On the readiness of physicians for pharmacogenomics testing: an empirical assessment.

This paper aims to explore the determinants of adoption of pharmacogenomics (PGx) testing by clinicians, and to assess whether this adoption differs with regard to area of specialization. Data were collected from a web-based survey among physicians in Québec (Canada). Our results highlighted that they perceived several benefits and had favorable attitudes toward PGx tests, but felt unprepared to use them. Results also show that practice specialties matter. Notably, being a family physician decreases the likelihood of adopting PGx tests. This might be explained by the fact that they perceived fewer benefits, used fewer sources of information, and received less training in PGx than their colleagues in other specialties. This is of particular concern given that family physicians are at the forefront of the healthcare system. Overcoming two knowledge barriers, that is, lack of information and clinical guidelines on PGx tests, might enhance physicians' readiness to adopt PGx testing.

Evaluation of an inference-based approach to treating obsessive-compulsive disorder.

This study evaluated an inference-based approach (IBA) to the treatment of obsessive-compulsive disorder (OCD) by comparing its efficacy with a treatment based on the cognitive appraisal model (CAM) and exposure and response prevention (ERP). IBA considers initial intrusions in OCD (e.g. "Maybe the door is open", "My hands could be dirty") as idiosyncratic inferences about possible states of affairs arrived at through inductive reasoning. In IBA such primary inferences represent the starting point of obsessional doubt, and the reasoning maintaining the doubt forms the focus for therapy. This is unlike CAM, which regards appraisals of intrusions as the maintaining factors in OCD. Fifty-four OCD participants, of whom 44 completed, were randomly allocated to CAM, ERP or IBA. After 20 weeks of treatment all groups showed a significant reduction in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Padua Inventory. Participants with high levels of obsessional conviction showed greater benefit from IBA than CAM. Appraisals of intrusions changed in all treatment conditions. Strength of primary inference was not correlated with symptom measures except in the case of strong obsessional conviction. Strength of primary inference correlated significantly with the Y-BOCS insight item. Treatment matching for high and low conviction levels to IBA and CAM, respectively, may optimize therapy outcome.

Interaction structure of husbands' and wives' disclosure of marital conflict to their respective best friend.

Husbands' and wives' conversations with their respective best friend (N = 88) were coded to assess spouses' and friends' mutual influence in regulating support and interference with regard to spouses' marriage and to assess the impact of spouses' sex and marital satisfaction on the conversation processes. Dissatisfied husbands and wives expressed fewer positive and more negative views of marriage than satisfied husbands and wives and the friends in the 2 groups. There were no group and no sex differences in interference sequences. There were group and sex differences in support sequences. Friends of satisfied wives and those of dissatisfied husbands were more likely than satisfied wives and dissatisfied husbands to get support for their positive views of marriage. The findings are discussed with reference to the specific effects of outsiders' support and interference on satisfied and dissatisfied spouses.

The effects of cholesterol uptake from high-density lipoprotein subfractions on biliary sterol secretion in rats with essential fatty-acid deficiency.

High-density lipoprotein (HDL) participates in the transfer of cholesterol to the liver, in which it is subsequently excreted into bile as bile acid and cholesterol. In this study, the effect of essential fatty-acid (EFA) deficiency on cholesterol contribution from HDL subfractions to bile was investigated. Rats that were rendered EFA-deficient over 4 weeks displayed changes in their plasma HDL subfractions and liver tissue fatty acids. Plasma linoleic (18:2n6), linolenic (18:3n3,) and arachidonic (20:4n6) acids decreased, whereas palmitoleic (16:1n7) and eicosatrienoic (20:3n9) acids increased. EFA deficiency was confirmed by an elevation of the 20:3(n-9)/20:4(n-6) index. To examine the hepatic handling of lipoprotein-derived cholesterol, HDL2 and HDL3 from donor rats were isolated, labeled with [14C]-cholesterol, and injected iv into EFA-deficient and normal rats with a bile fistula. In HDL subfractions from control rats, no significant variations were noted in the specific activity of cholesterol output in both groups of EFA recipient rats; however, the output of biliary bile acids was significantly decreased in EFA-deficient rats following the administration of labeled HDL3. In HDL2 and HDL3 originating from EFA-deficient rats, a decrease in the specific activity of both biliary cholesterol and bile acid output was recorded in EFA-deficient rats. Concomitant with the defective HDL2- and HDL3-[14C] cholesterol translocation into bile of EFA-deficient rats, increased hepatic very-low-density lipoprotein (VLDL)-[14C] cholesterol secretion was observed in vivo. HDL2 and HDL3 particles, derived from EFA-deficient rats, had an altered composition including a depletion in apo A-I and an enrichment in apo E isoforms, which are the the two major HDL apolipoproteins involved in the delivery of cholesterol to the liver. Taken together, these results show that normal EFA status is necessary for efficient HDL-cholesterol processing by the liver.

Apolipoprotein E polymorphism in a French Canadian population of northeastern Quebec: allele frequencies and effects on blood lipid and lipoprotein levels.

Apolipoprotein E phenotypes and plasma lipid and lipoprotein levels were determined in 435 individuals (233 men, 202 women) of French Canadian descent living in northeastern Quebec. This region is known for its high frequency of mutant genes responsible for rare genetic disorders. Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were adjusted for age, height, weight, body mass index (BMI), and waist circumference using regressions performed separately in men and in premenopausal and postmenopausal women. The APOE allele frequencies in this population-based sample were 0.137, 0.749, and 0.114 for the *2, *3, and *4 alleles, respectively. APOE2 (APOE 2,2 and APOE 3,2) subjects had lower total and LDL cholesterol levels than APOE3 (APOE 3,3) subjects. In APOE4 (APOE 4,3 and APOE 4,4) men and postmenopausal women levels of total and LDL cholesterol and triglycerides were significantly higher than in the corresponding APOE3 subjects. The *2 allele was also found to be associated with higher triglyceride levels in men and postmenopausal women. Men of the APOE4 group also presented lower HDL cholesterol levels. Although the impact of APOE polymorphism on blood lipid and lipoprotein levels in this French Canadian population is similar to what has been reported in other white populations, the frequency of the *2 allele is among the highest ever reported. This finding is discussed in terms of the founder effect characterizing the Quebec population.

Plasma concentration of apolipoprotein E in intermediate-sized remnant-like lipoproteins in normolipidemic and hyperlipidemic subjects.

Triglyceride-rich lipoprotein (TRL) remnants have been strongly implicated in the pathogenesis of atherosclerosis. To further investigate plasma remnant lipoprotein metabolism, we have determined the plasma concentration of apolipoprotein (apo) E (by polyclonal enzyme-linked immunoassay) in remnant-like lipoproteins, isolated by automated gel filtration chromatography as a fraction intermediate in size between VLDL and HDL. In normolipidemic subjects (n = 12), 1.2 +/- 0.11 mg/dL (33 +/- 2%, mean +/- SE) of total plasma apoE was associated with this fraction (termed ISL apoE). In hypercholesterolemic (type IIa, n = 12), hypertriglyceridemic (type IV, n = 12), and mixed hyperlipidemic (type IIb, n = 12) subjects, mean ISL apoE concentrations were 2.1 +/- 0.2, 2.5 +/- 0.2, and 3.8 +/- 0.4 mg/dL, respectively (P < .001 versus normal values) (45 +/- 2%, 32 +/- 2%, and 44 +/- 2% of total). ISL apoE was 8.7 +/- 1.4 mg/dL (42 +/- 3%) in type III dyslipidemic subjects (apoE2/2, n = 8). ISL apoE was positively correlated with plasma triglyceride (r = .41, P < .01), and at any given level of plasma triglyceride, subjects with an apoE2/2 or apoE3/2 phenotype tended to have a higher concentration of ISL apoE (P < .01) than apoE3/3 or E4/3 individuals. ISL apoE was also correlated (P < .001) with total plasma cholesterol (r = .66), TRL cholesterol (r = .49), TRL apoE (r = .47), LDL apoB (r = .42), and LDL+HDL triglyceride (r = .74). These results suggest that (1) a significant proportion of plasma apoE resides within an intermediate-sized remnant-like lipoprotein fraction in both normolipidemic and hyperlipidemic subjects; (2) plasma remnant lipoprotein accumulation is associated with an elevation in ISL apoE concentration; and (3) ISL apoE concentration is significantly correlated with various proatherogenic lipid parameters and may itself be a potentially important atherogenic index.

