The T allele of the hepatic lipase promoter variant C-480T is associated with increased fasting lipids and HDL and increased preprandial and postprandial LpCIII:B : European Atherosclerosis Research Study (EARS) II

The common C-480T transition in the hepatic lipase (HL) promoter has been shown to be associated with lower HL activity and increased high density lipoprotein (HDL) cholesterol. We examined the frequency and lipid associations of this HL polymorphism in 385 healthy, young (18- to 28-year-old) men whose fathers had had a premature myocardial infarction (designated cases) and 405 age-matched controls. These individuals were participants in the European Atherosclerosis Research Study II postprandial trial, who had been recruited from 11 European countries in 4 regions (the Baltic; United Kingdom; and central and southern Europe). Overall, the frequency of the T allele was 0.207 in controls and 0.244 in cases (P=0.08). The T allele was associated with higher fasting plasma total cholesterol (P<0.01), triglycerides (P<0.01), and HDL cholesterol (P<0.01). The strongest association was found with apolipoprotein (apo) A-I concentration, which was 10% higher in individuals homozygous for the T allele compared with those homozygous for the C allele (P<0.001). This polymorphism had no effect on the rise in plasma triglyceride levels after a fatty meal. However, before and after the fat load was ingested, levels of particles containing both apoC-III and apoB (LpC-III:B) were higher in carriers of the T allele, with homozygotes having 23% and 27% higher levels preprandially and postprandially, respectively, than those homozygous for the C allele (P<0.05). Thus, our results demonstrate that the C-480T polymorphism in the HL promoter is associated with alterations in plasma lipids and lipoproteins and the accumulation of atherogenic LpC-III:B particles

The genetics of the Lp antigen

The frequency distribution of the quantitative activity of the Lp antigen was found to be bimodal. It is hypothesized that a major genetic factor is operating to determine the modes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66117/1/j.1469-1809.1974.tb01991.x.pd

Low alanine aminotransferase and higher cardiovascular events in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes and associated with higher risk of cardiovascular disease. This study aimed to determine whether alanine aminotransferase (ALT) or gamma-glutamyltransferase (GGT), as markers of liver health and NAFLD, might predict cardiovascular events in this population. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (nonfatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years. Results ALT had a linear inverse relationship with the first cardiovascular event on study. After adjustment, for every standard deviation higher baseline ALT (13.2U/L), the risk of an event was 7%(95%CI 4–13, P=0.02) lower. Participants with ALT below and above the reference range 8–41 U/L for women and 9–59 U/L for men, had a hazard ratio of an event of 1.86(95%CI, 1.12–3.09) and 0.65(95%CI, 0.49–0.87), respectively (P=0.001). No relationship was found for GGT. Conclusions The data may indicate that in type 2 diabetes — associated with higher ALT due to prevalent NAFLD — lower ALT is a marker of hepatic or systemic frailty rather than health

Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of pre beta-high-density lipoproteins

High-density lipoproteins (HDLs) are considered anti-atherogenic because they mediate peripheral cell cholesterol transport to the liver for excretion and degradation. An important step in this reverse cholesterol-transport pathway is the uptake of cellular cholesterol by a specific subclass of small, lipid-poor apolipoprotein A-I particles designated pre beta-HDL. The two lipid-transfer proteins present in human plasma, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), have both been implicated in the formation of pre beta-HDL. In order to investigate the relative contribution of each of these proteins, we used transgenic mouse models. Comparisons were made between human CETP transgenic mice (huCETPtg), human PLTP transgenic mice (huPLTPtg) and mice transgenic for both lipid-transfer proteins (huCETPtg/huPLTPtg). These animals showed elevated plasma levels of CETP activity, PLTP activity or both activities, respectively. We evaluated the generation of pre beta-HDL in mouse plasma by immunoblotting and crossed immuno-electrophoresis. Generation of pre beta-HDL was equal in huCETPtg and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice, pre beta-HDL generation was 3-fold higher than in plasma from either wild-type or huCETPtg mice. Our findings demonstrate that, of the two plasma lipid-transfer proteins, PLTP rather than CETP is responsible for the generation of pre beta-HDL. These data support the hypothesis of a role for PLTP in the initial stage of reverse cholesterol transport

Studies on the heterogeneity of human serum Lp lipoproteins and on the occurrence of double Lp lipoprotein variants

Lp lipoproteins have been prepared by a mild method from the serum of a large number of individuals. Approximately 25% of the individuals tested showed the presence of a double Lp peak in analytical ultracentrifuge diagrams. These double peaks were designated Lp(a)-1 and Lp(a)-2 to distinguish them from the single Lp(a) peak. The mean viscosity-corrected sedimentation coefficient, S 1.004, 20 C and density of the single Lp(a) peak were 15.8±1.8 s ( n =32) and 1.076±0.01 g/ml, of the Lp(a)-1 peak were 13.5±1.1 s ( n =14) and 1.064±0.007 g/ml, and of the Lp(a)-2 peak were 16.8±1.7 s ( n =14) and 1.074±0.009 g/ml. Absorption tests using a double and single Lp preparation showed that both Lp peaks in the double variants possess Lp(a) specificity. Evidence is lacking as yet for individual specificities for either Lp(a)-1 or Lp(a)-2. Interand intra-individual heterogeneity among Lp lipoproteins is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44186/1/10528_2004_Article_BF00485737.pd

Effects of Fenofibrate Treatment on Cardiovascular Disease Risk in 9,795 Individuals With Type 2 Diabetes and Various Components of the Metabolic Syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

OBJECTIVE—We explored whether cardiovascular disease (CVD) risk and the effects of fenofibrate differed in subjects with and without metabolic syndrome and according to various features of metabolic syndrome defined by the Adult Treatment Panel III (ATP III) in subjects with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Effects of Fenofibrate Treatment on Cardiovascular Disease Risk in 9,795 Individuals With Type 2 Diabetes and Various Components of the Metabolic Syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

OBJECTIVE—We explored whether cardiovascular disease (CVD) risk and the effects of fenofibrate differed in subjects with and without metabolic syndrome and according to various features of metabolic syndrome defined by the Adult Treatment Panel III (ATP III) in subjects with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5 years. Results Over 5 years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p70 U/L, compared with GGT ≤70 U/L, had HR 1.82 (1.48−2.24), p70 U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. Conclusions As in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship 4 for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes