor of prolonged LOS. Further analysis for prolonged LOS was subsequently performed separating dissection and aneurysm patients. Aneurysm patients were older (71.2 ± 11.7 vs. 63.1 ± 13.6 years, P < 0.001), more often Caucasian (76.8% vs. 61.8%, P < 0.001), and had more medical comorbidities (chronic obstructive pulmonary disease, cardiac history, diabetes, peripheral vascular disease, transient ischemic attack [TIA], P < 0.001). In contrast, dissection patients had higher American Society of Anesthesiology (ASA) classification score (58.5% had >3 ASA vs. 45.5%, P < 0.001), longer hospitalizations (10.2 ± 9.3 vs. 8.5 ± 10.4 days, P < 0.001), were more likely to have been transferred from another hospital or emergency room (58.4% vs. 48.3%, P < 0.001), and were more often emergent (32.4% vs. 15.4%, P < 0.001). In dissection patients, ASA classification score (OR, 1.49; 95% CI, 1.1-2.1) and dialysis (OR, 1.98; 95% CI, 1.0-3.9) were independent predictors for prolonged LOS. In aneurysm patients, dependent functional status (OR, 2.03; 95% CI, 1.4-2.8), diabetes (OR, 1.75; 95% CI, 1.1-2.8), cardiac history (OR, 1.37; 95% CI, 1.0-1.9), emergency status (OR, 1.98; 95% CI, 1.4-2.8), and dialysis (OR, 2.08; 95% CI, 1.2-3.7) predicted prolonged LOS. Postoperative complications including stroke/TIA; failure to wean from ventilator, sepsis, and pneumonia; and need for reoperation similarly increased LOS in both dissection and aneurysm patients. CONCLUSIONS: Dissection and aneurysm patients undergoing TEVAR are comprised of different patient populations, with dissection patients more often enduring prolonged hospitalizations. In contrast, TEVAR performed for nonemergent aneurysm repair had the shortest LOS. These data support the development of separate pathways defined by indication and acuity for patients undergoing TEVAR.

20.
Nat Genet ; 50(9): 1225-1233, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29892015

RESUMO

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

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