Cardiovascular risk factors and lipoprotein profile in French Canadians with premature CAD: impact of the National Cholesterol Education Program II.

BACKGROUND: Coronary artery disease (CAD) is the major cause of death in Canadian adults. Regional differences in the prevalence of CAD in Canada are due, in part, to differences in cardiovascular risk factor distribution. Two hundred and forty-nine patients of predominantly French Canadian descent (greater than 90%), aged less than 60 years (202 men and 47 women) with angiographically documented CAD were examined in a cardiology secondary prevention clinic and their cardiovascular risk factors and lipoprotein cholesterol levels were determined. OBJECTIVES: To determine the prevalence of cardiovascular risk factors in a group of French Canadian subjects compared with subjects screened for the Quebec Heart Health Survey and to determine the impact of the National Cholesterol Education Program II (NCEP II) on screening and treatment of these patients. METHODS: Observation study of free-living subjects with CAD, compared with a reference group. RESULTS: Mean ages were 48.6 +/- 6.8 and 50.6 +/- 6.4 years for men and women, respectively. On average, the patients were on a diet containing approximately 31% of calories as fat, with 9.7% as saturated fats at the time of blood sampling. The mean number of risk factors was the same in men and women (3.5 +/- 1.2 for men versus 3.2 +/- 1.3 for women; P not significant) but their prevalence differed between sexes. Family history of CAD was seen in 78.5% of men versus 77.3% of women (P not significant), smoking (defined as more than 10 cigarettes per day in the year preceding the clinical evaluation) in 45.7% of men versus 41.9% of women (P not significant), a history of smoking in 75.5% of men versus 69.8% of women (P not significant) and diabetes in 14.7% of men and 25% of women (P not significant). There was less hypertension in men (31.4% versus 52.3%, P = 0.015) and fewer men had a low density lipoprotein cholesterol of 3.4 mmol/L or greater (66.8% in men versus 83% in women, P < 0.05). Men, however, had a higher prevalence of reduced high density lipoprotein cholesterol (less than 0.9 mmol/L, 57.4% in men versus 31.9% in women, P < 0.01). Only approximately 5% of premature CAD patients had familial hypercholesterolemia. Compared with a reference group from the Quebec Heart Health Survey, men and women with CAD had a higher prevalence of cardiovascular risk factors. With a cut-off point for total cholesterol of 5.2 mmol/L, 26.2% of men and 17% of women had 'normal' cholesterol levels; of these, 67.9% of men and 25% of women had high density lipoprotein less than 0.9 mmol/L. CONCLUSIONS: French Canadian men and women with CAD have a high prevalence of all cardiovascular risk factors. The patients are representative of the Montreal urban area and findings of the present study may not apply to the Quebec population with respect to the prevalence of risk factors. Under the treatment recommendations of NCEP II, 66.8% of men and 83% of women are candidates for drug therapy of dyslipoproteinemia aimed at reducing low density lipoprotein cholesterol levels. According to these data, cardiovascular risk stratification must be based on a complete lipoprotein profile or misclassification, especially in men, may occur.

Apolipoprotein E polymorphism and Alzheimer's disease.

Apolipoprotein E (apoE) is associated with Alzheimer's neurofibrillary tangles and beta-amyloid protein in senile plaques. It also appears to play an important part in the redistribution of lipids that follows deafferentation and neurodegeneration in the brain. The gene for apoE is on chromosome 19, within the genomic region previously associated with late-onset familial Alzheimer's disease (AD). We have studied apoE phenotype expression and the corresponding allele frequencies (epsilon 2, epsilon 3, epsilon 4) in 91 patients with sporadic AD and 74 controls. There was a significant association between epsilon 4 and sporadic AD (epsilon 4 frequency 0.380 in AD and 0.122 in controls, p < 0.01). Analysis of epsilon 4 in whom AD develops this tended to happen earlier in life than in those with epsilon 3 or epsilon 2. The epsilon 4/AD association was more pronounced in women. Octogenarians with AD had an epsilon 4 allele frequency that was 3 times higher than one reported, in a different study, in healthy octogenarians. ApoE may be an important susceptibility factor in the aetiopathology of sporadic AD.

Acute influence of smoking on platelet behaviour, endothelium and plasma lipids and normalization by aspirin.

