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1.  Replication of RYR3 gene polymorphism association with cIMT among HIV-infected whites 
AIDS (London, England)  2012;26(12):1571-1573.
To replicate the association of variants in RYR3 gene with common carotid intima-media thickness (cIMT), a surrogate marker of atherosclerosis, we genotyped single nucleotide polymorphisms (SNPs) rs2229116 and rs7177922 in a sub-population of 244 HIV-positive and HIV-negative men. SNP rs2229116 was associated with common cIMT in HIV infected white men after adjusting for age and use of stavudine (d4T). The association was more evident at younger ages and decreased among older individuals.
doi:10.1097/QAD.0b013e328355359f
PMCID: PMC3606588  PMID: 22627881
2.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
AIDS (London, England)  2010;24(14):2201-2209.
Background
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
Objective
To identify HIV-related risk factors for increased cIMT.
Methods
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
Results
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
Conclusion
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
doi:10.1097/QAD.0b013e32833d2132
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
3.  The CD14 C-260T single nucleotide polymorphism (SNP) modulates monocyte/macrophage activation in treated HIV-infected individuals 
Background
HIV-infected individuals have an increased risk of cardiovascular disease (CVD). T-allele carriers of the CD14 C-260T single-nucleotide polymorphism (SNP) have reported increased expression of the LPS-binding receptor, CD14 and inflammation in the general population. Our aim was to explore the relationship of this SNP with monocyte/macrophage activation and inflammation and its association with sub-clinical atherosclerosis in HIV-infected individuals.
Methods
Patients with no pre-existing CVD risk factors on suppressive antiretroviral therapy were recruited from University Malaya Medical Centre, Malaysia (n = 84). The CD14 C-260T and TLR4 SNPs, Asp299Gly and Thr399Ile were genotyped and soluble(s) CD14 and sCD163 and high-sensitivity C-reactive protein, hsCRP were measured in plasma. Subclinical atherosclerosis was assessed by measuring carotid intima media thickness (cIMT). The association between CD14 C-260T SNP carriage and cIMT was assessed in a multivariable quantile regression model where a p-value of <0.05 was considered significant.
Results
We found the CD14 C-260T T-allele in 56% of the cohort and evidence of subclinical atherosclerosis in 27%. TT genotype was associated with higher sCD163 (p = 0.009) but only marginally higher sCD14 (p = 0.209) and no difference in hsCRP (p = 0.296) compared to CC/CT. In multivariable analysis, only Framingham risk score was independently associated with higher cIMT while lower sCD163 was trending towards significance. No association was found in TT-genotype carriers and cIMT measurements.
Conclusion
The CD14 C-260T SNP was associated with increased monocyte activation but not systemic inflammation or cIMT in this HIV-infected cohort with low CVD risk profile.
doi:10.1186/s12967-015-0391-6
PMCID: PMC4311493  PMID: 25622527
HIV; Lipopolysaccharide; CD12 C-260T; Soluble CD14; Soluble CD163; Monocyte activation; C-reactive protein; Atherosclerosis; Carotid intima media thickness
4.  Effects of Aging and Smoking on Carotid Intima Media Thickness in HIV-infection 
AIDS (London, England)  2013;27(1):49-57.
Objectives
To investigate the effects of aging and smoking on carotid intima-media thickness (cIMT) among patients with and without HIV.
Methods
Data from a community sample of HIV-infected and HIV-uninfected participants were analyzed. Carotid intima-media thickness was measured via carotid ultrasound and smoking history was obtained via patient interview.
Results
Data on 166male and female participants with stable HIV-infection and 152 healthy HIV-uninfected participants were analyzed. Among the HIV-infected and HIV-uninfected participants, a significant association was observed between age and cIMT [r=0.51, P<0.0001 (HIV), r=0.39, P<0.0001, (non-HIV)], and between smoking burden and cIMT [r=0.42, P<0.0001 (HIV), r=0.24, P=0.003 (non-HIV)]. In multivariate regression modeling among all participants (HIV and non-HIV), a significant three-way interaction was observed between age, smoking burden, and HIV status with respect to cIMT (P<0.010), controlling for gender, race and traditional cardiovascular disease (CVD) risk factors, such that increased cIMT was associated with increased smoking burden and age to a greater degree among HIV-infected vs. HIV-uninfected participants. Among HIV-infected participants a significant interaction between smoking burden and age with respect to cIMT was seen (P=0.027), controlling for race, gender, CVD risk factors, immunological function and antiretroviral therapy use.
