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  • 1
    In: Heart, BMJ, Vol. 98, No. 12 ( 2012-06-15), p. 914-919
    Type of Medium: Online Resource
    ISSN: 1355-6037 , 1468-201X
    Language: English
    Publisher: BMJ
    Publication Date: 2012
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  • 2
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 30, No. 15 ( 2021-07-09), p. 1443-1456
    Abstract: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P  & lt; 5.30 × 10−7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer’s disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 3
    In: American Journal of Epidemiology, Oxford University Press (OUP), Vol. 191, No. 5 ( 2022-03-24), p. 886-899
    Abstract: Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008–2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm2 and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006–2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000–2007). Performance was comparable to the development setting in PIVUS (R2 = 0.63, RMSE = 42.4 cm2, calibration slope = 0.94) but lower in MESA (R2 = 0.44, RMSE = 60.7 cm2, calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements.
    Type of Medium: Online Resource
    ISSN: 0002-9262 , 1476-6256
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2030043-8
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  • 4
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 106, No. 2 ( 2021-01-23), p. 372-387
    Abstract: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. Objective Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. Design Genetics of Obesity-associated Liver Disease Consortium. Setting Population-based. Main Outcome Computed tomography measured liver attenuation. Results Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. Conclusions These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
    detail.hit.zdb_id: 2026217-6
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  • 5
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation: Cardiovascular Quality and Outcomes Vol. 10, No. suppl_3 ( 2017-03)
    In: Circulation: Cardiovascular Quality and Outcomes, Ovid Technologies (Wolters Kluwer Health), Vol. 10, No. suppl_3 ( 2017-03)
    Abstract: Background: Health insurance plays an important role in access to medical care and is the focus of extensive policy efforts. We examined the association of health insurance with cardiovascular disease (CVD) incidence. Methods and Results: The Multi-Ethnic Study of Atherosclerosis, sponsored by the National Heart, Lung and Blood Institute of the NIH, followed a US cohort, aged 45-84 without clinical CVD at baseline, for a median of 12.2 years; 788 events occurred among 6,674 individuals. Data were stratified by baseline health insurance status. Kaplan-Meier survival and Cox regression analyses were used to assess the association between health insurance and incident CVD (myocardial infarction, resuscitated cardiac arrest, stroke, CVD death, and angina), adjusting for biomedical CVD risk (traditional risk factors, including age and race/ethnicity, and markers of subclinical atherosclerosis) and socioeconomic status (SES). The majority of individuals had private insurance (51%). Uninsured individuals (9%) were more likely to have untreated hypertension and diabetes, less likely to be on lipid-lowering therapy, and more likely to receive care in an Emergency Department (p 〈 0.0001). Income, 10-year CVD risk, and 10-year event-free survival varied across insurance groups ( Table ). After adjustment for biomedical CVD risk, individuals with health insurance had a lower risk of incident CVD compared to the uninsured (HR 0.72, p=0.03). However, with additional adjustment for SES (income, education, and employment), insurance was no longer associated with incident CVD (HR 0.78, p=0.12). Among the insurance groups, those with private insurance had a lower risk of incident CVD after adjustment for both biomedical CVD risk and SES (HR 0.70, p=0.03). Medicare and Medicaid coverage were not associated with incident CVD. The military/VA group had a lower risk of incident CVD with adjustment for biomedical CVD risk (HR 0.57, p=0.02) that was no longer significant after adjustment for SES (HR 0.66, p=0.09). Conclusions: The association of health insurance with CVD incidence varied by insurance group, and private insurance was associated with a lower risk of incident CVD. Further exploration of the features of health insurance coverage that impact CVD incidence may facilitate improvements in the primary prevention of CVD.