This study was conducted to investigate acute effects of smoking on platelet function, endothelial cells and plasma lipids and to follow these parameters after Aspirin ingestion. Twelve fasting smokers each inhaled the smoke of one cigarette. Blood was drawn before and 10 min after smoking. Plasma nicotine, measured by gas chromatography, increased from 13.48 before smoking to 78.41 nM after smoking. Platelet aggregation to thrombin and ADP increased significantly (P less than 0.001). The platelet aggregate ratio decreased from 0.95 to 0.75 (P less than 0.005). Plasma beta-thromboglobulin also increased in post-smoking samples as measured using radioimmunoassay. 'Circulating endothelial cells' increased significantly after smoking (P less than 0.005). Triglycerides decreased (P less than 0.005) in plasma and in the VLDL fraction (P less than 0.05). Both post-smoking plasma free fatty acids and free glycerol increased, respectively, as compared with respective values. Lipase activity ascribable to lipoprotein lipase and hepatic lipase, absent in pre-smoking plasma samples, could be detected in post-smoking plasma without heparin injection. At least 1 week later, the subjects returned to follow an identical protocol except that they had ingested Aspirin (650 mg) 10-14 h before blood sampling. The same parameters were measured before and after smoking the same cigarette. Except for plasma nicotine, all the smoking-induced changes were abolished by ingestion of Aspirin. The results of this study indicate an interrelationship between platelet hyperactivity, endothelial injury and plasma lipids. They also demonstrate an inhibition of the major smoking-induced changes by Aspirin in the presence of high plasma nicotine levels. It is concluded that Aspirin may offset several of the deleterious acute effects of smoking. However, our conclusions cannot be, in any way, extended for long-term effects of both smoking and Aspirin treatment. Based on these data, it is suggested that there may be some links between platelet hyperactivity, endothelium injury and plasma lipids.

High-density lipoprotein particles in octogenarians.

High-density lipoprotein (HDL) particles exhibit considerable heterogeneity, specifically in apolipoprotein (apo) composition. Thus, apo A-I, the major protein of HDL, is present in two types of particles: one species contains both apo A-I and apo A-II (Lp A-I/A-II) while in the other (Lp A-I), apo A-II is absent. We used the hypothesis that octogenarians, who survived periods in life when the incidence of coronary heart disease (CHD) is very high, have several protective factors. We compared HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C), HDL3-cholesterol (HDL3-C), apo A-I, and apo A-II in octogenarians and younger control subjects smoking less than 10 cigarettes/d and not taking drugs known to affect lipid metabolism. Using a new procedure, we also compared the levels of Lp A-I and Lp A-I/A-II. The cholesterol content of total HDL was similar in octogenarian and control (38 +/- 8 years) men while HDL2-C was higher and HDL3-C, apo A-I, and A-II were lower in octogenarian than in control men. In women, the level of HDL-C and apo A-I was similar in premenopausal and octogenarian subjects but higher in postmenopausal women than in octogenarians, while HDL2-C and apo A-II were similar in the three groups. In contrast, HDL3-C was higher in the two groups of control women (premenopausal and postmenopausal) than in octogenarians. However, Lp A-I was significantly elevated in octogenarian men and women (men: 61 +/- 14 mg/dL; women: 70 +/- 14 mg/dL) by comparison with younger control subjects (men: 48 +/- 12 mg/dL; premenopausal women: 53 +/- 11 mg/dL; postmenopausal women: 63 +/- 19 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of clentiazem on lipid profile, lipoprotein composition and aortic fatty streaks in cholesterol-fed rabbits.

Numerous experimental studies have reported that common antihypertensive drugs such as diuretics, beta-blockers, and methyldopa have adverse effects on plasma lipids and lipoproteins. The present study was designed to define the effect of clentiazem (10 mg/kg/day) an antihypertensive drug, on hyperlipidemia in rabbits on a cholesterol-rich diet (1%) for 12 weeks. Compared with controls, clentiazem treated rabbits had lower plasma concentrations of triglycerides (55%), total cholesterol (24%), free cholesterol (27%), esterified cholesterol (23%) and phospholipids (24%). The decrease in cholesterol was accounted for by a reduction of VLDL-cholesterol (13%), IDL-cholesterol (24%) and primarily LDL-cholesterol (45%). Neither HDL-cholesterol nor chemical composition of VLDL, IDL, LDL and HDL was altered. When the aortic atherosclerotic involvement was evaluated by computerized planimetry, a 24% reduction of lesions was noted in clentiazem treated animals (P less than 0.05). Similarly, cholesterol content extracted from aortic wall was decreased. Our data therefore demonstrated that clentiazem is a potential antiatherosclerotic agent capable of decreasing plasma lipids and atherogenic lipoproteins as well as aortic fatty streaks.

