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  • 1
    Online Resource
    Online Resource
    Genome- and Phenome-Wide Analyses of Cardiac Conduction Identifies Markers of Arrhythmia Risk
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Circulation Vol. 127, No. 13 ( 2013-04-02), p. 1377-1385
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 127, No. 13 ( 2013-04-02), p. 1377-1385
    Abstract: ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias. Methods and Results— We performed a genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P =1.2×10 −8 (eMERGE) and P =2.5×10 −20 (CHARGE) and rs6795970 in SCN10A with P =6×10 −6 (eMERGE) and P =5×10 −27 (CHARGE). The other loci were in NFIA , near CDKN1A , and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 “heart-healthy” study population. Conclusions— We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.112.000604
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 2
    Online Resource
    Online Resource
    Associations of Genetically Predicted Lp(a) (Lipoprotein [a]) Levels With Cardiovascular Traits in Individuals of European and African Ancestry
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation: Genomic and Precision Medicine Vol. 14, No. 4 ( 2021-08)
    Details
    In: Circulation: Genomic and Precision Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 4 ( 2021-08)
    Abstract: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry. Methods: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization–phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants. Results: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA—odds ratio and 95% CI for coronary heart disease 1.28 (1.16–1.41); cerebrovascular disease 1.14 (1.07–1.21); peripheral artery disease 1.22 (1.11–1.34); abdominal aortic aneurysm 1.28 (1.17–1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99–1.24) and cerebrovascular disease 1.06 (0.99–1.14) but similar for peripheral artery disease 1.16 (1.01–1.33) and abdominal aortic aneurysm 1.34 (1.11–1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10–1.62), mitral valve disorders 1.18 (1.09–1.27), congestive heart failure 1.12 (1.05–1.19), and chronic kidney disease 1.07 (1.01–1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94–1.25), mitral valve disorders 1.02 (0.89–1.16), congestive heart failure 1.02 (0.95–1.10), or chronic kidney disease 1.05 (0.99–1.12). Mendelian randomization–phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. Conclusions: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.
    Type of Medium: Online Resource
    ISSN: 2574-8300
    URL: Article
    DOI: 10.1161/CIRCGEN.120.003354
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 3
    Online Resource
    Online Resource
    Abstract 15209: LPA Variants Are Associated With Aortic Valve Stenosis, Heart Failure and Chronic Kidney Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. Suppl_3 ( 2020-11-17)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. Suppl_3 ( 2020-11-17)
    Abstract: Background: The pathophysiology of lipoprotein (a) [Lp(a)] remains obscure. We conducted a phenome wide analysis study (PheWAS) to identify pleiotropic effects of LPA variants. Methods: Among 51,843 European-ancestry participants (age 58±16 years, 54% female) of the electronic MEdical Records and Genomics (eMERGE) network we assessed whether LPA variants exhibited pleiotropic affects through an electronic health record-based PheWAS. We adjusted significant associations by presence of atherosclerotic cardiovascular disease (ASCVD; defined as a composite of coronary heart disease, cerebrovascular disease, and peripheral artery disease) to determine whether those associations were independent of ASCVD. Results: In PheWAS analysis, we tested 864 phecodes with 36 independent LPA variants. We identified 21 significant associations with non-ASCVD phenotypes including heart failure, aortic valve stenosis, and chronic kidney disease of which 14 were replicated across independent cohorts. The strength of associations between the LPA variant rs10455872 and both heart failure and aortic valve stenosis related phecodes were significantly attenuated after adjustment for ASCVD. However, the association with chronic kidney disease phecode remained independent following adjustment for ASCVD without any attenuation in the estimated odds ratio (Table). Conclusions: LPA genetic variants were associated with aortic valve stenosis, heart failure and chronic kidney disease. The observed association of LPA variant rs10455872 with aortic stenosis and heart failure appear to be partially mediated by ASCVD, while the association with chronic kidney disease appears to be independent of ASCVD. Additional studies are needed to elucidate potential mechanisms by which Lp(a) may contribute to the pathogenesis of non-ASCVD disease phenotypes.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.142.suppl_3.15209
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation: Cardiovascular Genetics Vol. 10, No. 2 ( 2017-04)
    Details
    In: Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. 2 ( 2017-04)
    Abstract: One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. Methods and Results— We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=−0.88; P =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83–0.95; P =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=−0.03 [0.16]). Conclusions— The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
