Familial hypoalphalipoproteinemia in premature coronary artery disease.

Abstract

Hypoalphalipoproteinemia (HA) is a common finding in patients with premature coronary artery disease. To characterize the common familial forms of HA, we studied 102 families of probands with premature coronary artery disease; 40 probands (39.2%) had HA. Of these, 25 had at least one first-degree relative affected with HA; 11 had familial hypertriglyceridemia with HA (FTgHA); 10 had familial combined hyperlipidemia (FCH); and 4 had familial HA (FHA) with no other lipoprotein abnormalities. In the remaining 15 families, no lipoprotein abnormalities were observed in first-degree relatives. We measured apolipoprotein (apo) A-I, B, C-IH, and E levels as well as lipoprotein particle (Lp) levels of LpA-I (containing apoA-I only), LpA-I:A-II (containing both apoA-I and A-II), LpB:E, and LpB:C-III. Compared with a reference group of healthy men (n = 103) and women (n = 106), probands with familial forms of HA had lower high-density lipoprotein cholesterol levels by selection criteria. Triglyceride levels were higher in FTgHA and FCH probands than in the reference group or FHA subjects. Despite selection of FTgHA and FCH by low-density lipoprotein (LDL) cholesterol, the latter was not significantly different between the three groups and the reference group. ApoA-I levels were decreased in FCH, FHA, and FTgHA probands, and LpA-I and LpA-I:A-II were lower in FHA and FTgHA probands. ApoB levels were significantly higher in all familial HA groups compared with the reference group, being highest in FCH individuals, but not significantly higher between FCH, FTgHA, or FHA probands. LpB:E levels were higher in the FCH and FTgHA groups than in the reference group. There were no significant differences between groups for apoE, apoC-III, and LpB:C-III. LDL particle size was smaller in all three forms of FHA, which, in combination with higher apoB levels, reflects an increased number of smaller, denser LDL particles. Affected children had, on average, higher apoB and LpB:E levels than nonaflected siblings. Our data suggest that common forms of FHA in subjects with coronary artery disease represent a spectrum of overlapping disorders characterized by an increase in apoB-containing lipoproteins, especially LpB:E particles, and smaller, denser LDL particles. When using appropriate age-and gender-adjusted cutpoints, approximately half the offspring (in young adulthood) appeared to be affected.

Cellular Cholesterol Transport and Efflux in Fibroblasts Are Abnormal in Subjects With Familial HDL Deficiency

“…These features are consistent with the plurimetabolic syndrome of peripheral insulin resistance, obesity, and dyslipidemia. 38 Thus, the syndrome of severe hypoalphalipoproteinemia is heterogeneous and may be associated, in some instances, with increased apoB levels in plasma, as previously reported, 9 and apparently normal apoA-I-mediated cellular cholesterol efflux.…”

“…From casecontrol studies, it appears that a low HDL-C is often associated with an unhealthful life style or other lipid abnormalities and is part of a clustering of cardiovascular risk factors (cigarette smoking, obesity, hypertension, hypertriglyceridemia, and elevated apoB). 8,9 Secondary causes of low HDL-C, viz, cigarette smoking; the use of thiazide diuretics, ␤-adrenergic receptor blockers, or anabolic steroids; hospitalization; acute stress; trauma; or myocardial infarction do not, in our clinical experience, lead to severe HDL deficiency. With the exception of the drug probucol, medication does not account for severe HDL deficiency.…”

Genetic causes of high and low serum HDL-cholesterol

“…FHA is a common fi nding in patients with premature CAD ( 2,30 ). The metabolic etiology in many cases appears to be accelerated catabolism of HDL and its apolipoproteins ( 21 ), and some subjects, but not all, are characterized by small, lipid-poor HDL particles and defective lipid effl ux ( 31 ).…”

Effects on apoB-100 secretion and bile acid synthesis by redirecting cholesterol efflux from HepG2 cells

“…The study of familial dyslipoproteinemias by Genest et al was the next to firmly document the association. In their cohorts with familial hypoalphalipoproteinemia, total and LDL-C, and triglyceride levels were normal, but plasma apoB-100 levels were increased to the same extent as in familial combined hyperlipidemia (3). Based on these reports, we surveyed the database of the Quebec Cardiovascular Study and compared two groups, one of which was normotriglyceridemic with a low HDL-C, while the other was normotriglyceridemic with a high HDL-C. ApoB-100 was significantly higher in the former than in the latter (4).…”