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  • Ovid Technologies (Wolters Kluwer Health)  (12)
  • Yao, Jie  (12)
  • 1
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    Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Heart Association Vol. 6, No. 6 ( 2017-11-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 6 ( 2017-11-06)
    Abstract: Plasminogen activator inhibitor type 1 ( PAI ‐1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI ‐1 levels are associated with increased risk of coronary heart disease ( CHD ). However, it is unclear whether the association reflects a causal influence of PAI ‐1 on CHD risk. Methods and Results To evaluate the association between PAI ‐1 and CHD , we applied a 3‐step strategy. First, we investigated the observational association between PAI ‐1 and CHD incidence using a systematic review based on a literature search for PAI ‐1 and CHD studies. Second, we explored the causal association between PAI ‐1 and CHD using a Mendelian randomization approach using summary statistics from large genome‐wide association studies. Finally, we explored the causal effect of PAI ‐1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta‐analysis, the highest quantile of blood PAI ‐1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age‐ and sex‐adjusted model. The effect size was reduced in studies using a multivariable‐adjusted model (odds ratio=1.46; 95% CI : 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI ‐1 level on CHD risk (odds ratio=1.22 per unit increase of log‐transformed PAI ‐1; 95% CI : 1.01, 1.47). In addition, we also detected a causal effect of PAI ‐1 on elevating blood glucose and high‐density lipoprotein cholesterol. Conclusions Our study indicates a causal effect of elevated PAI ‐1 level on CHD risk, which may be mediated by glucose dysfunction.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.116.004918
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2653953-6
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  • 2
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    Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 145, No. 5 ( 2022-02), p. 357-370
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 145, No. 5 ( 2022-02), p. 357-370
    Abstract: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.121.055117
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 3
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    Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Obstetrical & Gynecological Survey Vol. 70, No. 12 ( 2015-12), p. 758-762
    Details
    In: Obstetrical & Gynecological Survey, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. 12 ( 2015-12), p. 758-762
    Type of Medium: Online Resource
    ISSN: 0029-7828
    URL: Article
    DOI: 10.1097/01.ogx.0000473766.71624.99
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2043471-6
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  • 4
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    Association Between Whole Blood–Derived Mitochondrial DNA Copy Number, Low‐Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Heart Association
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health)
    Abstract: The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P 〈 0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P 〈 0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P 〈 0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P 〈 0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.122.029090
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 5
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    Genetic Risk Prediction of Atrial Fibrillation
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation Vol. 135, No. 14 ( 2017-04-04), p. 1311-1320
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 135, No. 14 ( 2017-04-04), p. 1311-1320
    Abstract: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from 〈 1×10 −3 to 〈 1×10 −8 in a prior independent genetic association study. Results: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13–1.46; P =1.5×10 −4 ) to 1.67 (25 variants; 95% confidence interval, 1.47–1.90; P =9.3×10 −15 ). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39–4.58; P =2.7×10 −3 ). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20–4.40; P =0.01). Conclusions: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.116.024143
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 6
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    Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation: Genomic and Precision Medicine Vol. 13, No. 5 ( 2020-10), p. 387-395
    Details
    In: Circulation: Genomic and Precision Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 13, No. 5 ( 2020-10), p. 387-395
    Abstract: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.
    Type of Medium: Online Resource
    ISSN: 2574-8300 , 2574-8300
    URL: Article
    DOI: 10.1161/CIRCGEN.119.002874
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 7
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    Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation: Cardiovascular Genetics Vol. 9, No. 6 ( 2016-12), p. 511-520
    Details
    In: Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 6 ( 2016-12), p. 511-520
    Abstract: The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results— We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima–media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima–media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC ( P =3×10 − 10 ). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC ( P =1×10 − 12 ) and 1.4% reduced carotid intima–media thickness ( P =4×10 − 14 ) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P =1×10 − 11 ). Conclusions— Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
    Type of Medium: Online Resource
    ISSN: 1942-325X , 1942-3268
    URL: Article
    DOI: 10.1161/CIRCGENETICS.116.001572
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 8
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    Multiethnic Meta-Analysis of Genome-Wide Association Studies in 〉100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Circulation Vol. 128, No. 12 ( 2013-09-17), p. 1310-1324
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 128, No. 12 ( 2013-09-17), p. 1310-1324
    Abstract: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion ( 〈 2%) of its variation. Methods and Results— We conducted a meta-analysis of 28 genome-wide association studies including 〉 90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant ( P 〈 5×10 −8 ) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions— We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.113.002251
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 9
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    Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Stroke Vol. 54, No. 3 ( 2023-03), p. 810-818
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. 3 ( 2023-03), p. 810-818
    Abstract: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.122.040715
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1467823-8
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  • 10
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    Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation: Genomic and Precision Medicine Vol. 11, No. 5 ( 2018-05)
    Details
    In: Circulation: Genomic and Precision Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 11, No. 5 ( 2018-05)
    Abstract: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. Methods: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. Results: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction ( P 〈 1.2×10 −6 ), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 ( P =5.9×10 −11 ) and SCN5A ( P =1.1×10 −7 ) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. Conclusions: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
    Type of Medium: Online Resource
    ISSN: 2574-8300
    URL: Article
    DOI: 10.1161/CIRCGEN.117.002037
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2927603-2
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