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1.
J Clin Invest ; 129(12): 5474-5488, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31710311

RESUMO

Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.

2.
Chest ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31678306

RESUMO

BACKGROUND: Adipokines have inflammatory and fibrotic properties that may be critical in interstitial lung disease (ILD). We examined associations of serum adipokine levels with computed tomography (CT)-based measures of subclinical ILD and lung function among community-dwelling adults. METHODS: A subset of the original Multi-Ethnic Study of Atherosclerosis cohort (n=1,968) had adiponectin, leptin, and resistin measured during follow-up visits (2002-2005). We used regression models to examine associations of adiponectin, leptin, and resistin levels with 1) high attenuation areas (HAA) from CT scans (2004-2005, n=1,144), 2) interstitial lung abnormalities (ILA) from CT scans (2010-2012, n=872), and 3) forced vital capacity (FVC) from spirometry (2004-2006, n=1,446). We used (-1HAA2), which we denoted with H, to model HAA as our outcome to meet model assumptions. RESULTS: Higher adiponectin was associated with lower HAA on CT among adults with a body mass index (BMI) ≥25 kg/m2 (P for BMI interaction=0.07). Leptin was more strongly associated with ILA among never smokers compared to ever smokers (P for smoking interaction=0.004). For every 1-SD increment of log-transformed leptin, the % predicted FVC was 3.8% lower (95% CI: -5.0, -2.5). Higher serum resistin levels were associated with greater HAA on CT in a fully-adjusted model. For every 1-standard deviation (SD) increment of log-transformed resistin there was an increase in H of 14.8 (95% CI: 3.4, 26.3). CONCLUSIONS: Higher adiponectin levels were associated with lower HAA on CT among adults with a higher BMI. Higher leptin and resistin levels were associated with lower FVC and greater HAA, respectively.

4.
Am J Cardiol ; 124(11): 1701-1706, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575423

RESUMO

The Pooled Cohort Equation (PCE) predicts 10-year risk of first-time atherosclerotic cardiovascular disease (ASCVD) events and was incorporated in analyses of a primary and secondary prevention population in the Systolic Blood Pressure Intervention Trial (SPRINT). Whether PCE enhances risk prediction among secondary prevention populations is unknown. We sought to compare ASCVD events by level of PCE-predicted risk among primary and secondary prevention SPRINT populations. SPRINT randomized adults with hypertension and ≥1 CVD risk factor or previous CVD events to systolic blood pressure control targeting <120 mm Hg or 135 to 139 mm Hg. We calculated the hazard ratio (HR) of ASCVD events among secondary versus primary (reference) prevention subgroups overall and by predicted 10-year ASCVD risk categories (<10%, 10% to <20%, 20% to <30%, and ≥30%) and within risk subgroups, comparing to the lowest risk category. Among 8,151 participants, 16% with previous CVD, mean age was 66 years and 35% were women. The HR for ASCVD events overall was 2.51 (1.96, 3.20). HR was 2.97 (1.47, 5.99) among <10% 10-year risk and 2.23 (1.38, 3.59) among ≥30% risk. Within subgroups comparing ≥30% to <10% risk (reference) categories, the HR was 2.85 (1.76, 4.63) for primary and 2.14 (1.07, 4.30) for the secondary prevention. In conclusion, history of previous events was a potent risk factor for subsequent ASCVD events. The PCE does not enhance risk prediction among secondary prevention populations and may differentially underestimate risk in secondary prevention populations with lowest predicted risk.

