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      Apolipoprotein A-II Influences Apolipoprotein E-Linked Cardiovascular Disease Risk in Women with High Levels of HDL Cholesterol and C-Reactive Protein

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          Abstract

          Background

          In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C).

          To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups.

          Methodology/Principal

          Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12–25.17, p = 0.036). Furthermore, high LpA-I:A-II levels interacted with high apoE levels in establishing subgroup risk.

          Conclusions/Significance

          We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP.

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          Most cited references70

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          Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study.

          The role of triglycerides as a risk factor of ischemic heart disease (IHD) remains controversial. For the present study, we examined the relation between fasting triglycerides and risk of IHD in the Copenhagen Male Study. Baseline measurements of fasting lipids and other IHD risk factors were obtained for 2906 white men (age range, 53 to 74 years) who were initially free of overt cardiovascular disease. During an 8-year follow-up period, 229 men had a first IHD event. Crude cumulative incidence rates of IHD were 4.6% for the lowest, 7.7% for the middle, and 11.5% for the highest third of triglyceride levels (P for trend <.001). Compared with the lowest third level and adjusted for age, body mass index, alcohol, smoking, physical activity, hypertension, non-insulin-dependent diabetes mellitus, social class, and LDL and HDL cholesterol, relative risks of IHD (95% confidence interval) were 1.5 (1.0 to 2.3; P=.05) and 2.2 (1.4 to 3.4; P<.001) for the middle and highest third of triglyceride levels, respectively. When triglyceride levels were stratified by HDL cholesterol levels (triglyceride third multiplied by HDL cholesterol third), a clear gradient of risk of IHD was found with increasing triglyceride levels within each level of HDL cholesterol, including high HDL cholesterol level, which are thought to provide protection against IHD. In middle-aged and elderly white men, a high level of fasting triglycerides is a strong risk factor of IHD independent of other major risk factors, including HDL cholesterol.
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            Urinary albumin excretion is associated with renal functional abnormalities in a nondiabetic population.

            Microalbuminuria (MA) is an important early sign of diabetic nephropathy. Hyperfiltration and impaired filtration in relation to albuminuria has been well investigated in diabetic subjects. This study tested the hypothesis that an increased urinary albumin excretion (UAE) is associated with renal functional abnormalities also in nondiabetic subjects. The relation between UAE and creatinine clearances (Ccr) in 7728 nondiabetic subjects was studied. Subjects were divided in four groups according to UAE (mg/24 h): 0 to 15 (control), 15 to 30 (high-normal albuminuria [HNA]), 30 to 300 (MA), >300 (macroalbuminuria). An elevated filtration and a diminished filtration were defined as a Ccr exceeding or below 2x the SD of the control group corrected for age and gender. Ccr followed a parabolic trend, with a higher Ccr in the HNA as compared with control and a lower Ccr in the MA and macroalbuminuria group as compared with HNA. With each increasing UAE level, male sex, age, body mass index, minimal waist circumference, systolic and diastolic BP, plasma glucose, and a positive family history for diabetes all followed a significant linear increasing trend (P < 0.001). After adjustment for age, gender, body mass index, plasma glucose, a positive family history for diabetes, systolic and diastolic BP, antihypertensive medication, and smoking in a multivariate analysis, HNA and MA were independently associated with an elevated filtration (RR 1.8 [95% confidence interval, 1.30 to 2.51] and 1.7 [1.17 to 2. 45]). Macroalbuminuria was independently associated with a diminished filtration (4.3 [range, 1.97 to 9.36]). In conclusion, an elevated UAE might be an important and early sign for progressive renal function loss in a nondiabetic population.
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              Albuminuria assessed from first-morning-void urine samples versus 24-hour urine collections as a predictor of cardiovascular morbidity and mortality.

              Screening for albuminuria has been advocated because it is associated with cardiovascular morbidity and all-cause mortality. The "gold standard" to assess albuminuria is 24-hour urinary albumin excretion (UAE). Because 24-hour urine collection is cumbersome, guidelines suggest measuring albuminuria in a first morning void, either as urinary albumin concentration (UAC) or adjusted for creatinine concentration, the albumin:creatinine ratio (ACR). To decide which albuminuria measure to use in clinical practice, it is essential to know which best predicts clinical outcome. In a sample representative of the Groningen (the Netherlands) population (n = 3,414), the authors compared UAC, ACR, and UAE as predictors of cardiovascular events and all-cause mortality. During a median follow-up of 7.5 years, which ended December 31, 2005, they observed 278 events (a major adverse cardiovascular event or mortality). The area under the receiver operating characteristic curve predicting events was 0.65 for UAE, 0.62 for UAC (P = 0.06 vs. UAE), and 0.66 for ACR (P = 0.80 vs. UAE; P = 0.01 vs. UAC). When sex-specific subgroups were considered, UAE was superior to UAC in predicting outcome (P = 0.04) for females, whereas, for males as well as females, no difference was found between ACR and UAE. To predict cardiovascular morbidity and all-cause mortality, measuring ACR in a first-morning-void urine sample is a good alternative to measuring 24-hour UAE.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                18 June 2012
                : 7
                : 6
                : e39110
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America
                [2 ]Department of Nephrology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
                [3 ]Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
                INRCA, Italy
                Author notes

                Conceived and designed the experiments: JPC CES RPFD. Performed the experiments: JPC SJLB. Analyzed the data: JPC CES RPFD. Contributed reagents/materials/analysis tools: JPC SJLB. Wrote the paper: JPC CES RPFD.

                Article
                PONE-D-12-03752
                10.1371/journal.pone.0039110
                3377620
                22723940
                5fa24ed5-ee61-45a8-8071-05d08a10a8ee
                Corsetti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 7 February 2012
                : 17 May 2012
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Biochemistry
                Proteins
                Lipoproteins
                Apolipoprotein Genes
                Apolipoproteins
                C-Reactive Proteins
                Medicine
                Cardiovascular
                Atherosclerosis
                Cardiovascular Diseases in Women
                Coronary Artery Disease
                Vascular Biology
                Diagnostic Medicine
                Clinical Laboratory Sciences
                Clinical Chemistry
                Test Evaluation
                Epidemiology
                Biomarker Epidemiology
                Cardiovascular Disease Epidemiology
                Women's Health

                Uncategorized
                Uncategorized

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