Higher HDL cholesterol levels are associated with a lower incidence of chronic kidney disease in patients with type 2 diabetes

Background and aimsType 2 diabetes is one of the most important risk factor for the development of chronic kidney disease (CKD). Recently, it has been shown that lower high-density lipoprotein cholesterol (HDL-C) levels predicted the development of microalbuminuria in type 2 diabetic individuals. We have prospectively assessed the effects of plasma HDL-C levels on the incidence of CKD in a large cohort of type 2 diabetic patients.Methods and resultsWe followed 1987 type 2 diabetic outpatients with normal or near-normal kidney function at baseline for 5 years for the occurrence of incident CKD defined as glomerular filtration rate ≤ 60 mL/min/1.73 m² (as estimated by the abbreviated Modified Diet and Renal Disease Study equation). Cox proportional hazards models were used to examine the independent relationship between plasma HDL-C levels and incident CKD. During a median follow-up of 5 years, 11.8% (n = 234) of participants developed incident CKD. In multivariate regression analysis, higher HDL-C levels were associated with a lower risk of incident CKD (multiple-adjusted hazard ratio 0.76; 95% coefficient intervals 0.61–0.96; p = 0.025) independently of age, gender, body mass index, hypertension, smoking history, diabetes duration, hemoglobin A1c, plasma triglycerides, LDL-cholesterol, presence of diabetic retinopathy, baseline albuminuria, and current use of medications (anti-hypertensive, anti-platelet, lipid-lowering and hypoglycemic drugs).ConclusionsHigher plasma levels of HDL-C are associated with a lower risk of incident CKD in a large cohort of type 2 diabetic adults independently of numerous confounding factors.     

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men

AIMS/HYPOTHESIS: Insulin resistance is considered to be a risk factor for diabetes and coronary heart disease and is determined by the interaction between genetic and environmental factors. The SstI polymorphism in the apolipoprotein C-III gene has been related to the presence of different features of the insulin resistance syndrome. We investigate if this mutation influences the peripheral effect of insulin in healthy young subjects (30 men and 29 women) eating a westernised diet. METHODS: We investigated peripheral insulin sensitivity with the insulin suppression test after a 28-day westernised high-saturated fat diet (38% total fat and 18% saturated fat with 115 mg of cholesterol per 1000 Ju). RESULTS: Steady state plasma glucose values were lower in S1-S1 compared with S1-S2 men (p=0.018 by ANOVA), but not in women (p=0.723). CONCLUSION/INTERPRETATION: There was no difference between carriers and non-carriers of the S2 allele in relation to incidence and sensitivity; although on subgroup analysis there was an effect in men but not in women.     

Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth review

High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals.     

HDL cholesterol levels in patients with myocardial infarction and their families

The present study using a quartile distribution of myocardial infarction patients demonstrated that the first-degree relatives of the myocardial infarction patients with the lowest HDL cholesterol have similarly the lowest HDL cholesterol. Low HDL cholesterol among these relatives was not secondary to increased VLDL triglycerides, as it persisted when subjects with hyper VLDL triglycerides were excluded. Familial low HDL cholesterol could not be attributed to known environmental factors as their levels did not differ significantly between the groups compaired. There was a significant correlation between HDL cholesterol levels of the parents and that of their younger offspring. The correlation was not significant with the offspring aged 20 and over. It appeared that there was a familial trend in low HDL cholesterol levels, more apparent among the young offspring than among the adult offspring, who may possibly not share any more the parental environment for factors liable to influence HDL cholesterol. This finding is compatible with a hereditary trait.     