6.
Diabetes Care ; 42(11): 2075-2082, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471378

RESUMO

OBJECTIVE: Experimental studies have implicated soluble (s)CD14, an effector of lipopolysaccharide-induced inflammation, in insulin resistance, but its role in human metabolic endotoxemia has not been studied. We evaluated sCD14 in relation to dysglycemia in older adults and how this compares to other markers of inflammation. RESEARCH DESIGN AND METHODS: We investigated associations of sCD14, interleukin-6 (IL-6), CRP, and white blood cell (WBC) count with insulin resistance (quantitative insulin-sensitivity check index and HOMA 2 of insulin resistance) and incident type 2 diabetes in a population-based cohort of older adults. We also assessed the causal role of sCD14 in insulin resistance using an instrumental variable approach by Mendelian randomization. RESULTS: After adjustment for conventional risk factors, each of the four biomarkers showed positive cross-sectional associations with both insulin resistance measures. These associations persisted after mutual adjustment for all markers except sCD14. Over a median follow-up of 11.6 years, 466 cases of diabetes occurred. All biomarkers except sCD14 were positively associated with diabetes, although only WBC count remained associated (hazard ratio 1.43 per doubling [95% CI 1.07, 1.90]) after mutual adjustment. Instrumental variable analysis did not support a causal role for sCD14 in insulin resistance. CONCLUSIONS: Among older adults, sCD14 was associated with insulin resistance, but this disappeared after adjustment for other biomarkers, showed no evidence of a causal basis, and was not accompanied by a similar association with diabetes. IL-6, CRP, and WBC count were each associated with insulin resistance and diabetes, WBC count most robustly. These findings do not support a central role for sCD14, but they highlight the preeminence of WBC count as an inflammatory measure of diabetes risk in this population.

7.
PLoS One ; 14(8): e0219710, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437155

RESUMO

BACKGROUND: Biomarkers of monocyte activation (soluble CD14 [sCD14]), inflammation (interleukin-6 [IL-6]), and altered coagulation (D-dimer) are associated with increased mortality risk in people with HIV. The objective of the Russia Alcohol Research Collaboration on HIV/AIDS (ARCH) study was to evaluate the association between heavy alcohol use and inflammatory biomarkers over time. METHODS: The study sought antiretroviral therapy naive participants with HIV (n = 350) and assessed them at baseline, 12 and 24 months. Linear mixed effects models were used to determine whether heavy drinking (self-report augmented by phosphatidylethanol [PEth], an alcohol biomarker) was longitudinally associated with IL-6, sCD14 and D-dimer adjusting for potential confounders (e.g., demographics, HIV factors, comorbid conditions). RESULTS: Participants' baseline characteristics were as follows: 71% male; mean age of 34 years; 87% self-reported hepatitis C; and 86% current smokers. Mean log10 (HIV RNA) was 4.3 copies/mL. Heavy alcohol use, based on National Institute of Alcohol Abuse and Alcoholism risky drinking criteria and PEth (versus non-heavy alcohol use) was associated with higher sCD14 (adjusted mean difference 125 ng/mL [95% CI: 42, 209]), IL-6 (ratio of means 1.35 [95% CI: 1.17, 1.55] pg/mL), and D-dimer (ratio of means 1.20 [95% CI: 1.06, 1.37] ug/mL) across the two-year follow-up. CONCLUSION: Among HIV+ adults, current heavy alcohol use is associated with higher sCD14, IL-6 and D-dimer over time. Since these biomarkers are associated with mortality, interventions to mitigate effects of heavy drinking on these immune processes merit consideration.

8.
Eur Respir J ; 54(3)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31371443

RESUMO

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.

9.
J Natl Cancer Inst ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31321426

RESUMO

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or phase-shift aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors." Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.

10.
AIDS ; 33(13): 2043-2048, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31274541

RESUMO

OBJECTIVE: The aim of this study was to determine the utility of biomarkers of immune activation, systemic inflammation and coagulopathy prior to antiretroviral therapy to predict mortality during the first year of antiretroviral therapy (ART) in sub-Saharan Africa. DESIGN: A prospective, observational cohort. METHODS: We measured soluble CD14, interleukin-6 and D-dimer in nonpregnant individuals initiating ART in South Africa and Uganda in the Measuring Early Treatment Adherence (META) Study. We used survival analysis methods to estimate their association with 12-month mortality, and fit receiver operator curves (ROC) to assess the prognostic value of each biomarker. RESULTS: Six-hundred and sixty individuals were enrolled and had pretreatment biomarkers measured. Approximately 60% were women, with a median CD4 cell count of 187 cells/µl [interquartile range (IQR) 111-425] and approximately half were enrolled each from South Africa and Uganda. We observed 34 deaths for a crude mortality of 5.3 deaths/100 person-years (py) (95% confidence interval 3.8-7.4), which ranged from 0/100 py to 13.7/100 py in the lowest and highest tertile of pretreatment sCD14, respectively. In Cox models, all three biomarkers were strongly predictive of the hazard of death (adjusted hazard ratio 3-6, all P < 0.01). In multivariable models including biomarkers, both pretreatment CD4 cell count and pretreatment viral load became borderline or nonsignificantly associated with mortality. The c-statistic for area under ROC was higher for all three biomarkers than for CD4 cell count (P < 0.01). CONCLUSION: Biomarkers of immune activation, systemic inflammation and coagulopathy prior to ART initiation are strongly predictive of early death on treatment after adjustment for CD4 cell count. Such biomarkers might serve as important prognostic indicators for patient triage in this population.