    Type of Medium: Online Resource
    ISSN: 1941-7713 , 1941-7705
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2453882-6
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  • 6
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. suppl_1 ( 2015-03-10)
    Abstract: Depression is associated with an increased risk of heart failure (HF) among HIV infected (HIV+) and uninfected (HIV-) veterans. Antidepressants are commonly prescribed to mitigate psychosocial symptoms related to major depressive disorder (MDD). The purpose of this study was to determine whether antidepressant use was associated with lower HF risk among a large cohort of HIV+ and HIV- veterans with MDD. We analyzed data on 13,849 veterans (36.5% HIV+) from the Veterans Aging Cohort Study (VACS), a prospective study of HIV+ and matched HIV- veterans who had a diagnosis of MDD (ICD-9 codes 296.2x & 296.3x) and were free of cardiovascular disease (CVD) at baseline. Antidepressant use was defined as documentation of selective serotonin reuptake inhibitor (SSRIs), tricyclic antidepressant (TCAs), and non-SSRI, non-TCA antidepressant use from the VA pharmacy records during the baseline period (1998 - 2003). Incident HF was identified using ICD-9 codes and defined as first HF event on or after 4/1/2003 until 12/31/2009. We used Cox proportional hazards regression to assess the association between HIV infection, antidepressant use and incident HF, adjusting for covariates (Table). Most participants were on antidepressant therapy [90.2% (12,498 of 13,849)]. In the total sample, baseline antidepressant use was associated with a lower risk of HF, adjusting for all covariates including HIV (adjusted HR = 0.76, 95% CI = 0.58 - 0.99). The rates of incident HF were highest among HIV+ participants who did not use antidepressants (Table). Among the HIV+ participants, the association between antidepressant use and lower HF risk neared significance (p = 0.053). Antidepressant use was common among this cohort of veterans with MDD and was associated with a lower risk of incident HF. Our study lends support to further investigations to determine the importance of antidepressants as additional therapy for CVD prevention among MDD patients with and without HIV.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1466401-X
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  • 7
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. suppl_1 ( 2015-03-10)
    Abstract: Introduction: Fetuin-A, a hepatic secretory protein, has been associated with risk of diabetes. However, liver fat content may be an important confounder or effect modifier not fully accounted for in previous studies. Further, it remains unclear whether associations differ between women and men. Aim: In an ethnically diverse cohort of women and men, we assessed the association of fetuin-A with risk of diabetes and investigated the role of liver fat in this association. Methods: We conducted a case-cohort study nested in the Multi-Ethnic Study of Atherosclerosis among 1,957 subcohort members and 455 cases (265 of whom belonged to the subcohort) with follow-up from 2000-2012. Fetuin-A was measured from baseline plasma samples by enzyme-linked immunosorbent assay, and liver fat was assessed via computed tomography. Associations were estimated using multivariable-adjusted Cox models, with weighting to account for the case-cohort design. Results: The association of fetuin-A with risk of diabetes differed between women and men (p-interaction = 0.001). Each standard deviation (SD) higher fetuin-A concentration (0.10 g/L) was associated with a hazard ratio (HR) of 1.51 (95% CI: 1.32-1.74, p 〈 0.0001) among women and an HR of 1.12 (95% CI: 0.94-1.32, p = 0.20) among men. With additional adjustment for liver fat, associations were slightly attenuated in both women (HR per SD fetuin-A = 1.37, 95% CI: 1.19-1.59, p 〈 0.0001) and men (HR = 1.06, 95% CI: 0.90-1.24, p = 0.40). Additional adjustment for other clinical variables had minimal impact on multivariable-adjusted estimates (Figure). Associations did not differ by degree of liver fat content (p-heterogeneity 〉 0.25 for both women and men). Conclusions: Fetuin-A was associated with diabetes risk, particularly in women, even after adjustment for liver fat.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1466401-X
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  • 8
    In: Vascular Medicine, SAGE Publications, Vol. 19, No. 4 ( 2014-08), p. 264-271
    Abstract: Adipokines regulate metabolic processes linked to coronary artery (CAC) and abdominal aorta calcification (AAC). Because adipokine and other adiposity-associated inflammatory marker (AAIM) secretions differ between visceral and subcutaneous adipose tissue, we hypothesized that central adiposity modifies associations between AAIMs and CAC and AAC. We evaluated 1878 MESA participants with complete measures of AAIMs, anthropometry, CAC, and AAC. Associations of AAIMs with CAC and AAC prevalence and severity were analyzed per standard deviation of predictors (SD) using log binomial and linear regression models. The waist-to-hip ratio (WHR) was dichotomized at median WHR values based on sex/ethnicity. CAC and AAC prevalence were defined as any calcium (Agatston score 〉 0). Severity was defined as ln (Agatston score). Analyses examined interactions with WHR and were adjusted for traditional cardiovascular disease risk factors. Each SD higher interleukin-6 (IL-6), fibrinogen and CRP was associated with 5% higher CAC prevalence; and each SD higher IL-6 and fibrinogen was associated with 4% higher AAC prevalence. Associations of IL-6 and fibrinogen with CAC severity, but not CAC prevalence, were significantly different among WHR strata. Median-and-above WHR: each SD higher IL-6 was associated with 24.8% higher CAC severity. Below-median WHR: no association ( p interaction =0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association ( p interaction =0.034). Adiponectin, leptin, resistin, and tumor necrosis factor-alpha were not associated with CAC or AAC prevalence or severity. These results support findings that adiposity-associated inflammation is associated with arterial calcification, and further add that central adiposity may modify this association.