Atorvastatin increases HDL cholesterol in hypercholesterolemic patients. Evidence of a relationship with baseline HDL cholesterol

BACKGROUND AND AIM: It has been reported that atorvastatin increases high-density lipoprotein cholesterol (HDL-C) more in patients with low than in those with high baseline HDL-C levels. This may have a biological explanation, but also suggests a statistical artifact known as the regression to the mean. METHODS AND RESULTS: Atorvastatin 10 mg/day led to a 4% increase in HDL-C after two months in 67/121 patients with hypercholesterolemia (55%), who had lower baseline HDL-C levels than the patients in whom HDL-C did not increase. In the patients with baseline HDL-C below the median, HDL-C significantly increased whereas no change was observed in patients with baseline HDL-C above the median. The correlation coefficient between pre- and post-treatment HDL-C was 0.84, thus suggesting a regression to the mean. However, the regression artifact did not entirely explain the increase in HDL-C in patients with low baseline HDL-C or the lack of an increase in those with high baseline HDL-C. The adjusted mean increase was 5.4% in patients with low pretreatment HDL-C, and 2.4% in the patients with high pretreatment HDL-C. Multiple regression analysis with the changes in HDL-C as the dependent variable showed that baseline HDL-C and the changes in serum triglycerides independently contributed to the change in HDL-C levels. CONCLUSIONS: Atorvastatin 10 mg/day increases HDL-C more in patients with low pretreatment HDL-C levels, an effect that seems to be related to the hypotriglyceridemic activity of the drug.     

Serum HDL cholesterol values are associated with apoB-containing lipoprotein metabolism and triglyceride-body fat interrelation in young Japanese men

Serum levels of total cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein (apo) AI, ApoB, ApoE and body fat were measured in 226 fasting male Japanese college students aged 18 to 20 years. They were normolipidemic (total cholesterol: 169±31 mg/dl, triglyceride: 56±25 mg/dl) and their HDL cholesterol concentrations were high (61±13 mg/dl). An HDL cholesterol value <35 mg/dl was observed in only one student (0.4%). In contrast, 112 men (49.6%) had an HDL cholesterol level ≥60 mg/dl. Even in this normolipidemic group, as compared with students in a top HDL cholesterol tertile (HDL cholesterol; 75±9 mg/dl), students in a lower HDL cholesterol tertile (HDL cholesterol; 48±5 mg/dl) had significantly increased serum levels of LDL cholesterol (103±30 vs. 91±26 mg/dl), triglyceride (68±30 vs. 45±16 mg/dl) and apoB (83±20 vs 73±17 mg/dl). In addition, they had greater body mass index (23.2±3.6 vs. 20.6±2.5 kg/m²) and greater percent body fat (20.2±6.2 vs. 16.2±4.2%) determined using a bioelectrical impedance analyzer. HDL cholesterol levels were much more strongly related to triglyceride (r=−0.37) than was apoAI (r=−0.13). In stepwise multiple regression analysis in 184 nonsmokers, apoE, apoB and fat mass explained 21% of apoAI variability. Triglyceride in addition to these three parameters explained 41% of HDL cholesterol variability. These results suggest that serum levels of HDL cholesterol are associated with metabolism of apoB-containing lipoproteins as well as triglyceride-body fat interrelationship.     

Roles of scavenger receptor BI and APO A-I in selective uptake of HDL cholesterol by adrenal cells

Adrenal cells obtain cholesterol for steroid production via the selective uptake of cholesteryl ester (CE) from HDL particles, a process in which CE is transferred to the plasma membrane without degradation of the HDL particle. Although this process has been studied for two decades, only recently have the receptor and the HDL ligand been identified. Scavenger class B, type I, (SR-BI) is regulated by ACTH in adrenocortical cells in parallel with steroid production. Antibody to SR-BI blocks the uptake and utilization of HDL CE for steroid production in Y1-BS1 adrenal cells. The adrenal glands of SR-BI knockout mice are depleted in cholesterol providing complementary evidence that SR-BI is responsible for HDL CE accumulation in adrenal cells. SR-BI-mediated HDL CE selective uptake is a two-step process in which SR-BI first interacts with multiple sites in apoA-I with the amphipathic inverted alpha-helical repeat units of apoA-I serving as recognition motifs. This is followed by efficient CE transfer down its concentration gradient to the plasma membrane, a process requiring the extracellular domain of SR-BI. Other scavenger receptors bind HDL but do not afford the CE transfer step. Adrenal glands from apoA-I knockout mice lack CE stores, indicating that apoAI is essential for HDL selective uptake in vivo. ApoA-I knockout HDL particles bind normally to SR-BI but do not permit efficient CE transfer to the cell. These findings suggest that apoA-I has an important role in the transfer of HDL CE that goes beyond its function as a ligand for interaction with SR-BI.     

