Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.     

Plasma fasting and nonfasting triglycerides and high-density lipoprotein cholesterol in atherosclerotic stroke: Different profiles according to low-density lipoprotein cholesterol

Although low-density lipoprotein cholesterol (LDL-C) is the main lipid target for cardiovascular risk reduction, recent studies suggest that other lipid indicies are also associated with vascular events. We hypothesized that the association of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) with atherosclerotic stroke (AS) differs depending on LDL-C levels. Data prospectively collected on subjects admitted with acute ischemic stroke to a university medical center were analyzed. We divided the patients into AS and non-atherosclerotic stroke (NAS) groups and independent association of lipid parameters and genetic influences of apolipoprotein A5 (ApoA5) polymorphisms with AS were evaluated. Of 268 patients, 160 (59.7%) were classified with AS and 108 (40.3%) were classified with NAS. Vascular risk factors were more prevalent in AS patients than in those with NAS; additionally, AS patients' anthropometric indexes and laboratory findings showed that they were prone to atherosclerosis. AS was independently associated with fasting TG (OR per 10 mg/dL increase, 1.38; 95% CI, 1.16–1.64; OR for highest vs. lowest tertile, 12.85; 95% CI, 3.31–49.85), HDL-C (OR per 10 mg/dL increase, 0.61; 95% CI, 0.42–0.88; OR for lowest vs. highest tertile, 4.28; 95% CI, 1.16–15.86), and nonfasting TG (OR per 10 10 mg/dL increase, 1.25; 95% CI, 1.11–1.42; OR for highest vs. lowest tertile, 8.20; 95% CI, 1.98–33.88) only among patients with LDL <100 mg/dL. No interaction was observed between fasting and nonfasting TG and ApoA5 polymorphisms. In conclusion, fasting and nonfasting TG and HDL-C were associated with AS only when patients had low levels of LDL-C. Non-LDL-C may have an additional role in addition to the LDL-C levels in AS development.     

Associations between high-density lipoprotein cholesterol and both stroke and coronary heart disease in the Asia Pacific region.

BACKGROUND: The inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) is well established. Questions remain about the association between HDL cholesterol and stroke, particularly for stroke subtypes. METHODS AND RESULTS: Cox survival models were applied to individual participant data from 25 cohort studies (about 80 000 subjects), with a median of 6.8 years follow-up. After adjustment for age and regression dilution, hazard ratios (95% confidence intervals) for a 1 standard deviation (SD) lower level of HDL cholesterol (0.4 mmol/L) were: for CHD events, 1.39 (1.22-1.57); for ischaemic stroke, 0.90 (0.75-1.07), and for haemorrhagic stroke, 0.89 (0.74-1.07). As total cholesterol (TC) increased relative to HDL cholesterol, the risk of CHD increased, the risk of ischaemic stroke was unchanged but the risk of haemorrhagic stroke decreased. A 1 SD increase in TC/HDL cholesterol (1.63 units) was associated with a 27% decrease in the risk of haemorrhagic stroke (95% confidence interval, 7-44%). CONCLUSION: There is clear evidence of potential benefit for CHD of increases in HDL cholesterol and decreases in TC relative to HDL cholesterol, but no evidence of an association between either HDL cholesterol or TC/HDL cholesterol and ischaemic stroke. Increasing HDL cholesterol relative to TC may increase the risk of haemorrhagic stroke.     

Association between the severity of obstructive sleep apnea and the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol

