While the association between obesity and endometrial cancer (EC) is well established, the underlying mechanisms require further study. We assessed possible links between lipid profiles and EC risk, while also taking into account BMI, parity, and menopausal status at baseline.
Using the information available from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study we created a cohort of 225,432 women with baseline values for glucose, triglycerides (TG), and total cholesterol (TC). Two subgroups of 31,792 and 26,317 had, in addition, baseline measurements of HDL, LDL, apolipoprotein A-I and apoB and BMI, respectively. We used Multivariate Cox proportional hazards models to analyze quartiles and dichotomized values of these lipid components for a link to EC risk.
During mean follow-up of 12 years (SD: 4.15), 1,144 persons developed endometrial cancer. A statistically significant association was found between TG and EC risk when using both quartiles and a clinical cut-off (Hazard Ratio (HR): 1.10 (95%CI: 0.88-1.37), 1.34 (1.09-1.63), and 1.57 (1.28-1.92)) for the 2nd, 3rd, and 4th quartile, compared to the 1st, with P-value for trend: <0.001). The association remained after exclusion of the first three years of follow-up. Also total cholesterol and TG/HDL ratio were positively associated with EC risk, but no link was found for the other lipid components studied.
This detailed analysis of lipid components showed a consistent relation between TG levels and EC risk. Future research should continue to analyze the metabolic pathway and its relation to EC risk, as a pathway to further understand the relation of obesity and disease.
Lipid profiles; risk factor; endometrial cancer; Swedish AMORIS study
Observational studies have indicated that high calcium intake may prevent colorectal cancer, but as for randomized trials the results are inconclusive. Meanwhile, limited data on the link between serum calcium and cancer risk is available. We investigated the relation between serum calcium and risk of different gastrointestinal cancers in a prospective study.
A cohort based on 492,044 subjects with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Multivariable Cox proportional hazard models were used to analyse associations between standardised levels, quartiles and age/sex-specific categories of serum calcium and risk of oesophageal, stomach, colon, rectal cancer and also colorectal cancer combined, while taking into account serum albumin and other comorbidities.
During 12 years of follow-up, we identified 323 incident oesophageal cancers, 782 stomach cancers, 2519 colon cancers, and 1495 rectal cancers. A positive association was found between albumin-adjusted serum calcium and risk of oesophageal [HR: 4.82 (95% CI: 2.07 – 11.19) for high compared to normal age-specific calcium levels] and colon cancer [e.g. HR: 1.07 (95% CI: 1.00 – 1.14) for every SD increase of calcium] as well as colorectal cancer [e.g. HR: 1.06 (95% CI: 1.02-1.11) for every SD increase of calcium] in women. In men there were similar but weaker non-statistically significant trends.
The positive relation between serum calcium, oesophageal cancer and colorectal cancer calls for further studies including calcium regulators to evaluate whether there is a true link between calcium metabolism and development of gastrointestinal cancer.
Gastrointestinal cancer; Calcium; Albumin
Previous studies indicated that apolipoprotein measurements predicted cardiovascular disease (CVD) risk; however, associations between apolipoproteins and carotid intima-media thickness (CIMT) were less explored.
Methodology and Principal Findings
The cross-sectional study included 6069 participants aged 40 years or older with NGT from Shanghai, China. Serum fasting traditional lipids (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides [TG]), apoA-I and apoB were assessed. A high-resolution B-mode ultrasonography was performed to measure CIMT. We found CIMT increased progressively across the quartiles of serum apoB (p for trend <0.0001). In logistic regression, concentrations of apoB (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.18–1.36), TC (OR 1.23, 95% CI 1.14–1.32), LDL-C (OR 1.25, 95% CI 1.16–1.34) and TG (OR 1.11, 95% CI 1.04–1.20) were significantly related to elevated CIMT after adjusted for age and sex. Meanwhile, the apoB/apoA-I ratio (OR 1.25, 95% CI 1.17–1.34) related to elevated CIMT. ApoB (OR 1.23, 95% CI 1.00–1.51) and the apoB/apoA-I ratio (OR 1.19, 95% CI 1.04–1.36) remained significantly associated with elevated CIMT, after adjusted for the traditional CVD risk factors including traditional lipids.
Conclusions and Significance
There were significant associations between serum apoB, the apoB/apoA-I ratio and elevated CIMT. Serum apoB and the apoB/apoA-I ratio might be independent predictors of early atherosclerosis in NGT.