Blood HDL cholesterol levels influence association of alcohol intake with blood pressure in young men but not in middle-aged men

BACKGROUND: Both blood pressure and HDL cholesterol are affected by alcohol drinking. However, it has not been determined whether association of alcohol drinking with blood pressure varies depending on blood HDL level. METHODS: The subjects were male workers aged 20 to 29 year and 50 to 59 year (n = 21,301), representing young and middle ages, respectively, who had received periodic health checkup examinations. The subjects were divided into tertile groups by serum HDL level, and they were further divided into 3 subgroups based on the average daily alcohol intake [nondrinkers, light drinkers (<30 g of ethanol per day) and heavy drinkers (30 g or more of ethanol per day)]. Blood pressure and incidence of high blood pressure were compared among the 3 alcohol subgroups in each age and HDL group. RESULTS: In the lowest HDL tertile of 20 to 29-year-old subjects, systolic and diastolic blood pressure and incidences of high systolic and diastolic blood pressure were not significantly different among the 3 alcohol subgroups. In the middle and highest HDL tertiles of the twenties age group, systolic and diastolic blood pressure was significantly higher in heavy drinkers than in nondrinkers, and incidences of high systolic and diastolic blood pressure were significantly higher in drinkers than in nondrinkers. On the other hand, in all HDL tertile groups of 50 to 59-year-old subjects, blood pressure was significantly higher in light drinkers and heavy drinkers than in nondrinkers, and incidences of high systolic and diastolic blood pressure were significantly higher in drinkers than in nondrinkers. CONCLUSIONS: The results suggest that blood pressure of middle-aged men is elevated by alcohol drinking independently of blood HDL level and is more sensitive to drinking than is blood pressure of young men.     

Lifestyle determinants of HDL2- and HDL3-cholesterol levels in a hypercholesterolemic male population

In this cross-sectional study we investigated the role of lifestyle and other factors in determining serum HDL2- and HDL3-cholesterol levels among 82 dyslipidemic (total cholesterol minus HDL-cholesterol greater than or equal to 5.2 mmol/l) middle-aged participants of the Helsinki Heart Study. Alcohol consumption correlated positively with both subfractions of HDL-cholesterol, while leisure time physical activity had a significant correlation with the HDL3-subfraction only. HDL levels were lower in smokers than in non-smokers but the differences were not statistically significant. Using the multiple linear regression model, alcohol consumption emerged as the only significant factor influencing both HDL cholesterol subfraction levels. Leisure time physical activity had an independent contribution to HDL3-level, but lifestyle variables other than alcohol consumption did not contribute significantly to HDL2-cholesterol level. The model incorporating alcohol consumption, physical activity, smoking and relative body weight explained 13.4% of the variation in HDL2 and 17.5% in HDL3-cholesterol.     

Evaluation of the gene-age interactions in HDL cholesterol, LDL cholesterol, and triglyceride levels: the impact of the SORT1 polymorphism on LDL cholesterol levels is age dependent

Several genes that influence HDL-C, LDL-C, and triglyceride levels have been identified. The effects of genetic polymorphisms on lipid levels may be age dependent. We replicated 17 of these previously identified associations and then used cross-sectional and longitudinal analysis to investigate age-SNP interaction effects. The rs646776 SNP at the SORT1 locus showed an age interaction that was significant in cross-sectional analyses of 1350 individuals from Utah (p = 0.0003) and in 2977 individuals from the NHLBI Family Heart Study (p = 0.007) as well as in longitudinal analysis of a subsample of 1099 individuals from the Utah cohort that had been followed for over 20 years (p = 0.0001). The rs646776 genotype-specific difference in LDL-C levels was significantly greater for younger individuals than for older individuals. These findings may help elucidate the mode of action of the SORT1 gene and impact potential therapeutic interventions targeting this pathway.     