    Type of Medium: Online Resource
    ISSN: 1942-325X , 1942-3268
    URL: Article
    DOI: 10.1161/CIRCGENETICS.116.001482
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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    detail.hit.zdb_id: 2477394-3
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  • 5
    Online Resource
    Online Resource
    Defining a Contemporary Ischemic Heart Disease Genetic Risk Profile Using Historical Data
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation: Cardiovascular Genetics Vol. 9, No. 6 ( 2016-12), p. 521-530
    Details
    In: Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 6 ( 2016-12), p. 521-530
    Abstract: Continued reductions in morbidity and mortality attributable to ischemic heart disease (IHD) require an understanding of the changing epidemiology of this disease. We hypothesized that we could use genetic correlations, which quantify the shared genetic architectures of phenotype pairs and extant risk factors from a historical prospective study to define the risk profile of a contemporary IHD phenotype. Methods and Results— We used 37 phenotypes measured in the ARIC study (Atherosclerosis Risk in Communities; n=7716, European ancestry subjects) and clinical diagnoses from an electronic health record (EHR) data set (n=19 093). All subjects had genome-wide single-nucleotide polymorphism genotyping. We measured pairwise genetic correlations (rG) between the ARIC and EHR phenotypes using linear mixed models. The genetic correlation estimates between the ARIC risk factors and the EHR IHD were modestly linearly correlated with hazards ratio estimates for incident IHD in ARIC (Pearson correlation [ r ]=0.62), indicating that the 2 IHD phenotypes had differing risk profiles. For comparison, this correlation was 0.80 when comparing EHR and ARIC type 2 diabetes mellitus phenotypes. The EHR IHD phenotype was most strongly correlated with ARIC metabolic phenotypes, including total:high-density lipoprotein cholesterol ratio (rG=−0.44, P =0.005), high-density lipoprotein (rG=−0.48, P =0.005), systolic blood pressure (rG=0.44, P =0.02), and triglycerides (rG=0.38, P =0.02). EHR phenotypes related to type 2 diabetes mellitus, atherosclerotic, and hypertensive diseases were also genetically correlated with these ARIC risk factors. Conclusions— The EHR IHD risk profile differed from ARIC and indicates that treatment and prevention efforts in this population should target hypertensive and metabolic disease.
    Type of Medium: Online Resource
    ISSN: 1942-325X , 1942-3268
    URL: Article
    DOI: 10.1161/CIRCGENETICS.116.001530
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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    detail.hit.zdb_id: 2477394-3
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  • 6
    Online Resource
    Online Resource
    SARS-CoV-2 Testing and Positivity Among Persons With and Without HIV in 6 US Cohorts
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  JAIDS Journal of Acquired Immune Deficiency Syndromes Vol. 90, No. 3 ( 2022-07-1), p. 249-255
    Details
    In: JAIDS Journal of Acquired Immune Deficiency Syndromes, Ovid Technologies (Wolters Kluwer Health), Vol. 90, No. 3 ( 2022-07-1), p. 249-255
    Abstract: It is not definitively known if persons with HIV (PWH) are more likely to be SARS-CoV-2 tested or test positive than persons without HIV (PWoH). We describe SARS-CoV-2 testing and positivity in 6 large geographically and demographically diverse cohorts of PWH and PWoH in the United States. Setting: The Corona Infectious Virus Epidemiology Team comprises 5 clinical cohorts within a health system (Kaiser Permanente Northern California, Oakland, CA; Kaiser Permanente Mid-Atlantic States, Rockville, MD; University of North Carolina Health, Chapel Hill, NC; Vanderbilt University Medical Center, Nashville, TN; and Veterans Aging Cohort Study) and 1 interval cohort (Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study). Methods: We calculated the proportion of patients SARS-CoV-2 tested and the test positivity proportion by HIV status from March 1 to December 31, 2020. Results: The cohorts ranged in size from 1675 to 31,304 PWH and 1430 to 3,742,604 PWoH. The proportion of PWH who were tested for SARS-CoV-2 (19.6%–40.5% across sites) was significantly higher than PWoH (14.8%–29.4%) in the clinical cohorts. However, among those tested, the proportion of patients with positive SARS-CoV-2 tests was comparable by HIV status; the difference in proportion of SARS-CoV-2 positivity ranged from 4.7% lower to 1.4% higher. Conclusions: Although PWH had higher testing proportions compared with PWoH, we did not find evidence of increased positivity in 6 large, diverse populations across the United States. Ongoing monitoring of testing, positivity, and COVID-19–related outcomes in PWH are needed, given availability, response, and durability of COVID-19 vaccines; emergence of SARS-CoV-2 variants; and latest therapeutic options.
    Type of Medium: Online Resource
    ISSN: 1525-4135
    URL: Article
    DOI: 10.1097/QAI.0000000000002943
    RVK:
    XA 10000
    RVK:
    XA 51942
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 645053-2
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