Conclusion
A significant interaction between HIV, age and smoking on cIMT was observed, suggesting that HIV-infection modifies the relationship of age and smoking on cIMT in this population. These findings emphasize the need to encourage smoking cessation in this population, due to its deleterious effect on subclinical atherosclerosis in older HIV-infected patients.
doi:10.1097/QAD.0b013e328358b29c
PMCID: PMC3690796  PMID: 22874518
HIV; Aging; Cardiovascular Diseases; Smoking
5.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Background/Aims
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Methods
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
Results
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
Conclusions
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
doi:10.1159/000327606
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
6.  Effect of inter-reader variability on outcomes in studies using carotid intima media thickness quantified by carotid ultrasonography 
European journal of epidemiology  2010;25(6):385-392.
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
doi:10.1007/s10654-010-9442-8
PMCID: PMC3161119  PMID: 20309612
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
7.  Carotid intima media thickness is associated with body fat abnormalities in HIV-infected patients 
BMC Infectious Diseases  2014;14:348.
Background
HIV-infected patients may be at increased risk of cardiovascular (CV) events, and lipodystrophy is generally associated with proatherogenic metabolic disturbances. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis and it has been shown to be an independent risk factor for CV disease. Our objective was to evaluate cIMT in HIV-infected patients on combined anti-retroviral therapy (cART) with and without lipodystrophy defined by fat mass ratio (L-FMR), and to determine the association of lipodystrophy and visceral obesity [(visceral (VAT), subcutaneous adipose tissue (SAT) volume and VAT/SAT ratio, objectively evaluated by CT scan] with cIMT.
Methods
Cross-sectional study of 199 HIV-infected patients. Body composition by DXA and abdominal CT, lipids, blood pressure, inflammatory markers, and cIMT by ultrasonography were performed. L-FMR was defined as the ratio of the percentage of trunk fat mass to the percentage of lower limb fat mass by DXA. Categorical variables were compared using the chi-square or Fisher’s exact test. Spearman correlation coefficients were estimated to study the association between cIMT and clinical and metabolic characteristics. Means of cIMT, adjusted for age, were calculated, using generalized linear models.
Results
L-FMR was present in 41.2% of patients and cIMT was higher in these patients [0.81 (0.24) vs. 0.76 (0.25); p = 0.037)]. Lipodystrophic patients had higher VAT and VAT/SAT ratio and lower SAT. cIMT was associated with lipodystrophy evaluated by FMR, trunk fat, total abdominal fat, VAT and VAT/SAT ratio. No association was observed between cIMT and leg fat mass. Using generalized linear models, cIMT means were adjusted for age and no significant differences remained after this adjustment. The adjusted mean of cIMT was 0.787 (95% CI: 0.751-0.823) in patients without lipodystrophy, and 0.775 (95% CI: 0.732-0.817) in those with lipodystrophy (p = 0.671).
Conclusions
HIV-infected patients on cART with lipodystrophy defined by FMR, had a significantly higher cIMT. Carotid IMT was also associated with classical cardiovascular risk factors. In these patients, visceral adipose tissue had a significant impact on cIMT, although age was the strongest associated factor.
doi:10.1186/1471-2334-14-348
PMCID: PMC4087129  PMID: 24958511
Lipodystrophy; HIV; Carotid intima media thickness; Fat mass ratio; Body composition
8.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
Background
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Methods
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
Results
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
Conclusions
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
doi:10.1016/j.atherosclerosis.2013.02.038
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
9.  Clinical Factors Associated with Carotid Plaque and Intima-Medial Thickness in HIV-Infected Patients 
Yonsei Medical Journal  2013;54(4):990-998.
Purpose
HIV-infected patients are at increased risk for cardiovascular disease, which may be mediated in part by inflammation. This study aimed to evaluate the risk factors of carotid plaque, and clinical factors associated with carotid atherosclerosis measured by carotid intima-medial thickness (cIMT) in HIV patients.
Materials and Methods
Clinical and cardiometabolic factors as well as cIMT were prospectively measured in 145 HIV-infected participants who had received combined antiretroviral therapy for ≥6 months. The mean value of the bilateral average cIMT level was used as Mean-IMT in the analysis, and the greatest value among the measured cIMT levels was used as Max-IMT.
Results
Among 145 patients, 34 (23.4%) had carotid plaque. Multivariate logistic regression analysis revealed three independent risk factors of carotid plaque: old age [odds ratio (OR) 6.16, 95% confidence interval (CI) 1.09-34.88; p=0.040], hypertension (OR 12.62, 95% CI 1.72-92.49; p=0.013) and higher low-density lipoprotein cholesterol (LDL-C) (OR 1.08, 95% CI 1.01-1.16; p=0.039). Levels of estimated glomerular filtration rate were inversely associated with Mean-IMT (r=-0.379, p<0.001) and Max-IMT (r=-0.389, p<0.001). Stepwise multivariate regression analyses revealed that age, total cholesterol and fasting glucose were positively correlated with cIMT, independent of other risk factors.