High levels of HDL cholesterol do not predict protection from cardiovascular disease in women

Elevated levels >or= 60 mg/dL) of high-density lipoprotein cholesterol have been felt to be protective for cardiovascular disease in women. While cardiovascular disease is the leading killer of women in the United States, this is underrecognized, and women's symptoms are often atypical, leading to underdiagnosis. When high-density lipoprotein cholesterol is high, physicians may underestimate a woman's cardiovascular risk. This tendency may have adverse health consequences.     

Increased levels of anti-oxidized low-density lipoprotein antibodies are associated with reduced levels of cholesterol in the general population

Autoantibodies against epitopes of oxidized low-density lipoprotein (LDL), initially shown in human sera, were later related with the atherosclerotic process, although recent studies have questioned this association. Moreover, their association with total cholesterol and plasma LDL, or with the other lipoproteins, is not clear. We studied the relation between the levels of autoantibodies to oxidized LDL and lipoproteins in a population of 400 subjects from the lower Guadalhorce area in Malaga, Spain. Anti-oxidized LDL antibodies were measured by enzyme-linked immunosorbent assay (ELISA), and total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and lipoprotein(a) [Lp(a)] were measured with commercial kits. Subjects who were positive for anti-oxidized LDL antibodies had significantly lower levels of total cholesterol (P <.01) and LDL cholesterol (P <.01). There was a negative correlation between titers of anti-oxidized LDL antibodies and levels of total cholesterol (P =.007) and LDL cholesterol (P =.024). This inverse relation between the levels of anti-oxidized LDL antibodies and the levels of total cholesterol and LDL cholesterol in a large population study, together with the discordances already published, suggests that the relation between anti-oxidized LDL antibodies, arteriosclerosis, and lipids is more complex than initially thought.     

A novel mutant, ApoA-I nichinan (Glu235-->0), is associated with low HDL cholesterol levels and decreased cholesterol efflux from cells.

A novel variant of apolipoprotein (apo) A-I associated with low high density lipoprotein (HDL) cholesterolemia has been identified in a Japanese family during screening for apoA-I variants by isoelectric focusing (IEF) gel analysis. ApoA-I (Glu235-->0) Nichinan was caused by a 3-bp deletion of nucleotides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma concentrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. There were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, plasma lecithin:cholesterol acyltransferase activity was normal. Functional consequences of the mutation were examined by expressing the mutated and wild-type proapoA-I cDNAs in Escherichia coli. Cholesterol efflux to recombinant proapoA-I Nichinan from mouse peritoneal macrophages loaded with [3H]cholesterol-labeled acetylated low density lipoprotein was decreased by 54% when compared that of normal recombinant proapoA-I. In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu235-->0) Nichinan induced a critical structural change in the carboxyl-terminal domain of apoA-I for cellular cholesterol efflux and increased the catabolism of apoA-I, resulting in low HDL cholesterol levels.     

Plasma lipids and geriatric assessment in a very aged population of south Italy

A very old population of a rural area of Southern Italy with a mean age of 87 years was investigated in order to evaluate serum lipid levels and their possible association with health conditions, such as mental status, social behaviour and physical autonomy. Among 101 subjects with ages above 82 years, 73 were investigated (participation rate 72%, 31 men and 42 women). Mean +/- SD serum cholesterol level was 199 +/- 36 and 210 +/- 40 mg/dl and mean serum triglyceride level was 107 +/- 43 and 148 +/- 74 mg/dl (P less than 0.05) in men and women, respectively. Mean high density lipoprotein (HDL)-cholesterol level was 49 mg/dl in both sexes. All subjects were investigated by means of geriatric and neuropsychometric scales such as Sandoz Clinical Assessment Geriatric Scale (SCAGS), Hachinski Dementia Scale (HDS), Plutchik Geriatric Rating Scale (PGRS) and Indexes of Activity of Daily Living (ADL). When subjects were divided into 3 groups according to levels of serum lipids, HDL-cholesterol appeared to be better related to clinical conditions than total serum cholesterol: the group with the higher HDL-cholesterol level presented better scores at all the administered assessment scales when compared to the groups with lower and modal levels (P range between less than 0.05 and less than 0.001). Subjects in the higher serum cholesterol group presented better scores at PGRS only (P less than 0.01). No relation was observed between serum total triglyceride levels and geriatric assessment scores.