The positive association between the ratio of serum low-density lipoprotein cholesterol (LDL-C) to serum high-density lipoprotein cholesterol (HDL-C) and cardiovascular events has recently been receiving much attention. However, the association between the severity of obstructive sleep apnea (OSA) and this ratio has not yet been investigated. Accordingly, we sought to clarify this association and the effect of continuous positive airway pressure (CPAP) therapy on the ratio. We performed polysomnography and LDL-C/HDL-C measurements in 215 patients who were suspected of having OSA. Furthermore, LDL-C/HDL-C was again evaluated 6 months after polysomnography in 30 OSA patients for whom CPAP therapy was initiated and continued, and in 11 age- and sex-matched OSA patients for whom the therapy could not be initiated. The LDL-C/HDL-C correlated positively with apnea-hypopnea index (ρ = 0.28, P < .001) and negatively with the lowest arterial oxyhemoglobin saturation (ρ = -0.30, P < .001). Multivariate regression analysis revealed that ln apnea-hypopnea index (or ln lowest arterial oxyhemoglobin saturation) was independently associated with LDL-C/HDL-C. The LDL-C/HDL-C decreased after 6 months in the CPAP group (2.29 ± 0.67 to 2.11 ± 0.74, P = .02), whereas it did not change in the non-CPAP group (2.65 ± 0.82 to 2.62 ± 0.66, P = .81). The severity of OSA was independently associated with LDL-C/HDL-C, and LDL-C/HDL-C was significantly reduced at 6 months after CPAP therapy. These findings suggest that LDL-C/HDL-C increases in proportion to the severity of OSA, which may contribute partly to an increased risk for cardiovascular events in OSA patients.     

Addressing cardiovascular risk beyond low-density lipoprotein cholesterol: the high-density lipoprotein cholesterol story

A large body of evidence from numerous, well-controlled, randomized trials demonstrates that treatment with statins reduce morbidity and mortality from cardiovascular disease (CVD). Although these observations are important and have resulted in the adoption of standard of care approaches to the management of CVD risk, they do not tell the whole story. When reviewing these landmark trials it is clear that on average two thirds of events are not prevented. This leads to the evaluation of risk beyond low-density lipoprotein cholesterol. This review focuses on the association of low high-density lipoprotein (HDL) cholesterol and increased CVD risk, the published trials that study the effect of raising HDL cholesterol on CVD outcomes, and the novel approaches toward HDL cholesterol raising that are on the horizon.     

Baseline levels of low-density lipoprotein cholesterol and lipoprotein (a) and the AvaII polymorphism of the low-density lipoprotein receptor gene influence the response of low-density lipoprotein cholesterol to pravastatin treatment

To investigate some individual and genetic factors that may influence the response of low-density lipoprotein cholesterol (LDL-C) to pravastatin treatment, we recruited 440 subjects with hypercholesterolemia (mean age, 57 years; 43% men) from 21 primary health care centers-outpatient clinics into a prospective, multicentered intervention trial. Pravastatin (20 mg/d) was prescribed for 16 weeks. The main outcome was the percentage variation in LDL-C concentration relative to baseline. Blood analyses and genotyping were performed centrally. The results indicated that LDL-C decreased by 20.5% (range, +21% to -66%) after pravastatin treatment. Baseline concentration of LDL-C (the higher the concentration, the greater the decrease), lipoprotein (a) levels (the lower the concentration, the greater the response), and Ava II polymorphism of the LDL-receptor gene significantly influenced the hypolipemic effect ( P < .001, P = .014, and P = .004, respectively). These 3 factors combined explained 10.6% of the variation in LDL-C response. Age, sex, smoking habit, alcohol consumption, body mass index, and apolipoprotein E genotype had no significant effect on response. We conclude that baseline levels of LDL-C and lipoprotein (a) together with the Ava II polymorphism of the LDL-receptor gene have a significant influence on the LDL-C response to pravastatin treatment in patients monitored in a standard primary health care outpatient clinic setting.     

Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol.