Conclusion
The presence of hypertension, old age and a higher level of LDL-C were independent risk factors of carotid plaque among HIV-infected subjects.
doi:10.3349/ymj.2013.54.4.990
PMCID: PMC3663240  PMID: 23709436
Carotid plaque; carotid artery intima-media thickness; atherosclerosis; combined antiretroviral therapy; HIV infection
10.  Genes Linked to Energy Metabolism and Immunoregulatory Mechanisms are Associated with Subcutaneous Adipose Tissue Distribution in HIV-infected Men 
Pharmacogenetics and genomics  2011;21(12):798-807.
Objective
Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).
Methods
Subcutaneous adipose tissue (SAT) volume measured by magnetic resonance imaging (MRI) in leg, lower trunk, upper trunk, and arm was examined in 192 HIV-infected Caucasian men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Multivariate and univariate genome wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis (FAA) using Ingenuity Systems Pathway Analysis tool (IPA) was carried out for markers with P<10-3 near known genes identified by multivariate analysis.
Results
Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with upper trunk and arm SAT (9.8*10-7≤P<7.8*10-6). Loci (rs193139, rs7523050, rs1761621) in and near a gene rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin binding protein 3 (STXBP3) were significantly associated with lower body SAT depots (9.9*10-7≤P<9.5*10-6). GPSM2 is associated with cell division and cancer while STXBP3 is associated with glucose metabolism in adipoctyes. IPA identified atherosclerosis, mitochondrial function and T-Cell mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P<5*10-3).
Conclusions
Our results are limited by the small sample size and replication is needed, however this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.
doi:10.1097/FPC.0b013e32834b68f9
PMCID: PMC3210910  PMID: 21897333
HIV; HAART; GWAS; Subcutaneous Fat; SAT
11.  Carotid Intimal Medial Thickness in Human Immunodeficiency Virus-Infected Women: Effects of Protease Inhibitor Use, Cardiac Risk Factors, and the Metabolic Syndrome 
Context
Little is known regarding carotid intimal medial thickness (IMT) in HIV-infected women and the risk factors for subclinical atherosclerosis in this population, including antiretroviral therapy and the metabolic syndrome.
Objective
Our objective was to assess carotid IMT in relationship to HIV status and antiretroviral therapy in HIV-infected women in comparison with healthy age- and body mass index (BMI)-matched control subjects.
Setting and Subjects
The study took place at an academic medical center and included 97 HIV-infected women compared with 86 age-and BMI-matched healthy control subjects.
Main Outcome Measures
We assessed carotid IMT, metabolic syndrome, and risk factors for increased IMT.
Results
Carotid IMT was not increased in HIV-infected women [0.62 mm (0.57–0.68); median (IQR)] compared with non-HIV-infected women [0.61 mm (0.55–0.68)] matched for age and BMI (P = 0.07) but was increased significantly among HIV patients receiving a protease inhibitor (PI) [0.65 (0.59–0.71) mm] vs. non-PI-treated patients [0.61 (0.57–0.66) mm] (P < 0.05) and vs. control subjects [0.61 (0.55–0.68) mm] (P < 0.05). The prevalence of metabolic syndrome was significantly increased among the HIV-infected women compared with control subjects and particularly in PI- vs. non-PI-treated HIV patients (45 vs. 19%, P = 0.001). Metabolic syndrome score correlated with IMT among non-HIV patients but not among the HIV group. Individual risk factors most strongly associated with IMT in multivariate regression modeling in the control group were age and waist-to-hip ratio, and among the HIV group age and waist circumference.
Conclusions
These data demonstrate increased carotid IMT in HIV-infected women receiving PI therapy, which may be due to associated metabolic abnormalities related to PI therapy or more direct effects of this medication class on the vasculature. Additional studies of the mechanisms by which PI uses results in subclinical atherosclerosis are needed.
doi:10.1210/jc.2006-1140
PMCID: PMC3205451  PMID: 17003092
12.  Hemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study 
Objective
This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway.
Methods
Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs.
Results
None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best-performing logic regression tree combined two SNPs in MAP2K5—rs745212 and rs12905175— and common cIMT; this association was not significant, corrected P-value=0.062.
Conclusion
There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults.