The ratio between apolipoprotein B and apolipoprotein A-I (apoB/apoA-I) has been suggested to be a powerful and more accurate predictor of future cardiovascular disease risk than total cholesterol and HDL cholesterol. Since diet and lifestyle can directly influence dyslipidemia, it is of interest to identify modifiable factors that are associated with high levels of the apolipoprotein ratio and if they can have a different association with a more traditional indicator of cardiovascular risk such as total cholesterol/HDL. The relationship between obesity and dyslipidemia is established and it is of interest to determine which factors can modify this association. This study investigated the cross-sectional association of obesity, diet and lifestyle factors with apoB/apoA-I and total cholesterol/HDL respectively, in a Swedish population of 2,907 subjects (1,537 women) as part of the INTERGENE study. The apolipoprotein and lipoprotein ratios were highly correlated, particularly in women, and obesity was strongly associated with both. Additionally, age, cigarette smoking and alcohol intake were important determinants of these ratios. Alcohol was the only dietary factor that appreciably attenuated the association between obesity and each of the ratios, with a stronger attenuation in women. Other dietary intake and lifestyle-related factors such as smoking status and physical activity had a lower effect on this association. Because the apolipoprotein and lipoprotein ratios share similar diet and lifestyle determinants as well as being highly correlated, we conclude that either of these ratios may be a sufficient indicator of dyslipidemia.
Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are the well-established standards by which clinicians identify individuals at risk for coronary artery disease (CAD), yet nearly 50% of people who have a myocardial infarction have normal cholesterol levels. Measurement of additional biomarkers may be useful to more fully stratify patients according to disease risk. The typical lipid panel includes TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Emerging biomarkers for cardiovascular risk include measures of LDL-C pattern, size, and density; LDL particle number; lipoprotein(a); apolipoproteins (apoA1 and apoB100 being the most useful); C-reactive protein; and lipoprotein-associated phospholipase A2. Some of these emerging biomarkers have been proven to add to, or be more accurate than, traditional risk factors in predicting coronary artery disease and, thus, may be useful for clinical decision-making in high-risk patients and in patients with borderline traditional risk factors. However, we still believe that until treatment strategies can uniquely address these added risk factors—ie, until protocols to rectify unhealthy findings are shown to improve cardiovascular outcomes—healthcare providers should continue to focus primarily on helping patients reach optimal LDL-C, HDL-C, and TG levels.
Traditional lipid indices have been associated with type 2 diabetes, but it remains uncertain which lipid index is the best discriminator for diabetes. In this study, we aimed to assess lipoproteins, traditional lipid variables, and other variables to discover their association with diabetes in the Taiwanese population.
Data from a nationwide cross-sectional population-based survey of 3087 men and 3373 women in 2002 were analyzed in this study. All participants were assessed for anthropometry, glycosylated hemoglobin, fasting sugar and lipid profiles with triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoprotein A1 (ApoA1) and B (ApoB). The ratio of LDL-C/HDL-C, ApoB/ApoA1, ApoB/LDL-C and ApoA1/HDL-C and other variables were analyzed to determine their potential roles in type 2 diabetes in the Taiwanese population. The Odds ratios (ORs) of the risk variables for diabetes were estimated using logistic regression and were adjusted for confounding factors.
The increased ratio of ApoA1/HDL-C was significantly associated with diabetes in men (top tertile vs. lowest: OR 2.98; 95% CI: 1.12 - 7.92; P-trend = 0.030) and women (top tertile vs. lowest: OR 2.15; 95% CI: 1.00 - 4.59; P-trend = 0.047). A modest increased diabetic risk was evident with ApoB/LDL-C in women (top tertile vs. lowest: OR 2.03; 95% CI: 1.07- 3.85; P-trend = 0.028), but not in men (top tertile v. lowest: OR 1.69; 95% CI: 0.79- 3.62; P-trend = 0.198).
ApoA1/HDL-C had a significant linear association with diabetes in both sexes and was superior to other lipid and lipoprotein variables among the general Taiwanese population.
Apolipoprotein A1; Apolipoprotein B; High density lipoprotein-cholesterol; Low density lipoprotein-cholesterol; Diabetes
OBJECTIVE—To understand why atherogenic risk differs more between diabetic and nondiabetic women than between diabetic and nondiabetic men.