A phenocopy of type III dysbetalipoproteinemia occurring in a candidate family for a putative apo E receptor defect.

On theoretical grounds, an apo E receptor defect should be manifested by the accumulation of lipoprotein remnants that are normally cleared by this receptor and cannot be processed by the normal apo B, E receptor (LDL-receptor). Furthermore, the defect should not be selective for a specific apo E phenotype since none of the isoforms would be cleared preferentially. Our search for such an occurrence led us to the discovery, in five members of a family of ten, of a unique dyslipoproteinemia mimicking type III. As in type III, plasma levels of cholesterol, triglycerides, VLDL-cholesterol, VLDL-triglycerides and apo E, as well as the VLDL-C/TG ratio, were high. LDL-cholesterol and HDL-cholesterol tended to be low. The clearance of plasma triglycerides after a fat load was impaired. Tubero-eruptive xanthomas, arcus corneae and manifestations of atherosclerosis were present in some individuals. In contrast to type III, the dyslipoproteinemia occurred in subjects bearing three different apo E phenotypes: E4/2, E4/3 and E3/2. VLDL-apo B levels were markedly increased, the VLDL-C/VLDL-B ratio was low and a double pre-beta band was present on lipoprotein electrophoresis. In spite of high apo E and borderline high apo CIII plasma levels, levels of the lipoprotein particles LpCIII:B and LpE:B, which characterize type III, were not raised. Rapid weight loss or treatment with a fibrate was observed to normalize the lipoprotein profile. It is surmised that the apo E-rich lipoprotein particles accumulating in this type III phenocopy with "hyperapoprebetalipoproteinemia" could be those that are normally cleared by an apo E receptor.

Prevalence of radiologically defined osteoarthritis in the finger and wrist joints of adult residents of Tecumseh, Michigan, 1962-65.

Radiographs of the fingers and wrists of adult participants in the Tecumseh Community Health Study in 1962-65 were examined for signs of osteoarthritis (OA). The severity of OA for each of 32 joints of the fingers and wrists was recorded for each individual. Attention was restricted to the 3035 participants who were 32 years of age or older and for whom a diagnosis of OA was available for each of 32 joints. Joint-specific prevalence rates of OA increased sharply with age for both sexes, and at the older ages, the prevalence rates for most joints were higher for females. Older individuals with OA also had a greater number of affected joints, with females having a greater number of affected joints than males. Of those individuals aged 44 years or younger, only 6.2% had one or more joints affected with OA. The percentages were 21.6 and 42.0% for those aged 45-59 years and 60 or more years, respectively. The distal interphalangeal (DIP) joints were the most frequently affected joints in all age categories for both sexes and OA in the proximal interphalangeal (PIP) joints was positively associated with OA in the DIP joints. However, controlling for the number of affected DIP joints, the PIP joints of older subjects were more likely to exhibit OA than the PIP joints of younger subjects. Though there is an association between OA in the DIP and PIP joints, there was only a small, nonsignificant association (OR = 1.24, 95% CI = 0.83, 1.84) between disease in the DIP and PIP joints of the same finger.

Apolipoprotein E polymorphism and plasma cholesterol response to probucol.

Probucol has been shown to be an effective and well-tolerated cholesterol-lowering drug. However, response in terms of cholesterol reduction has been shown to vary significantly among individuals. The purpose of this study was to assess the role of apolipoprotein E polymorphism in determining this variation. A retrospective study of 89 hypercholesterolemic type II patients who had been treated with probucol (1 g/d) and for whom the apolipoprotein E phenotype was known was carried out. The patients were first grouped into those with heterozygous familial hypercholesterolemia (FH) and those considered to have other forms of hypercholesterolemia (non-FH). Further subclassification of the individuals in both groups as IIa or IIb, allowed the definition of four diagnostic classes, FH IIa or IIb and non-FH IIa or IIb. Among these classes there was no significant heterogeneity for the relationship between response and age or sex. After correction for between-class heterogeneity in duration of probucol treatment, comparison of individuals with the apo E3/3 phenotype with those carrying the epsilon 4 allele showed significant differences in cholesterol reduction both absolute change and percent change. Further contrasts between diagnostic and apo E genotype stratifications of these data showed that the FH patients carrying the epsilon 4 allele had the greatest reduction in cholesterol level.