PMCID: PMC3376916  PMID: 22724054
Cardiovascular Health Study (CHS); candidate gene study; carotid intima-media thickness (cIMT); hemodynamics response; fluid shear stress; endothelium / endothelial cells; Kruppel-like factor 2 (KLF2); Mitogen-activated protein kinase 7 (MAPK7); Myocyte-specific enhancer factor 2 A/C (MEF2A/C); Mitogen-activated protein kinase kinase 5 (MAP2K5)
13.  Relationship between Carotid Intima-Media Thickness and Left Ventricular Mass in Type 1 Diabetes: results from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study 
The American journal of cardiology  2012;110(10):1534-1540.
Introduction
Type 1 diabetes mellitus is associated with early atherosclerosis and enhanced cardiovascular mortality. The relationship between carotid IMT (cIMT), a marker of subclinical atherosclerosis and left ventricular (LV) mass, an independent predictor of cardiovascular morbidity has not been previously studied in type 1 diabetics.
Methods
The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter observational study designed to follow up the Diabetes Control and Complications Trial (DCCT) cohort. LV mass was measured with cardiac MRI at EDIC year 15 and common cIMT was assessed using B-mode ultrasound at EDIC year 12. Multivariable linear regression models were used to assess the relationship between cIMT at year 12 and LV mass at year 15.
Results
A total of 889 participants had both cardiac MRI and cIMT measures available for these analyses. At EDIC year 15, the mean age of the participants was 49 (±7) years; mean diabetes duration was 28 (±5) years and 52% were males. Spearman correlation coefficient (r) between LV mass and cIMT was 0.33 (p<0.0001). After adjusting for basic covariates (machine, reader, age and gender), a significant association between LV mass and cIMT (estimate 2.0 g/m2 per 0.1 mm cIMT increment, p < 0.0001) was observed. This association was diminished by the addition of systolic blood pressure in particular 1.15 g/m2 per 0.1 mm cIMT increment, p<0.0001) and to a lessor extent other cardiovascular disease (CVD) risk factors. The relationship observed between LV mass and cIMT was stronger (HOW MUCH) in patients with shorter diabetes duration.
Conclusion
In a well characterized population with type 1 diabetes, cIMT was an independent predictor of higher LV mass. These findings suggest a common pathway, possibly mediated by blood pressure dependent mechanisms, for vascular and myocardial structural change in T1DM.
doi:10.1016/j.amjcard.2012.07.014
PMCID: PMC3488435  PMID: 22884107
14.  Association of the RYR3 gene polymorphisms with atherosclerosis in elderly Japanese population 
Background
The Ryanodine receptor 3 gene (RYR3) encodes an intracellular calcium channel that mediates the efflux of Ca2+ from intracellular stores. Two single-nucleotide polymorphisms (SNPs) in the RYR3 gene have been shown to associate with stroke (rs877087) and carotid intima-media thickness (rs2229116) in two independent genome-wide association studies (GWAS) in Caucasian. We investigated the effect of these two SNPs as well as the 31.1 kilobases spanning region on atherosclerosis in Japanese population.
Methods
Atherosclerotic severity was assessed by carotid artery (n = 1374) and pathological atherosclerosis index (PAI) (n = 1262), which is a macroscopic examination of the luminal surfaces of 8 systemic arteries in consecutive autopsy samples. 4 tag SNPs in the 31.1 Kb region, rs877087, rs2132207, rs658750 and rs2229116, were genotyped and haplotypes were inferred to study the association with atherosclerotic indices.
Results
rs877087 and rs2229116 were associated with PAI (OR = 2.07 [1.04-4.12] (95% CI), p = 0.038; and OR = 1.38 [1.02-1.86], p = 0.035, respectively). rs2229116 was also associated with common carotid atherosclerosis (OR = 1.45 [1.13-1.86], p = 0.003). The risk allele of rs2229116 was opposite from the original report. The haplotype block of this 31.1 Kb region was different between Caucasian and Japanese. Haplotype analysis revealed that only TAGG haplotype was associated with PAI (OR = 0.67 [0.48-0.94], p = 0.020) and atherosclerosis of common carotid artery (OR = 0.75 [0.58-0.98], p = 0.034).
Conclusion
rs877087 and rs2229116 of RYR3 gene are associated with atherosclerosis severity in Japanese. The functional difference caused by rs2229116 needs to be investigated.
doi:10.1186/1471-2261-14-6
PMCID: PMC3898238  PMID: 24423397
Atherosclerosis; Polymorphism; Ryanodine receptor 3; Japanese
15.  Carotid artery intima–media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure 
AIDS (London, England)  2005;19(9):927-933.