RESEARCH DESIGN AND METHODS AND RESULTS—Measures of cardiovascular risk, body composition, and serum hormones from the baseline examinations of the Insulin Resistance Atherosclerosis Study on 524 nondiabetic women, 258 diabetic women, 421 nondiabetic men, and 220 diabetic men were compared to detect greater adverse differences in women than in men. Systolic blood pressure; apolipoprotein B (apoB); total cholesterol; apoB–to–apoA-I ratio; non-HDL cholesterol; LDL particle count, small LDL, and intermediate-density lipoprotein by nuclear magnetic resonance; and C-reactive protein exhibited significant diabetes-sex interaction (P < 0.05). ApoB exhibited the most significant interaction (P = 0.0005). Age- and ethnicity-adjusted apoB means were lower in nondiabetic women than nondiabetic men (102.4 vs. 106.8 mg/dl, P < 0.05) but higher in diabetes (115.7 vs. 110.2 mg/dl, P < 0.01). Plotted against BMI, waist circumference was 6% higher and hip circumference 10% lower in diabetic than nondiabetic women (both P < 0.05), whereas the circumference measures did not differ conspicuously between diabetic and nondiabetic men.
CONCLUSIONS—In diabetic women, an elevated level of atherogenic particles, as manifested by apoB and LDL particle count, which may result from abdominal adiposity, represents a major treatable cardiovascular risk factor.
Primordial prevention of chronic disease is of clinical and public health importance. Considering the fetal onset of atherosclerosis, we aimed to determine the cord blood level of lipoproteins and apolipoproteins as well as their correlation with birth weight and gestational age.
This cross-sectional study comprised 100 healthy Indian newborns. Ten ml. of cord blood was collected from placental end of umbilical vein. Serum was separated by centrifugation and analyzed on the same day for lipid profile including total cholesterol (TC), triglycerides (TG), high density lipoprotein- cholesterol (HDL-C), very low density lipoproteincholesterol (VLDL) and low density lipoprotein-cholesterol (LDL-C), apolipoproteins A-I and B (ApoA-I, ApoB). Atherogenic index (AI) was calculated as the ratio of ApoB to ApoA-I.
Cord blood of female newborns had higher TC, HDL-C, LDL-C, Apo A-I, Apo B and AI as compared to male newborns, whereas TG and VLDL-C were higher in male than in female newborns. Significant positive correlation was observed between cord blood Apo A-I and HDL-C (r= 0.45, p<0.01), and between cord blood Apo-B and LDL-C (r= 0.44, p<0.01). Non-significant inverse correlation was observed between Apo A-I and ApoB with gestational age. There was a significant inverse correlation between TG and gestational age (r= –0.197, p <0.05). Positive non-significant correlation was observed between AI and birth weight (r=0.046, p>0.05).
These findings are another confirmatory evidence for the association of prenatal factors with cord blood lipid profile, and can serve as starting point for studying lipid transport system changes during early life.
Cord blood; Fetal period; Lipoprotein; Apolipoprotein; Primordial prevention
There is a paucity of data regarding relations of apolipoproteins (apolipoprotein B [ApoB] and apolipoprotein A-1 [Apo A-1]), lipoprotein particle measures (low-density lipoprotein particle concentration [LDLp] and high-density lipoprotein particle concentration [HDLp]), and lipoprotein cholesterol measures (low-density lipoprotein cholesterol [LDL-C], non–high-density lipoprotein cholesterol [non– HDL-C], and high-density lipoprotein cholesterol [HDL-C]) with atherosclerotic plaque burden, plaque eccentricity, and lipid-rich core presence as a marker of high-risk plaques.
Carotid artery magnetic resonance imaging was performed in 1,670 Atherosclerosis Risk in Communities study participants. Vessel wall and lipid cores were measured; normalized wall index (NWI), standard deviation (SD) of wall thickness (measure of plaque eccentricity) were calculated; and lipid cores were detected in vessels with ≥1.5 mm thickness. Fasting concentrations of cholesterol, ApoB and Apo A-1, and LDLp and HDLp were measured.
