Christian Ehnholm

Serum Total Cholesterol, Apolipoprotein E {FC12}e4 Allele, and Alzheimer’s Disease

The σ4 allele of the apolipoprotein E (apoE) is associated with Alzheimer’s disease (AD) and also with elevated serum total cholesterol and low-density lipoprotein levels. However, the interrelationships between apoE genotype, plasma cholesterol levels and AD risk have been studied very little. We examined the possible role of serum total cholesterol in the pathogenesis of AD in a population-based sample of 444 men, aged 70–89 years, who were survivors of the Finnish cohorts of the Seven Countries Study. Previous high serum cholesterol level (mean level ≥6.5 mmol/l) was a significant predictor of the prevalence of AD (odds ratio = 3.1; 95% confidence interval = 1.2, 8.5) after controlling for age and the presence of apoE σ4 allele. In men who subsequently developed AD the cholesterol level decreased before the clinical manifestations of AD. We conclude that high serum total cholesterol may be an independent risk factor for AD and some of the effect of the apoE σ4 allele on risk of AD might be mediated through high serum cholesterol.

Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study

The relation of serum total homocysteine and lipoprotein(a) (Lp(a)) with the incidence of atherosclerotic disease was investigated among 7424 men and women aged 40-64 years free of atherosclerotic disease at baseline in 1977. During the 9-year follow-up, 134 male and 131 female cases with either myocardial infarction or stroke were identified. For each case a control subject was selected belonging to the same sex and 5-year age group. Serum samples collected in 1977 were stored at -20 degrees C and analyzed in 1991. The mean serum homocysteine concentration of male cases and controls was 9.99 mumol/l and 9.82 mumol/l at baseline and that of female cases and controls 9.58 mumol/l and 9.24 mumol/l, respectively. The median serum Lp(a) concentration of male cases and controls was 73 mg/l and 108 mg/l and that of female cases and controls 113 mg/l and 91 mg/l, respectively. The differences between cases and controls were not statistically significant. There was also no significant association between either homocysteine or Lp(a) and atherosclerotic disease, myocardial infarction or stroke in logistic regression analyses. The odds ratios varied from 1.00 to 1.26 for homocysteine and from 0.81 to 1.06 for Lp(a). The results of this prospective population-based study do not support the hypotheses that serum homocysteine or Lp(a) are risk factors for atherosclerotic disease. The lack of association between serum homocysteine and atherosclerotic disease may be due to the exceptionally low gene frequency predisposing to homocysteinemia in Finland.

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. RESEARCH DESIGN AND METHODS—The prevalence of metabolic syndrome and its features was calculated. Cox proportional models adjusted for age, sex, CVD status, and baseline A1C levels were used to determine the independent contributions of metabolic syndrome features to total CVD event rates and the effects of fenofibrate. RESULTS—More than 80% of FIELD participants met the ATP III criteria for metabolic syndrome. Each ATP III feature of metabolic syndrome, apart from increased waist circumference, increased the absolute risk of CVD events over 5 years by at least 3%. Those with marked dyslipidemia (elevated triglycerides ≥2.3 mmol/l and low HDL cholesterol) were at the highest risk of CVD (17.8% over 5 years). Fenofibrate significantly reduced CVD events in those with low HDL cholesterol or hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia in whom a 27% relative risk reduction (95% CI 9–42, P = 0.005; number needed to treat = 23) was observed. Subjects with no prior CVD had greater risk reductions than the entire group. CONCLUSIONS—Metabolic syndrome components identify higher CVD risk in individuals with type 2 diabetes, so the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia.

Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype.

Relationship between the efficiency of cholesterol absorption and apolipoprotein E (apoE) phenotype was studied in a random sample of middle-aged Finnish men. Subjects that were either heterozygous or homozygous for the allele epsilon 2 absorbed less and synthesized more cholesterol than those with the phenotype E4/3 and E4/4, the values for the individuals with the most frequent phenotype E3/3 (56% of the population sample) falling in between. Among the whole study group, the sum of the subscripts of apoE phenotype (e.g., E2/3 = 5) was correlated positively with the fractional absorption of cholesterol (r = 0.40; P less than 0.05) and negatively with the serum level of lathosterol, a cholesterol precursor sterol reflecting the activity of cholesterol synthesis (r = -0.48; P less than 0.01). Thus, apoE polymorphism appears to affect the efficiency of cholesterol absorption and may by this mechanism contribute to the variation in plasma total and low density lipoprotein cholesterol concentration.

Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants

To prospectively assess the role of lipoprotein(a) (Lp(a)) as a risk factor for coronary heart disease, the serum Lp(a) concentration was determined in 130 subjects without coronary events and in 138 patients in whom coronary events (i.e. fatal and non-fatal myocardial infarction and cardiac death) occurred during the 5-year Helsinki Heart Study. The participants of this study (n = 4081) were 40-55-year-old men who were devoid of coronary heart disease at the beginning of the trial; half were randomized to gemfibrozil and the other half to placebo treatment. In patients with coronary events blood pressure and total cholesterol were not significant predictors of the events but their LDL cholesterol was higher than compared to the control group in this cohort (P less than 0.05). The serum Lp(a) concentration was determined by immunoassay from samples obtained 3 months after the beginning of the trial and then stored at -20 degrees C until analysed. Studies on the effect of long term storage at -20 degrees C on serum Lp(a) levels did not reveal significant changes in Lp(a) concentration in sera stored for up to 8.5 years. The distribution of Lp(a) concentrations were similar in the men with coronary events and the controls. Nor did the mean or median levels of Lp(a) differ significantly between the two groups. Measurements of Lp(a) levels in fresh samples using 2 different immunoassays did not reveal any significant difference between the participants who had survived a myocardial infarction or participants without cardiac events. Thus, we conclude that in the Helsinki Heart Study cohort the serum Lp(a) level was not a predictor of future coronary events.

