SEVERE FAMILIAL HDL DEFICIENCY IN FRENCH-CANADIAN KINDREDS - CLINICAL, BIOCHEMICAL, AND MOLECULAR CHARACTERIZATION

A decreased level of HDL cholesterol (HDL-C) is the most common lipopr otein abnormality seen in people with premature coronary artery diseas e (CAD). In many cases, HDL-C reduction in patients with CAD may be th e result of increased apo B-containing lipoprotein production by the l iver with secondary hypoalphalipoproteinemia. Primary hypoalphalipopro teinemia is seen in approximately 4% of people with CAD. We report fin dings in four subjects with severe familial HDL deficiency (HDL-C<<5th percentile for age and sex; 0.08 to 0.38 mmol/L) in three French-Cana dian kindreds with autosomal codominant inheritance. By inclusion crit eria, all four subjects had normal fasting triglycerides and none were diabetic. HDL particle size by gradient gel electrophoresis revealed small HDL particles (estimated Stokes' diameter, 8.14 to 8.30 nm). Apo AI analysis by polyacrylamide gel electrophoresis and use of isoelect rofocusing gels in affected subjects revealed normal molecular weight (28.3 kD) and normal isoelectrofocusing point but a relative increase in proapolipoprotein AI, with near-normal levels of proapolipoprotein AI in plasma, suggesting normal secretion of apo AI. Quantitative Sout hern blot analysis of the apo AI-CIII-AIV gene cluster reveals no gene rearrangements or allele deletion. Haplotypes of the apo AI gene, det ermined by use of the restriction enzymes Pst I, Xmn I, and Sst I and of the apo AII gene by use of the enzyme Msp I, did not reveal segrega tion of the low HDL-C trait with either the apo AI or the AII gene. Se quence analysis of the promoter region of the apo AI gene reveals hete rozygosity for guanine-to-adenine substitution at position 76 in two k indreds with no evidence of segregation with the low HDL trait. None o f the patients had mutations of the lipoprotein lipase gene common in subjects of French-Canadian descent. Haplotype analysis of the lipopro tein lipase gene did not show segregation with the low HDL trait. Plas ma lecithin: cholesterol acyltransferase (LCAT) activity was found to be within normal levels in affected subjects and in nonaffected first- degree relatives. None of the affected subjects had clinical manifesta tions of Tangier disease. Two of the four cases examined, both men, ha d severe CAD and had undergone revascularization procedures. The third is a younger brother of one of these probands and the fourth is a 30- year-old woman, and both were free of clinical CAD. However, in none o f the families did the low HDL trait unequivocally cosegregate with CA D. The data reveal that the molecular defect in our patients with seve re hypoalphalipoproteinemia is not linked to the apo AI-CIII-AIV gene cluster, LCAT activity, elevated triglycerides, or lipoprotein lipase gene defects. CAD was identified in two probands, but both had several risk factors for CAD. Although hypercatabolism of HDL particles and a po AI has been shown to occur in patients with hypoalphalipoproteinemi a, the exact metabolic and molecular defect(s) remain unknown. We hypo thesize that an alteration in HDL-mediated cholesterol efflux or in in tracellular cholesterol transport to the cell surface may explain the metabolic abnormalities observed.