OBJECTIVES: We sought to evaluate the significance of high-density lipoprotein cholesterol (HDL-C) in the context of low low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Earlier studies support an inverse correlation between circulating HDL-C and coronary risk in patients with normal or elevated LDL-C. METHODS: This study involved 4,188 patients attending the Palo Alto Veterans Administration Medical Center or affiliated clinics with LDL-C levels below 60 mg/dl. Outcomes were examined 1 year after the index LDL-C date. The combined primary end point was myocardial injury or hospitalization from ischemic heart disease. The secondary end point was all-cause mortality. RESULTS: Mean HDL-C levels (mg/dl) by quartile (Q) were: Q1 28 mg/dl, Q2 36 mg/dl, Q3 43 mg/dl, and Q4 63 mg/dl. The rate of myocardial injury or hospitalization for ischemic heart disease showed an inverse relationship to HDL-C (adjusted odds ratios: Q1 1.59 [95% confidence interval (CI) 1.16 to 2.19], Q2 1.39 [95% CI 1.01 to 1.92], Q3 1.33 [95% CI 0.96 to 1.84], and Q4 reference) that persisted regardless of statin use or recent myocardial injury. Analyzing HDL-C as a continuous variable revealed a 10% [95% CI 3% to 17%] increase in the combined end point of myocardial injury or hospitalization for ischemic heart disease for every 10-mg/dl decrease in HDL-C. The unadjusted and adjusted incidence of all-cause mortality demonstrated a U-shaped relationship to HDL-C (adjusted odds ratios: Q1 1.13 [95% CI 0.79 to 1.62], Q2 0.97 [95% CI 0.67 to 1.40], Q3 0.74 [95% CI 0.50 to 1.09], and Q4 reference). CONCLUSIONS: The inverse relationship between HDL-C and coronary risk persists even among patients with LDL-C below 60 mg/dl, although a U-shaped relationship is observed between HDL-C and all-cause mortality.     

Effect of low-density lipoprotein apheresis on inflammatory and noninflammatory high-density lipoprotein cholesterol

Low-density lipoprotein (LDL) apheresis, a treatment for familial hypercholesterolemia, significantly decreases LDL cholesterol and inflammatory markers such as C-reactive protein, CD40 ligand, and tissue factor. LDL apheresis also decreases high-density lipoprotein (HDL) cholesterol, which might be considered therapeutically counterproductive because HDL is known to be anti-inflammatory. However, recent studies have shown that HDL also possesses proinflammatory properties, as seen in its ability to alter LDL-induced monocyte chemotactic activity. We examined the acute effects of LDL apheresis on inflammatory HDL activity in 13 patients with familial hypercholesterolemia and cardiovascular disease who had been receiving bi-weekly LDL apheresis treatments. Immediately before and immediately after treatment, each patient's plasma was collected for analysis of inflammatory HDL and full lipid profile. LDL apheresis reduced LDL by 52% (from 208 +/- 89 to 99 +/- 48 mg/dl, p <0.002), and HDL decreased by 16% (49 +/- 15 to 41 +/- 13 mg/dl, p <0.003). At the same time, inflammatory HDL activity (in migrated monocytes per high-power field) decreased from 22 +/- 4 to 14 +/- 2, a 37% acute reduction (p <0.003). Moreover, inflammatory HDL before HDL apheresis was highly correlated with its acute reduction (r(s) = 0.85, p <0.001). In conclusion, our findings indicate that, in addition to decreasing LDL, LDL apheresis also decreases inflammatory HDL. The clinical significance of reducing inflammatory HDL is currently unknown, and further research is needed to examine its potential benefit for cardiovascular disease.     

Small dense low-density lipoprotein cholesterol concentration and carotid atherosclerosis

Low-density lipoprotein cholesterol (LDL-C) and the small dense LDL (SdLDL) phenotype are both predictors for ischemic heart disease. We examined whether cholesterol of SdLDL (SdLDL-C) is more closely associated with carotid artery intima-media thickness (CA-IMT), a surrogate measure of atherosclerosis, than LDL-C and other lipid parameters. The subjects were 326 consecutive participants including those with dyslipidemia, diabetes mellitus, hypertension, chronic kidney disease, and smokers. SdLDL-C was quantified by a newly developed precipitation method, and CA-IMT by high-resolution B-mode ultrasound. In univariate analysis, CA-IMT was most strongly correlated with SdLDL-C (Spearman's r=0.441, P<0.001), followed by apolipoprotein (apo) B, LDL-C, non-high-density lipoprotein cholesterol (Non-HDL-C), and plasma triglycerides (TG). HDL-C and apo A-I correlated inversely with CA-IMT. Non-lipid variables that were associated with CA-IMT were age, sex, presence of diabetes mellitus, presence of hypertension, estimate glomerular filtration rate (eGFR), and C-reactive protein (CRP). Even after adjustment for age, sex, diabetes mellitus, hypertension, smoking, eGFR and CRP, the positive association of CA-IMT with SdLDL-C remained significant, and again stronger than the associations with others lipid parameters. Further analyses revealed that the level of SdLDL-C was elevated in subgroups of the subjects including men, older subjects, smokers, those with higher CRP levels, those with diabetes mellitus, and hypertensive patients. These results indicate that SdLDL-C was the best marker of carotid atherosclerosis among the lipid parameters tested, and suggest that quantitative measurement of SdLDL-C gives useful information in the risk assessment for atherosclerotic disease.     