Measures of plaque burden (carotid wall volume, wall thickness, and NWI) were positively associated with atherogenic cholesterol and lipoproteins (p<0.05 for total cholesterol, LDL-C, non–HDL-C, ApoB, and LDLp), but not with HDL-C, Apo A-1, or HDLp. SD of wall thickness was associated with total cholesterol (p 0.01) and non-HDL-C (p 0.02). Although measures of atherogenic or anti-atherogenic cholesterol or lipoprotein were not individually associated with detection of a lipid-rich core, their ratios (total cholesterol/HDL-C, non–HDL-C/ HDL-C, and LDLp/HDLp) were associated with lipid-rich core presence (p≤0.05).
Extent of carotid atherosclerosis is associated with atherogenic cholesterol and lipoproteins. Atherogenic/anti-atherogenic cholesterol or particle ratios were associated with presence of a detectable lipid-rich core.
atherogenic lipoproteins; anti-atherogenic lipoproteins; plaque burden; lipid-rich necrotic core
A number of plasma lipid parameters have been used to estimate cardiovascular risk and to be targets for treatment to reduce risk. Most risk algorithms are based on total cholesterol (T-C) or low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and most intervention trials have targeted the LDL-C levels. Emerging measures, which in some cases may be better for risk calculation and as alternative treatment targets, are apolipoprotein B and non-HDL-C. Other lipid measures that may contribute in risk analysis are triglycerides (TG), lipoprotein(a), and lipoprotein-associated phospholipase A2. The primary treatment target in cardiovascular prevention is LDL-C, and potential alternative targets are apoB and non-HDL-C. In selected individuals at high cardiovascular (CV) risk, TG should be targeted, but HDL-C, Lp(a), and ratios such as LDL-C/HDL-C or apoB/apoAI are not recommended as treatment targets. Lipids should be monitored during titration to targets. Thereafter, lipids should be checked at least once a year or more frequently to improve treatment adherence if indicated. Monitoring of muscle and liver enzymes should be done before the start of treatment. In stable conditions during treatment, the focus should be on clinical symptoms that may alert muscle or liver complications. Routine measurement of CK or ALT is not necessary during treatment with statins.
Dyslipidemia; Cardiovascular prevention; Statin; Lipoprotein; Myalgia; Treatment; Lipids; Enzymes; Creatine kinase; Lipid-lowering drug therapy
Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population-based study (n = 220,642).
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years.
We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95 % CI 1.01–1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95 % CI 1.02–1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95 % CI 1.08–1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer.
As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers.
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
Dyslipoproteinaemia is a cardinal feature of the metabolic syndrome that accelerates atherosclerosis. It is usually characterised by high plasma concentrations of triglyceride-rich and apolipoprotein (apo) B-containing lipoproteins, with depressed concentrations of high-density lipoprotein (HDL). Dysregulation of lipoprotein metabolism in these subjects may be due to a combination of overproduction of very-low-density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles, and increased catabolism of HDL apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance that increases the flux of fatty acids from adipose tissue to the liver, the accumulation of fat in the liver, the increased hepatic secretion of VLDL-triglycerides and the remodelling of both low-density lipoprotein (LDL) and HDL particles in the circulation; perturbations in lipolytic enzymes and lipid transfer proteins contribute to the dyslipidaemia. Our in vivo understanding of the kinetic defects in lipoprotein metabolism in the metabolic syndrome has been chiefly achieved by ongoing developments in the use of stable isotope tracers and mathematical modelling. Knowledge of the pathophysiology of lipoprotein metabolism in the metabolic syndrome is well complemented by extensive cell biological data. Nutritional modifications and increased physical exercise may favourably alter lipoprotein transport in the metabolic syndrome by collectively decreasing the hepatic secretion of VLDL-apoB and the catabolism of HDL apoA-I, as well as by increasing the clearance of LDL-apoB. Pharmacological treatments, such as statins, fibrates or fish oils, can also correct the dyslipidaemia by several mechanisms of action including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. The complementary mechanisms of action of lifestyle and drug therapies support the use of combination regimens to treat dyslipidaemia in the metabolic syndrome.
Lowering low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerosis. LDL and high-density lipoprotein (HDL) are commonly measured by their cholesterol content, but non-HDL cholesterol, LDL particle number (LDL-P), or total apolipoprotein B (apoB) may better predict cardiovascular risk. Few studies have examined relations among lipoprotein levels and composition before and after interventions to lower LDL-C and non-HDL-C.
To measure changes in carotid artery intimal media thickness (CIMT) and lipid concentration and composition during 36 months of statin therapy.