Familial combined hyperlipidemia is associated with upstream transcription factor 1 ( USF1 )

Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both, is observed in about 20% of individuals with premature coronary heart disease. We previously identified a locus linked to FCHL on 1q21–q23 in Finnish families with the disease. This region has also been linked to FCHL in families from other populations as well as to type 2 diabetes mellitus. These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice, is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism.

The effects of fenofibrate treatment on cardiovascular disease risk in 9795 people with type 2 diabetes and various components of the metabolic syndrome: the 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. RESEARCH DESIGN AND METHODS—The prevalence of metabolic syndrome and its features was calculated. Cox proportional models adjusted for age, sex, CVD status, and baseline A1C levels were used to determine the independent contributions of metabolic syndrome features to total CVD event rates and the effects of fenofibrate. RESULTS—More than 80% of FIELD participants met the ATP III criteria for metabolic syndrome. Each ATP III feature of metabolic syndrome, apart from increased waist circumference, increased the absolute risk of CVD events over 5 years by at least 3%. Those with marked dyslipidemia (elevated triglycerides ≥2.3 mmol/l and low HDL cholesterol) were at the highest risk of CVD (17.8% over 5 years). Fenofibrate significantly reduced CVD events in those with low HDL cholesterol or hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia in whom a 27% relative risk reduction (95% CI 9–42, P = 0.005; number needed to treat = 23) was observed. Subjects with no prior CVD had greater risk reductions than the entire group. CONCLUSIONS—Metabolic syndrome components identify higher CVD risk in individuals with type 2 diabetes, so the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia.

An immunochemical method for the selective measurement of two triglyceride lipases in human postheparin plasma

A new method for the selective measurement of postheparin plasma lipoprotein lipase and hepatic lipase is described and validated. The activity of lipoprotein lipase is determined at 0.1 M NaCl after removal of hepatic lipase by specific antiserum, and the hepatic lipase is assayed in a medium containing 1.0 M NaCl but no additional serum. The optimal conditions for the determination of the two postheparin plasma triglyceride hydrolases were shown to be similar to those described for the purified enzymes. The new assay methods are simple, accurate and highly specific for the two lipase activities. VLDL and LDL do not interfere with the measurement, making the methods suitable for studies of patients with various hyperlipidemias. More than 90% of the total triglyceride hydrolase activity in postheparin plasma is precipitated with antisera raised against purified human postheparin plasma hepatic lipase and bovine milk lipoprotein lipase. The time and dose dependence of the two postheparin plasma lipase responses differ. For optimal activity of both enzymes, plasma taken 15 minutes after intravenous administration of 100 I.U./kg of heparin, should be used. The activity of postheparin plasma lipoprotein lipase and hepatic lipase in 12 young, healthy males is reported.

Effect of moderate physical exercise on serum lipoproteins. A controlled clinical trial with special reference to serum high-density lipoproteins.

A controlled trial is reported on the effects of mild-to-moderate physical activity on serum lipoproteins. After two baseline examinations 100 asymptomatic middle-aged men were randomly assigned to exercise and control groups. The exercise group participated in a 4-month exercise program that consisted of 3-4 weekly sessions. The control group was advised to maintain their previous exercise habits. The success of the program was corroborated by the increase in VO2 in the training group, but not in the control group. Serum triglycerides decreased from 1.54 +/- 0.10 to 1.27 +/- 0.08 mmol/1 (p less than 0.001) and high-density lipoprotein (HDL) cholesterol increased from 1.27 +/- 0.04 to 1.41 +/- 0.04 mmol/1 (p less than 0.01) in the exercise group during the trial. No change was seen in the control group. As the concentration of apolipoprotein AI stayed constant in both groups, the ratio HDL cholesterol/apolipoprotein AI increased only in the exercise group. The level of low-density lipoprotein (LDL) cholesterol and apolipoprotein AII decreased in both groups during the trial. The alterations in serum triglycerides and HDL cholesterol in the exercise group were not dependent on weight reduction; similar changes were also seen in subjects with constant body weight during the intervention.

The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns.

The human paraoxonase gene (HUMPONA) is codominantly expressed as alleles A and G. The A allele codes for glutamine (A genotype) and the G allele for arginine (B genotype) at position 191 of the paraoxonase enzyme. This genetic polymorphism has been suggested to be associated with the predisposition to coronary artery disease (CAD). We investigated the frequency of paraoxonase A and G alleles in 380 well-characterized CAD patients and in 169 controls. The most common genotype in both the patients with CAD (211/380) and in healthy Finnish individuals (87/169) was AA (Gln/Gln). The heterozygous AM (Gln/Arg) genotype was present in 140 of the patients and in 75 controls. The frequency of the A allele was 0.74 in both patients and controls. The genotype distribution between the two groups did not differ (P = 0.12, chi2 test). The genotype distributions were also similar to those reported earlier in other caucasoid populations. In conclusion, we found no association between the Gln-Arg 191 polymorphism of the human paraoxonase gene and coronary artery disease in Finns.