    Type of Medium: Online Resource
    ISSN: 1358-863X , 1477-0377
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
    detail.hit.zdb_id: 2027562-6
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  • 9
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
    Abstract: Background: The presence of coronary artery calcium (CAC) is an independent marker of cardiovascular disease (CVD) events and mortality. However, the predictive value of thoracic aorta calcification (TAC), which can be additionally examined without further scanning during assessment of CAC, in predicting coronary heart disease (CHD) events in asymptomatic women and men, is not well-established. Methods: We collected data on risk factors and performed scanning for both TAC and CAC in a multi-ethnic population-based cohort of 6809 individuals (62±10 years, 47% males). Using the same images for each participant, TAC and CAC were computed using the Agatston method. The study subjects had no clinical cardiovascular disease at entry and were followed for a median of 4.1 years. Results: The mean age of the study population was 62±10 years (47% males). At baseline 1904 (28%) participants had detectable TAC, whereas 3392 (50%) had CAC 〉 0. During the follow-up interval, 189 (2.78%) and 108 (1.59%) participants suffered any CHD and hard CHD event, respectively. Table below provide the hazard ratio (95% CI) for coronary events with presence of TAC. Overall TAC was a stronger predictor of CHD risk in women than in men. . Conclusion: Our study result suggests that TAC imparts independent prognostic power to predict future coronary events in women and may provide rationale for more intensive risk factor modification. Hazard Ratios (95% CI) of All CHD and Hard CHD Events with TAC (TAC 〉 0 vs. TAC=0)
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1466401-X
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  • 10
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 129, No. suppl_1 ( 2014-03-25)
    Abstract: Background: The extent of atherosclerosis across multiple vascular beds in persons with metabolic syndrome (Mets) and diabetes (DM) has not been documented. We hypothesized a greater presence/extent of multisite atherosclerosis in MetS and DM, vs. neither. Methods: We analyzed four vascular beds (coronary (CA), abdominal aorta (AA), carotid, peripheral vascular) in subjects without cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis, who had complete data on these measures. Multisite atherosclerosis was defined as the presence/extent of CA calcium, AA calcium, carotid intimal medial thickness (disease ≥1mm) and borderline/abnormal ( 〈 1 or ≥1.3) ankle brachial index. We then created a composite score summing the continuous gender-stratified standardized z-scores for each measure. ANOVA compared least squares means across disease states; logistic regression gave odds of being in the top quartile of the composite score distribution. We adjusted for non-MetS risk factors (age, gender, ethnicity, smoking, LDL-C, lipid medications, family history). Results: Of 1,771 subjects (mean age 64, 50% male, 40% Caucasian, 25% Hispanic, 21% African American, 14% Chinese), 25% had MetS and 13% DM. Persons with DM or Mets had a greater number of sites positive for atherosclerosis ( figure ). Adjusted mean composite scores increased across disease groups (neither disease 0.24, MetS 0.88, DM 1.38, p 〈 0.001 between groups). Adjusted logistic regression showed that the odds of being in the top quartile of the composite score were higher for those with DM OR=4.42 [2.21-8.83] p 〈 0.001 and MetS OR=2.72 [1.63-4.56] p 〈 0.001, vs. neither condition. Conclusions: Those with MetS or DM have an increased prevalence and extent of multisite atherosclerosis. Whether disease in one vascular bed should prompt further evaluation, and how this relates to future CVD events, requires further investigation. Our findings support the concept that atherosclerosis in those with MetS or DM is more likely to be systemic vs. site-specific.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1466401-X
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