Analyses were conducted on 418 diabetic individuals, with complete data and no prior cardiovascular events, who were randomized to aggressive (AG) versus standard (STD) treatment for LDL-C, non-HDL-C, and systolic blood pressure (SBP) as part of the Stop Atherosclerosis in Native Diabetics Study (SANDS).
The AG group achieved average LDL-C and non-HDL-C of 71mg/dL and 100mg/dL and a decrease in CIMT. No significant interactions were observed between treatment effect and initial levels of LDL-C, non-HDL-C, HDL-C, triglycerides, apoB, or LDL-P. Decreases in LDL-C (p<.005) and non-HDL-C (p<.001) were independently correlated with CIMT regression in the AG group. Changes in apoB and LDL-P showed borderline correlations with CIMT regression (p=.07 and p=.09).
In diabetic adults with no prior cardiovascular events, treatment to current targets for lipids and SBP reduces atherosclerosis progression and when more aggressive targets are met, atherosclerosis regresses. The aggressive targets for LDL-C and non-HDL-C appeared to be the main determinants of CIMT regression and were more predictive of this outcome than changes in LDL-P or apoB.
atherosclerosis; cardiovascular disease; carotid arteries; cholesterol; lipoproteins
Subnormal plasma levels of high-density lipoprotein cholesterol (HDL-C) constitute a major cardiovascular risk factor; raising low HDL-C levels may therefore reduce the residual cardiovascular risk that frequently presents in dyslipidaemic subjects despite statin therapy. Cholesteryl ester transfer protein (CETP), a key modulator not only of the intravascular metabolism of HDL and apolipoprotein (apo) A-I but also of triglyceride (TG)-rich particles and low-density lipoprotein (LDL), mediates the transfer of cholesteryl esters from HDL to pro-atherogenic apoB-lipoproteins, with heterotransfer of TG mainly from very low-density lipoprotein to HDL. Cholesteryl ester transfer protein activity is elevated in the dyslipidaemias of metabolic disease involving insulin resistance and moderate to marked hypertriglyceridaemia, and is intimately associated with premature atherosclerosis and high cardiovascular risk. Cholesteryl ester transfer protein inhibition therefore presents a preferential target for elevation of HDL-C and reduction in atherosclerosis. This review appraises recent evidence for a central role of CETP in the action of current lipid-modulating agents with HDL-raising potential, i.e. statins, fibrates, and niacin, and compares their mechanisms of action with those of pharmacological agents under development which directly inhibit CETP. New CETP inhibitors, such as dalcetrapib and anacetrapib, are targeted to normalize HDL/apoA-I levels and anti-atherogenic activities of HDL particles. Further studies of these CETP inhibitors, in particular in long-term, large-scale outcome trials, will provide essential information on their safety and efficacy in reducing residual cardiovascular risk.
HDL; Atherosclerosis; Cholesteryl ester transfer protein; Cholesteryl ester transfer protein inhibitor; Triglycerides; Reverse cholesterol transport
Plasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A1, the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear.
Methods and results
Case–control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA1 than to HDL-C. The ratio apoB/apoA1 was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8–9.2)] and varied little with age. The ratio apoB/apoA1 was substantially more informative about risk (χ12 = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (χ12 = 407, 334, 204, and 105, respectively). Given apoB and apoA1, the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA1 and pre-onset HDL-C with risk in such retrospective case–control studies.
Apolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.
Myocardial infarction; Lipoproteins; Lipids; Cholesterol; Risk factors
LDL that contains apolipoprotein C-III (apoC-III) comprises only 10 to 20% of plasma LDL, but has a markedly altered metabolism and proatherogenic effects on vascular cells.
Methods and results
We examined the association between plasma LDL with apoC-III and coronary heart disease (CHD) in 320 women and 419 men initially free of cardiovascular disease who developed a fatal or non-fatal myocardial infarction during 10 to 14 years of follow-up, and matched controls who remained free of CHD.
Concentrations of LDL with apoC-III (measured as apoB in this fraction) were associated with risk of CHD in multivariable analysis that included the total cholesterol to HDL cholesterol ratio, LDL cholesterol, apolipoprotein B, triglycerides, or HDL cholesterol; and other risk factors. In all models, the relative risks for the top versus bottom quintile of LDL with apoC-III were greater than those for LDL without apoC-III. When included in the same multivariable adjusted model, the risk associated with LDL with apoC-III (relative risk for top versus bottom quintile 2.38, 95 percent confidence interval, 1.54 to 3.68; P for trend <0.001) was significantly greater than that associated with LDL without apoC-III (relative risk for top versus bottom quintile 1.25, 95 percent confidence interval, 0.76 to 2.05; P for trend=0.97), P for interaction <0.001. This divergence in association with CHD persisted even after adjustment for plasma triglycerides.