Novel nonstatin strategies to lower low-density lipoprotein cholesterol

There remains an unmet need to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients who are maximized on current therapy or intolerant to statins. Several novel agents have been developed to lower LDL-C, either as monotherapy or in combination with statins. These novel therapies include squalene synthase inhibitors, microsomal triglyceride transfer protein inhibitors, and antisense apolipoprotein B. Although each of these novel therapies effectively lowers LDL-C, challenges remain in the clinical development to assess long-term safety.     

Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease

Recent clinical trials in patients with coronary artery disease (CAD) provide evidence that low-density lipoprotein cholesterol (LDL-C) levels should be lowered even further to prevent recurrent CAD. However, despite more aggressive interventions for lowering LDL-C levels, the majority of CAD events go undeterred, perhaps related to the fact that intervention was not started earlier in life or that LDL-C levels represent an incomplete picture of atherogenic potential. Nevertheless, LDL-C remains the contemporary standard as the primary goal for aggressive LDL reduction. If triglycerides are >200 mg/dl, the measurement of non-high-density lipoprotein cholesterol (HDL-C) is recommended. Measurement of apolipoprotein (apo)B has been shown in nearly all studies to outperform LDL-C and non-HDL-C as a predictor of CAD events and as an index of residual CAD risk. This is because apoB reflects the total number of atherogenic apoB-containing lipoproteins and is a superior predictor of the number of low-density lipoprotein particles (LDL-P). Estimates of LDL-P and size can also be made by nuclear magnetic resonance spectroscopy, density gradient ultracentrifugation, and gradient gel electrophoresis. Although a number of studies show that such estimates predict CAD, LDL-P, and size often accompany low HDL-C and high triglyceride levels, and therefore such additional lipoprotein testing has not been recommended for routine screening and follow-up. Because apoB is a superior predictor of LDL-P, we recommend that apoB and the apoB/apoA-I ratio be determined after measurement of LDL-C, non-HDL-C, and the ratio of total cholesterol/HDL-C to better predict CAD and assess efficacy of treatment.     

成人血低密度脂蛋白胆固醇水平升高及代谢综合征与卒中相关性研究

目的 分析血LDL-C水平升高伴或不伴代谢综合征(MS)对中国成人卒中发病的影响.方法 将2002年中国居民营养与健康状况调查中42 626例25～75岁成人,根据LDL-C水平分为<2.00 mmol/L组、2.00～2.50 mmol/L组、2.51～3.31 mmol/L组、≥3.32 mmol/L组.MS采用2005年国际糖尿病联盟的诊断定义.比较各组MS和卒中的患病率,以及伴或不伴MS时致卒中危险性.结果 (1)MS和卒中的患病率均随LDL-C水平升高而增加.与LDL-C<2.00 mmoL/L组相比,LDL-C≥3.32 mmol/L组MS和卒中的患病率分别增加了2.5倍(7.9%比20.1%)和4.2倍(0.5%比2.1%),P值均<0.01.(2)在同-LDL-C水平组,卒中患病率均为伴MS亚组高于不伴MS亚组,P值均<0.01.(3)logistic回归分析调整年龄、性别、吸烟后显示,LDL-C、MS与卒中发生正相关,致卒中的相对危险度(OR值)分别为2.35和3.15,P值均<0.0001.(4)与LDL-C<2.00mmol/L不伴MS亚组相比,LDL-C 2.00～2.50、2.51～3.31和≥3.32 mmol/L不伴MS各亚组发生卒中的OR值分别为1.03、1.89和2.08.LDL-C水平相似的伴MS亚组与不伴MS亚组相比,致卒中危险增加约3～4倍(OR值分别为4.38、5.23和6.15),P值均<0.0001.结论 LDL-C水平升高和MS均为卒中发生的独立危险因素,当二者并存时这种危险将进一步增加.对二者同时进行干预治疗对防治卒中十分重要.