11.
Alzheimers Dement ; 15(8): 1029-1038, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31255494

RESUMO

INTRODUCTION: Both high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. METHODS: We examined baseline plasma ß-amyloid (Aß) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. RESULTS: Increased plasma Aß1-40 and Aß1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aß1-42 and Aß1-42/Aß1-40 ratio compared with those who did not. Aß levels did not predict dementia in mild cognitive impairment participants. DISCUSSION: There was an inverse association between Aß1-42 and Aß1-42/Aß1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aß levels and must be considered in evaluations of relationship of plasma Aß and subsequent risk of dementia.

12.
J Clin Hypertens (Greenwich) ; 21(8): 1230-1241, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31278845

RESUMO

We sought to describe changes in blood pressure and estimate the effect of HIV on blood pressure (BP) over 4 years of observation in a cohort of 155 HIV-infected adults (≥40 years) on antiretroviral therapy (ART) and 154 sex- and age-quartile-matched, population-based, HIV-uninfected controls for four years in rural Uganda, we compared changes in blood pressure (BP) by HIV serostatus and tested whether body mass index and inflammation (high-sensitivity C-reactive protein and interleukin-6) and immune activation (sCD14 and sCD163) mediated the effects of HIV on BP using hierarchical multivariate and two-stage parametric regression models. Overall HIV-uninfected participants had higher mean BP than HIV-infected counterparts (differences in trend P < 0.0001 for diastolic BP and P = 0.164 for systolic BP). After initial declines in BP in both groups between years 1 and 2, BP moderately increased in both groups through year 4, with greater change over time observed in the HIV-uninfected group. Body mass index mediated 72% (95%CI 57, 97) of the association between HIV and systolic BP. We found a minimal mediating effect of sCD14 on the relationship between HIV and SBP (9%, 95% CI 5%, 21%), but found no association between other HIV-related biomarkers. Over four years of observation, HIV-infected people in rural Uganda have lower BP than HIV-uninfected counterparts despite having higher levels of inflammation. BMI, rather than measures of HIV-associated inflammation, explained a majority of the difference in BP observed.

13.
J Infect Dis ; 220(7): 1172-1177, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31188451

RESUMO

Chronic inflammation predicts complications in persons with human immunodeficiency virus infection. We compared D-dimer, soluble CD14, and interleukin 6 levels before and 12 months after antiretroviral therapy (ART) initiation, among individuals starting ART during earlier-stage (CD4 T-cell count >350/µL) or late-stage disease (CD4 T-cell count <200/µL). Female sex, older age, viral load, and late-stage disease were associated with pre-ART biomarkers (n = 661; P < .05). However, there were no differences in biomarkers by disease stage after 12 months of ART (n = 438; P > .05), owing to loss from observation and greater declines in biomarkers in late-stage initiators (P < .001). Earlier initiation of ART is associated with decreased inflammation, but levels seem to converge between earlier and later initiators surviving to 12 months.