The risk of CHD contributed by LDL appeared to result to a large extent from LDL that contains apoC-III.
apolipoproteins; risk factors; metabolism; cholesterol; myocardial infarction
Extended-release niacin effectively lowers plasma TG levels and raises plasma HDL cholesterol levels, but the mechanisms responsible for these effects are unclear.
Methods and Results
We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and LDL, and apoB-48 in TRL in five men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 due to increased LDL apoB-100 FCR.
Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.
Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB.
This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease.
Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced.
The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband’s wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband’s lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification.
LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.
Apolipoprotein B; Cholesterol esterification; Familial hypobetalipoproteinemia; Familial LCAT deficiency; HDL subclasses; High-density lipoproteins; Lecithin:cholesterol acyltransferase
The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high- and low-density lipoprotein particle concentrations (HDL-P and LDL-P) and apolipoprotein (Apo) levels are not well described.
In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) to immediately initiate ART (‘VS group’) or to defer it (‘DC group’), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization.
Compared to DC group (n=126), HDL-P and ApoA1 levels increased among VS participants (n=128) after starting ART. At 6 months, VS participants had 13% higher total HDL-P (p < 0.001) and 9% higher ApoA1 (p < 0.001). LDL-P, VLDL-P, and ApoB did not differ significantly between the VS and DC groups. Among VS participants, predictors of HDL-P and ApoA1 increases included baseline levels of hsCRP and IL-6, but not HIV RNA level, CD4 count or traditional CVD risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (p=0.001 and 0.08, respectively, for interaction) or hsCRP (p=0.01 and 0.04, respectively, for interaction).
HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.
HIV infection; antiretroviral therapy; high-density lipoprotein; apolipoprotein A1; inflammation
To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non–HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed.
Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16–0.94], highest versus lowest quartile; Ptrend = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59–0.98]), whereas apoB (per SD increase, 1.31 [1.02–1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13–1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%.
ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures.
High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance.
The purpose of this study was to investigate the variations of paraoxonase activity and lipid profile in bipolar I patients, and the association of this activity with the sociodemographic, clinical and therapeutic characteristics of this population.
Patients and methods
Our study included 66 patients with bipolar I disorder and 64 controls aged 37.9 ± 12.6 and 36.3 ± 18.2 years, respectively. Paraoxonase activity was determined by kinetic methods; high-density lipoprotein cholesterol (c-HDL), low-density lipoprotein cholesterol (c-LDL), triglycerides and total cholesterol were determined by enzymatic methods; apolipoprotein (Apo)A1, ApoB and lipoprotein (a) (Lp(a)) were determined by immunoturbidimetry using Konelab 30 equipment (Thermo Scientific).
Compared with controls, patients had a significantly lower paraoxonase activity and ApoA1 level, and significantly higher total cholesterol, c-LDL and Lp(a) level and ApoB/ApoA1 ratio. Furthermore, paraoxonase activity was significantly correlated with c-HDL values (r = 0.5612; P < 0.001). The lowest paraoxonase activity was noted in relation to age and body mass index (BMI). Moreover, it was associated with gender but not with smoking and alcohol consumption status. In patients, there was no significant change in paraoxonase activity in relation to illness episodes, whereas the lowest values of this activity were seen in manic patients. In contrast, paraoxonase activity was significantly associated with treatment. Indeed, patients taking lithium had the lowest levels.
Bipolar patients had a significant decrease in paraoxonase activity and perturbations in their lipid profile that contribute to increased risk of cardiovascular diseases. Decrease in this activity was significantly associated with treatment with lithium but not with sociodemographic and clinical characteristics. Therefore, such patients require specific care, particularly with regard to their lipid profile.