Context
The impact of HIV infection and exposure to antiretroviral therapy on the development of subclinical atherosclerosis is incompletely understood.
Objective
To compare intima–media thickness (IMT) of the carotid artery between HIV-infected subjects receiving protease inhibitor-containing regimens and subjects not receiving these regimens and to compare differences in the IMT of the carotid artery between HIV-infected subjects and HIV-uninfected subjects.
Methods
A prospective matched cohort study in university-based outpatient clinics. Groups of three individuals (triads) matched on the following characteristics were enrolled: age, sex, race/ethnicity, smoking status, blood pressure and menopausal status. Group 1, HIV-infected subjects with continuous use of protease inhibitor (PI) therapy for ≥ 2 years; group 2, HIV-infected subjects without prior PI use; and group 3: HIV-uninfected. Ultrasonographers at six sites sent standardized ultrasound images to a central reading site for carotid IMT measurements. Carotid IMT was compared within the HIV-infected groups (1 and 2) and between the HIV-infected and uninfected groups in a matched analysis.
Results
One hundred and thirty-four individuals were enrolled in 45 triads. The median IMT in groups 1, 2 and 3 was 0.690, 0.712 and 0.698 mm, respectively. There were no statistically significant differences in IMT between groups 1 and 2, or in the combined HIV groups compared with the HIV uninfected group. Significant predictors of carotid IMT in a multivariate model included high-density lipoprotein (HDL) cholesterol, the interaction of HDL cholesterol and triglycerides, age and body mass index.
Conclusions
We found no association between PI inhibitor exposure or HIV infection and carotid IMT.
PMCID: PMC1373680  PMID: 15905673
atherosclerosis; HIV infection; carotid intima; media thickness; protease inhibitors
16.  Evaluation of endothelial function and subclinical atherosclerosis in association with hepatitis C virus in HIV-infected patients: a cross-sectional study 
BMC Infectious Diseases  2011;11:265.
Background
Relationship of hepatitis C virus (HCV) infection with an increased risk of cardiovascular disease (CVD) in HIV-infected patients remains controversial. We evaluated endothelial function and subclinical atherosclerosis in HIV-infected patients with and without HCV.
Methods
Flow-mediated dilatation (FMD) of the brachial artery and circulating levels of cell adhesion molecules (CAM) were measured in HCV/HIV-coinfected and HIV-monoinfected patients. Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT).
Results
63 (31%) HCV/HIV-coinfected and 138 (69%) HIV-monoinfected patients were included. Median soluble vascular CAM-1 (sVCAM-1) and intercellular CAM-1 (sICAM-1) levels were significantly higher in HIV/HCV-coinfected patients (P < 0.001 for both cases). Median (interquartile range) FMD was 6.21% (2.86-9.62) in HCV/HIV-coinfected and 5.54% (2.13-9.13) in HIV-monoinfected patients (P = 0.37). Adjustment for variables associated with HCV and FMD disclosed similar results. FMD correlated inversely with cIMT and age. Carotid IMT did not differ between HCV/HIV-coinfected and HIV-monoinfected patients in unadjusted (0.61 [0.55-0.65] mm vs 0.60 [0.53-0.72] mm; P = 0.39) or adjusted analyses.
Conclusion
HCV infection was associated with higher levels of sICAM-1 and sVCAM-1, but no evidence of increased subclinical atherosclerosis was found when endothelial function was evaluated through FMD, or when assessing the cIMT.
doi:10.1186/1471-2334-11-265
PMCID: PMC3198698  PMID: 21967471
17.  Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study 
AIDS (London, England)  2009;23(14):1841-1849.
Background
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Methods
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
Results
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Conclusions
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
doi:10.1097/QAD.0b013e32832d3b85
PMCID: PMC3156613  PMID: 19455012
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
18.  Polymorphisms of the methylenetetrahydrofolate reductase, vascular endothelial growth factor, endothelial nitric oxide synthase, monocyte chemoattractant protein-1 and apolipoprotein E genes are not associated with carotid intima-media thickness 
BACKGROUND:
Single nucleotide polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), monocyte chemoattractant protein-1 (MCP-1) and apolipoprotein E (ApoE) genes appear to be a genetic risk factor for atherosclerosis. Common carotid intima-media thickness (cIMT) provides information on the severity of atherosclerosis.
OBJECTIVE:
To investigate the relationship between cIMT and gene polymorphisms associated with atherosclerosis in Turkish patients with coronary artery disease (CAD).