Severe hypoalphalipoproteinemia induced by a combination of probucol and clofibrate.

Observation of a markedly depressed HDL-cholesterol (5 mg/dL) in a patient with familial hypercholesterolemia (FH) receiving probucol (1 g/day) and clofibrate (2 g/day) prompted a review of all cases treated by this combination at our lipid clinic. Hypoalphalipoproteinemia (HDL-C less than 15 mg/dL) developed in 19 of 28 (70%) hyperlipidemic subjects who received this combination for an average of 1.5 years. This effect was sustained and reversible; it did not occur on either drug alone and was manifested on average 17 weeks after the combination was started. Plasma triglycerides increased significantly in most of those patients susceptible to this reduction in HDL-C. Plasma apolipoprotein A-I was decreased 82%, in proportion to the HDL-C fall, whereas apo A-II was lowered 65%. Since apo C-III concentrations tended to be high, the apo A-I/C-III ratio was markedly depressed. Apo E levels were unchanged and apo B levels reflected the high LDL concentrations of the underlying disease. An intermediate response was observed in subjects whose HDL-C remained well above 15 mg/dL on the combination. No deleterious side-effects could be attributed directly to the administration of the combined drugs in this high-risk group. One patient actually showed complete regression of xanthelasma and extensor tendon xanthomas of the finger on the combination. A parallel is drawn with Fish-Eye disease and the presence of the apolipoprotein A-I Milano variant, where similar HDL-C levels are observed in the absence of an increased atherogenic risk. It is mandatory to monitor plasma HDL-C in hypercholesterolemic patients treated with this combination, otherwise the pronounced HDL-deficiency could go unnoticed.

Apo E allele frequency in primary endogenous hypertriglyceridemia (type IV) with and without hyperapobetalipoproteinemia.

Apolipoprotein E polymorphism is responsible for the existence in the population of six apo E phenotypes determined by three alleles acting at a single gene locus. We have previously reported an enrichment in the epsilon 2 allele and the E2-bearing phenotypes in an unselected sample of subjects with primary hyperlipidemia consisting mainly of endogenous hypertriglyceridemia (Type IV). A study was carried out on 214 Type IV hypertriglyceridemic subjects to determine whether there was the same distribution in subjects with hyperapobetalipoproteinemia as in those without. The study showed that the relative enrichment in the epsilon 2 allele was associated only with Type IV subjects without hyperapobetalipoproteinemia. Since hyperapobetalipoproteinemia is a presumed marker for familial combined hyperlipidemia (FCHL), this finding may provide further evidence that FCHL and familial hypertriglyceridemia, both associated with a Type IV lipoprotein pattern, are truly separate disease entities.

Distribution of apolipoprotein E phenotypes in Friedreich's ataxia.

Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles epsilon 2, epsilon 3, and epsilon 4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the epsilon 2 allele in the genotype tends to be associated with higher triglyceride levels, a study was undertaken to determine if a higher frequency of this allele could account for the presence of higher plasma triglycerides in subsets of patients with Friedreich's Ataxia. The frequency of the apo E phenotypes was determined in 37 subjects with Friedreich's Ataxia and compared with that of 102 normolipidemic and 102 hyperlipidemic individuals. There was no increased prevalence of the E3/2 phenotype and the epsilon 2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the epsilon 2 subset did not have significantly higher plasma triglycerides than the non-epsilon 2 subset and the hypothesis was rejected. On the other hand, there was a trend for a decreased frequency of the E4/3 phenotype in the Friedreich's sample relative to the hyperlipidemic group but the difference did not reach statistical significance. The apo E phenotype distribution was also measured in a smaller sample of Charlevoix-Saguenay disease; this led to the discovery of two siblings with the relatively rare E2/2 phenotype and unexpectedly low levels of plasma lipid and lipoprotein concentrations. Plasma apolipoprotein E concentrations in both diseases were within the normal range except for subjects bearing the E2/2 phenotype.