The aim of this study is to assess the association of two polymorphisms, the cartilage
intermediate layer protein 2 (CILP2) G/T and angiotensin converting
enzyme (ACE) I/D, with blood pressure and anthropometrical and
biochemical parameters related to the development of cardiovascular disease. The entire
study sample comprised 341 women ranging in age from 39 to 65 years. The
CILP2 genotypes were determined by PCR-RFLP and the ACE genotypes
by PCR. The Bonferroni pairwise comparisons showed the effect of the CILP2 genotype
on high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C),
apolipoprotein B (apoB), apoB-to-apoA1 ratio, the total cholesterol (TC)-to-HDL-C ratio,
non-HDL-C, and the LDL-C-to-HDL-C ratio (P < 0.05). Here, higher mean levels of HDL-C and lower mean levels of the remaining above
mentioned lipid parameters were registered in the GT/TT genotype carriers
than in GG carriers. Statistically significant association was identified between the
ACE genotype and the following parameters: TC, LDL-C, and non-HDL-C (P < 0.05). The II genotype can lower serum level of TC (B = 0.40), LDL-C (B = 0.37), and non-HDL-C levels. The results of this study suggest that the minor T
allele of CILP2 gene and I allele of ACE gene have a protective
effect against elevated serum lipid and lipoprotein levels.
Apolipoprotein M (apoM) is present in 5% of high-density lipoprotein (HDL) particles in plasma. It is a carrier of sphingosine-1-phosphate (S1P), which is important for vascular barrier protection. The aim was to determine the plasma concentrations of apoM during sepsis and systemic inflammatory response syndrome (SIRS) and correlate them to levels of apolipoprotein A-I (apoA1), apolipoprotein B (apoB), HDL-, and low-density lipoprotein (LDL)-cholesterol.
Plasma samples from patients with (1), severe sepsis with shock (n = 26); (2), severe sepsis without shock (n = 44); (3), sepsis (n = 100); (4), infections without SIRS (n = 43); and (5) SIRS without infection (n = 20) were analyzed. The concentrations of apoM, apoA1, and apoB were measured with enzyme-linked immunosorbent assays (ELISAs). Total, HDL-, and LDL-cholesterol concentrations were measured with a commercial HDL/LDL cholesterol test.
ApoM concentrations correlated negatively to acute-phase markers. Thus, apoM behaved as a negative acute-phase protein. Decreased values were observed in all patient groups (P < 0.0001), with the most drastic decreases observed in the severely sick patients. ApoM levels correlated strongly to those of apoA1, apoB, HDL, and LDL cholesterol. The HDL and LDL cholesterol levels were low in all patient groups, as compared with controls (P < 0.0001), in particular, HDL cholesterol. ApoA1 and apoB concentrations were low only in the more severely affected patients.
During sepsis and SIRS, the plasma concentrations of apoM decrease dramatically, the degree of decrease reflecting the severity of the disease. As a carrier for barrier-protective S1P in HDL, the decrease in apoM could contribute to the increased vascular leakage observed in sepsis and SIRS.
A 7-yr-old girl with high density lipoprotein (HDL) deficiency and xanthomas has been identified in a Turkish kindred with repetitive consanguinity. She has severely reduced HDL-cholesterol and no apolipoprotein (apo) A-I. ApoA-II is reduced, whereas apoA-IV and apoC-III are normal. ApoB and low density lipoprotein (LDL)-cholesterol are increased. This is reflected in hypercholesterolemia. VLDL and IDL particles are low, and serum triglycerides are normal. The genetic defect could be identified as a base insertion into the third exon of the apoA-I gene. This leads to a nonsense peptide sequence beginning at amino acid 5 of the mature plasma protein and early termination of translation. The patient is homozygous for this mutation. Pedigree analysis indicated an autosomal dominant inheritance with no evidence of another genetic defect of lipoprotein metabolism in the kindred. In HDL deficiency, HDL binding to leukocytes was increased compared to normal. In the postprandial state, binding of labeled HDL3 to leukocytes is unchanged. This is in contrast to results with postprandially isolated leukocytes from controls or Tangier patients, which have a reduced binding capacity for HDL3. These results indicate that postprandial HDL precursors may compete the binding of labeled HDL3. The metabolic consequences of HDL deficiency were analyzed. There is only a small number of HDL-like particles containing apoA-II, apoA-IV, apoE, and lecithin/cholesteryl acyl transferase. The C-apolipoproteins were normal in the proband. Due to the lack of HDL they can only associate with apoB-containing particles, where they may interfere with cellular uptake. Thus, pure apoA-I deficiency leads to a complex metabolic derangement.