METHODS:
Sixty-two patients with angiographically diagnosed stable CAD were divided into two groups according to their cIMT values (group 1: n=35, cIMT of 1 mm or greater; group 2: n=27, cIMT of less than 1 mm). MTHFR 677 C/T, VEGF–460 C/T, eNOS 894 G/T, MCP-1–2518 A/G and ApoE (E2, E3 and E4) gene polymorphisms (where A is adenine, C is cytosine, G is guanine and T is thymine) were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Evaluations of cardiovascular risk factors and coronary atherosclerotic lesions were performed in all patients. Serum homocysteine and high-sensitivity C-reactive protein were measured and compared between the two groups.
RESULTS:
Serum high-sensitivity C-reactive protein (P=0.04) and homocysteine (P=0.006) levels were higher in group 1 than in group 2. The ratio of multivessel CAD and previous myocardial infarction was significantly higher in group 1 than in group 2 (P=0.014). In the study population, no significant difference in cIMT was observed according to the polymorphisms studied. Only hyperhomocysteinemia (OR 1.17 [95% CI 1.01 to 1.35], P=0.033) and previous myocardial infarction (OR 3.76 [95% CI 1.10 to 12.81], P=0.034) maintained a significant correlation with cIMT on multiple logistic regression analysis.
CONCLUSION:
cIMT is increased in patients with hyperhomocysteinemia, inflammation and extended CAD. MTHFR 677 C/T, VEGF–460 C/T, eNOS 894 G/T, MCP-1–2518 A/G and ApoE single nucleotide polymorphisms were not associated with increased cIMT.
PMCID: PMC2691882  PMID: 19148342
Atherosclerosis-related genes; Carotid intima-media thickness; Coronary artery disease; Homocysteine
19.  Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment 
Background
Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly-active antiretroviral therapy (HAART).
Methods
In the Women's Interagency HIV Study (WIHS), 127 HIV-infected women studied pre- and post-HAART were matched to HIV-uninfected controls. Six semi-annual measurements of soluble CD14, tumor necrosis factor (TNF)-alpha, soluble interleukin (IL)-2 receptor, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness (CIMT) was measured by B-mode ultrasound.
Results
Relative to HIV-uninfected controls, HAART-naïve HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P<0.0001), TNF-alpha (6.3 vs 3.4 pg/mL, P<0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P<0.0001), IL-10 (3.3 vs 1.9 pg/mL, P<0.0001), MCP-1 (190 vs 163 pg/mL, P<0.0001) and D-dimer (0.43 vs 0.31 µg/mL, P<0.01). Elevated biomarker levels declined after HAART. While most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-alpha levels remained elevated compared to HIV-uninfected women (+0.8 pg/mL, P=0.0002). Higher post-HAART levels of soluble IL-2 receptor (P=0.02), IL-6 (P=0.05), and D-dimer (P=0.03) were associated with increased CIMT.
Conclusions
Untreated HIV infection is associated with abnormal hemostasis (e.g., D-dimer), and pro-atherogenic (e.g., TNF-alpha) and anti-atherogenic (e.g., IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.
doi:10.1097/QAI.0b013e31825b03be
PMCID: PMC3400505  PMID: 22592585
antiretroviral therapy; cardiovascular diseases; cytokines; hemostasis; HIV; inflammation
20.  Normative values and correlates of carotid artery intima-media thickness and carotid atherosclerosis in Andean-Hispanics: The PREVENCION Study 
Atherosclerosis  2010;211(2):499-505.
Objectives
Carotid intima-media thickness (cIMT) is an independent predictor of cardiovascular risk. Furthermore, ethnicity and gender-specific normative data are required to assess cIMT, which are not available for Andean-Hispanics. In addition, data regarding correlates of subclinical atherosclerosis in ethnic population are needed.
Methods
We studied 1448 adults enrolled in a population-based study in Peru. cIMT and carotid plaque were measured with high-resolution ultrasonography. A healthy reference sample (n=472) with no cardiovascular disease, normal weight and normal metabolic parameters was selected to establish normative cIMT values. Correlates of abnormal cIMT and carotid plaque were assessed in the entire population.
Results
In the reference sample, 95th-percentile cIMT values were both age and gender-dependent. In stepwise regression, selected predictors of increasing cIMT were: older age, impaired fasting glucose, diabetes mellitus, higher systolic blood pressure, higher LDL-cholesterol, smoking and male gender. Predictors of carotid plaque included older age, male gender, higher systolic blood pressure, lower diastolic blood pressure and higher LDL-cholesterol. HDL-cholesterol and C-reactive protein were not associated with cIMT or carotid plaque. The lack of association with HDL-cholesterol was confirmed using high performance liquid chromatography.