14.
PLoS One ; 14(6): e0218115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242253

RESUMO

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

15.
AIDS Patient Care STDS ; 33(7): 299-307, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188016

RESUMO

We conducted a cross-sectional study of 148 HIV+ on HIV antiretroviral therapy and 149 HIV- adults in Mbarara, Uganda, to estimate the association between HIV infection and homeostasis model assessment of insulin resistance (HOMA-IR) using multivariable regression analysis. In addition, we evaluated whether intestinal fatty acid-binding protein (I-FABP), monocyte activation markers soluble (s)CD14 and sCD163, and proinflammatory cytokine interleukin 6 (IL-6) mediated this association. HOMA-IR was greater among HIV+ than HIV- adults [median (interquartile range): 1.3 (0.7-2.5) vs. 0.9 (0.5-2.4); p = 0.008]. In models adjusted for sociodemographic variables, diet, hypertension, and smoking history, HIV infection was associated with 37% [95% confidence intervals (95% CIs): 5-77] greater HOMA-IR compared with HIV- participants. The magnitude of association was greater when I-FABP was included as a covariate although the additive effect was modest (40% CI: 8-82). By contrast adding sCD14 to the model was associated with greater HOMA-IR (59%; 95% CI: 21-109) among HIV+ participants compared with HIV- participants. Among HIV+ participants, greater CD4 nadir was non-significantly associated with greater HOMA-IR (22%; 95% CI: -2 to 52). Each 5-unit increase in body mass index (BMI; 49% greater HOMA-IR; 95% CI: 18-87) and female sex (71%; 95% CI: 17-150) remained associated in adjusted models. In this study of mainly normal-weight Ugandan adults, HIV infection, female sex, and greater BMI were all associated with greater insulin resistance (IR). This association was strengthened modestly after adjustment for sCD14, suggesting possible distinct immune pathways to IR that are independent of HIV or related to inflammatory changes occurring on HIV treatment.

16.
Eur Heart J ; 40(34): 2883-2896, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31102408

RESUMO

AIMS: To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). METHODS AND RESULTS: We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05). CONCLUSION: Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.

17.
Diab Vasc Dis Res ; 16(5): 483-485, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31064218

RESUMO

Carboxymethyl-lysine is an advanced glycation end product that is detectable in the serum. Higher carboxymethyl-lysine levels have been associated with increased risk of coronary heart disease, stroke and cardiovascular mortality. We determined whether high carboxymethyl-lysine levels are also associated with the risk of peripheral artery disease in Cardiovascular Health Study participants who were all aged 65 years and older at baseline. Multivariate Cox proportional hazards models were used to determine the association of baseline carboxymethyl-lysine levels with incident peripheral artery disease in 3267 individuals followed for a median length of 10.0 years. A total of 157 cases of incident peripheral artery disease occurred during follow-up. No significant relationship between carboxymethyl-lysine and risk of peripheral artery disease was found (hazard ratio per standard deviation increment = 1.03; 95% confidence interval = 0.87, 1.23).

18.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

19.
PLoS One ; 14(4): e0214735, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30946765

RESUMO

BACKGROUND: HIV-infected persons have an increased risk of atherosclerosis relative to uninfected individuals. Inflammatory processes may contribute to this risk. We evaluated the associations of 10 biomarkers of systemic inflammation (CRP, IL-6, sTNF-αR1 and 2), monocyte activation (CCL2, sCD163, sCD14), coagulation (fibrinogen, D-dimer), and endothelial dysfunction (ICAM-1) with subclinical carotid atherosclerosis among participants in the Multicenter AIDS Cohort Study (MACS). METHODS: Carotid plaque and intima media thickness (IMT) in the common carotid (CCA-IMT) and bifurcation region were assessed by B mode ultrasound among 452 HIV-infected and 276 HIV-uninfected men from 2010-2013. Associations between levels of each biomarker and presence of focal plaque and IMT were assessed by logistic and linear regression models, adjusting for demographics, risk behaviors, traditional cardiovascular disease (CVD) risk factors, and HIV disease characteristics. RESULTS: Compared to HIV-uninfected men, HIV-infected men had significantly higher levels of 8 of the 10 biomarkers. Overall, men with sCD163, CCL2, IL-6, and CRP levels in the highest quintile had approximately 2 times the odds of carotid plaque relative to those with levels in the lowest quintile, independent of demographic and CVD risk factors. Fibrinogen levels were positively associated with CCA-IMT while ICAM-1, CCL2, and sTNF-αR1 levels were positively associated with bifurcation-IMT. Among HIV-uninfected men, higher levels of sTNF-αR2 were positively associated with CCA-IMT, fibrinogen with bifurcation-IMT and carotid plaque, and ICAM-1 with carotid plaque. CONCLUSION: In addition to greater levels of systemic inflammation, heightened monocyte activation (sCD163, CCL2) may contribute to the burden of atherosclerosis among HIV-infected persons.

20.
J Acquir Immune Defic Syndr ; 81(1): 36-43, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30789451

RESUMO

BACKGROUND: Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women. SETTING: In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques. METHODS: Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP). RESULTS: Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation. CONCLUSIONS: Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.

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