Conclusions
We present ethnic-specific cutoffs for abnormal cIMT applicable to Andean-Hispanics and correlates of subclinical atherosclerosis in this population. Pending longitudinal studies, our data supports several risk associations seen in other populations and can be used to identify Andean-Hispanics at increased risk for atherosclerotic cardiovascular disease. The lack of association between HDL-C and cIMT or carotid plaque in this population requires further investigation.
doi:10.1016/j.atherosclerosis.2010.04.009
PMCID: PMC2928715  PMID: 20510418
carotid intima-media thickness; Andean-Hispanics; definitions; cardiovascular disease; Latin America
21.  Low CD4+ T cell count as a major atherosclerosis risk factor in HIV-infected women and men 
AIDS (London, England)  2008;22(13):1615-1624.
Objective
To assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical carotid artery atherosclerosis.
Design
Cross-sectional study nested within a prospective cohort study
Methods
Among participants in the Women's Interagency HIV Study (1,331 HIV-infected women, 534 HIV-uninfected women) and Multicenter AIDS Cohort Study (600 HIV-infected men, 325 HIV-uninfected men), we measured subclinical carotid artery lesions and common carotid artery intima-media thickness (CIMT) using B-mode ultrasound. We estimated adjusted mean CIMT differences and prevalence ratios (PRs) for carotid lesions associated with HIV-related disease and treatments, with multivariate adjustment to control for possible confounding variables.
Results
Among HIV-infected individuals, a low CD4+ T cell count was independently associated with an increased prevalence of carotid lesions. Compared to the reference group of HIV-uninfected individuals, the adjusted PR for lesions among HIV-infected individuals with CD4+ T-cell count <200 cells/mm3 was 2.00 (95% confidence interval 1.22, 3.28) in women and 1.74 (95% confidence interval 1.04, 2.93) in men. No consistent association of antiretroviral medications with carotid atherosclerosis was observed, except for a borderline significant association between protease inhibitor use and carotid lesions in men (with no association among women). History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis.
Conclusions
Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased subclinical carotid atherosclerosis in HIV-infected women and men.
doi:10.1097/QAD.0b013e328300581d
PMCID: PMC2624572  PMID: 18670221
22.  The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis 
Background
Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample.
Methods
The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography.
Results
No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 – 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed.
Conclusions
None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.
doi:10.1186/1476-511X-11-130
PMCID: PMC3503625  PMID: 23039379
Carotid atherosclerosis; Carotid intima-media thickness; Cholesteryl ester transfer protein; Genetic polymorphism
23.  Genome-wide algorithm for detecting CNV associations with diseases 
BMC Bioinformatics  2011;12:331.
Background
SNP genotyping arrays have been developed to characterize single-nucleotide polymorphisms (SNPs) and DNA copy number variations (CNVs). Nonparametric and model-based statistical algorithms have been developed to detect CNVs from SNP data using the marker intensities. However, these algorithms lack specificity to detect small CNVs owing to the high false positive rate when calling CNVs based on the intensity values. Therefore, the resulting association tests lack power even if the CNVs affecting disease risk are common. An alternative procedure called PennCNV uses information from both the marker intensities as well as the genotypes and therefore has increased sensitivity.
Results
By using the hidden Markov model (HMM) implemented in PennCNV to derive the probabilities of different copy number states which we subsequently used in a logistic regression model, we developed a new genome-wide algorithm to detect CNV associations with diseases. We compared this new method with association test applied to the most probable copy number state for each individual that is provided by PennCNV after it performs an initial HMM analysis followed by application of the Viterbi algorithm, which removes information about copy number probabilities. In one of our simulation studies, we showed that for large CNVs (number of SNPs ≥ 10), the association tests based on PennCNV calls gave more significant results, but the new algorithm retained high power. For small CNVs (number of SNPs <10), the logistic algorithm provided smaller average p-values (e.g., p = 7.54e - 17 when relative risk RR = 3.0) in all the scenarios and could capture signals that PennCNV did not (e.g., p = 0.020 when RR = 3.0). From a second set of simulations, we showed that the new algorithm is more powerful in detecting disease associations with small CNVs (number of SNPs ranging from 3 to 5) under different penetrance models (e.g., when RR = 3.0, for relatively weak signals, power = 0.8030 comparing to 0.2879 obtained from the association tests based on PennCNV calls). The new method was implemented in software GWCNV. It is freely available at http://gwcnv.sourceforge.net, distributed under a GPL license.
Conclusions
We conclude that the new algorithm is more sensitive and can be more powerful in detecting CNV associations with diseases than the existing HMM algorithm, especially when the CNV association signal is weak and a limited number of SNPs are located in the CNV.
doi:10.1186/1471-2105-12-331
PMCID: PMC3173460  PMID: 21827692
24.  The Effect of HIV Infection on Atherosclerosis and Lipoprotein Metabolism: a One Year Prospective Study 
Atherosclerosis  2013;229(1):206-211.
Objectives
HIV infection is associated with dyslipidaemia and increased risk of cardiovascular disease. The effects of HIV infection and antiretroviral treatment on surrogate markers of atherosclerosis, and lipoprotein metabolism were evaluated in a 12 month prospective study.
Methods and Results
Treatment-naive HIV patients were recruited into one of three groups: untreated HIV infection not likely to require initiation of antiretroviral therapy (ART) for at least 12 months; initiating treatment with non nucleoside reverse transcriptase inhibitor-containing ART regimen and initiating treatment with protease inhibitor-containing ART regimen. The patients underwent assessment of carotid intima-media thickness (cIMT), pulse wave velocity (PWV), brachial flow-mediated dilation (FMD) and variables of plasma lipoprotein metabolism at baseline and 12 months. The findings were compared with published values for age and sex matched HIV-negative healthy subjects in a cross-sectional fashion. cIMT and FMD were lower while PWV was higher in HIV-patients compared with HIV-negative individuals; none of the markers changed significantly during 12 months follow up. HIV patients had hypoalphalipoproteinemia and elevated plasma levels of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein. The only significant changes in lipid-related variables were elevation of total cholesterol and triglycerides in patients treated with PI-containing regimen and elevation of plasma LCAT levels in patients treated with NNRTI-containing regimen. The ability of whole and apoB-depleted plasma to effect cholesterol efflux was not impaired in all three groups.
Conclusions
This study did not find evidence for rapid progression of subclinical atherosclerosis and deterioration of dyslipidaemia in HIV patients within 1 year.
doi:10.1016/j.atherosclerosis.2013.04.010
PMCID: PMC3691344  PMID: 23642913
HIV; atherosclerosis; lipoproteins; cholesterol metabolism
25.  T-Cell Phenotypes, Apoptosis and Inflammation in HIV+ Patients on Virologically Effective cART with Early Atherosclerosis 
PLoS ONE  2012;7(9):e46073.
Objective
We investigated the potential relationship between T-cell phenotype, inflammation, endotoxemia, and atherosclerosis evaluated by carotid intima-media thickness (IMT) in a cohort of HIV-positive patients undergoing long-term virologically suppressive combination antiretroviral therapy (cART).
Design
We studied 163 patients receiving virologically suppressive cART.
Methods
We measured IMT (carotid ultrasound); CD4+/CD8+ T-cell activation (CD38, CD45R0), differentiation (CD127), apoptosis (CD95), and senescence (CD28, CD57) (flow cytometry); plasma sCD14, IL-6, TNF- α, sVCAM-1, hs-CRP, anti-CMV IgG (ELISA); LPS (LAL). The results were compared by Mann-Whitney, Kruskal-Wallis or Chi-square tests, and factors associated with IMT were evaluated by multivariable logistic regression.
Results
Of 163 patients, 112 demonstrated normal IMT (nIMT), whereas 51 (31.3%) had pathological IMT (pIMT: ≥1 mm). Of the patients with pIMT, 22 demonstrated an increased IMT (iIMT), and 29 were shown to have plaques. These patient groups had comparable nadir and current CD4+, VLs and total length of time on cART. Despite similar proportions of CD38-expressing CD8+ cells (p = .95), pIMT patients exhibited higher activated memory CD8+CD38+CD45R0+ cells (p = .038) and apoptotic CD4+CD95+ (p = .01) and CD8+CD95+ cells (p = .003). In comparison to nIMT patients, iIMT patients tended to have lower numbers of early differentiated CD28+CD57− memory CD4+ (p = .048) and CD28–CD57−CD8+ cells (p = .006), both of which are associated with a higher proliferative potential. Despite no differences in plasma LPS levels, pIMT patients showed significantly higher circulating levels of sCD14 than did nIMT patients (p = .046). No differences in anti-CMV IgG was shown. Although circulating levels of sCD14 seemed to be associated with a risk of ATS in an unadjusted analysis, this effect was lost after adjusting for classical cardiovascular predictors.
Conclusions
Despite the provision of full viral suppression by cART, a hyperactivated, pro-apoptotic T-cell profile characterizes HIV-infected patients with early vascular damage, for whom the potential contribution of subclinical endotoxemia and anti-CMV immunity should be investigated further.
doi:10.1371/journal.pone.0046073
PMCID: PMC3459872  PMID: 23029393

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