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Severe familial HDL deficiency in French-Canadian kindreds. Clinical, biochemical, and molecular characterization
M Marcil1, B Boucher, L Krimbou
1Cardiovascular Genetics Laboratory, Clinical Research Institute of Montréal, Québec, Canada.
Insights
This study investigates severe familial high-density lipoprotein deficiency (HDL-C) in French-Canadian families. Genetic analysis ruled out common mutations, suggesting a novel cause for low HDL-C and its link to coronary artery disease.
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Medicine
- Lipid Metabolism
Background:
- Low high-density lipoprotein cholesterol (HDL-C) is a common abnormality in premature coronary artery disease (CAD).
- Secondary hypoalphalipoproteinemia, often due to increased apo B-containing lipoprotein production, is a frequent cause of low HDL-C in CAD patients.
- Primary hypoalphalipoproteinemia affects about 4% of CAD individuals.
Observation:
- Four subjects from three French-Canadian kindreds presented with severe familial HDL deficiency (HDL-C << 5th percentile).
- Affected individuals had normal triglycerides, were not diabetic, and exhibited small HDL particles.
- Analysis revealed normal apo AI molecular weight and isoelectric point, with a relative increase in proapoliprotein AI.
Findings:
- Quantitative Southern blot and haplotype analysis of apo AI and apo AII genes showed no rearrangements, deletions, or segregation with the low HDL-C trait.
- Sequence analysis of the apo AI gene promoter identified a guanine-to-adenine substitution at position 76 in two kindreds, but it did not segregate with the trait.
- No mutations in the lipoprotein lipase gene were found, and plasma lecithin: cholesterol acyltransferase (LCAT) activity was normal.
Implications:
- The genetic basis for severe familial HDL deficiency in these French-Canadian kindreds remains elusive, suggesting a potentially novel genetic defect.
- While two affected individuals had severe CAD, the low HDL trait did not unequivocally cosegregate with CAD within the families studied.
- Further research is needed to identify the specific genetic cause of this severe HDL deficiency and its precise role in CAD pathogenesis.
Abstract:
A decreased level of HDL cholesterol (HDL-C) is the most common lipoprotein abnormality seen in people with premature coronary artery disease (CAD). In many cases, HDL-C reduction in patients with CAD may be the result of increased apo B-containing lipoprotein production by the liver with secondary hypoalphalipoproteinemia. Primary hypoalphalipoproteinemia is seen in approximately 4% of people with CAD. We report findings 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-Canadian kindreds with autosomal codominant inheritance. By inclusion criteria, 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 isoelectrofocusing gels in affected subjects revealed normal molecular weight (28.3 kD) and normal isoelectrofocusing point but a relative increase in proapoliprotein AI, with near-normal levels of proapolipoprotein AI in plasma, suggesting normal secretion of apo AI. Quantitative Southern blot analysis of the apo AI-CIII-AIV gene cluster reveals no gene rearrangements or allele deletion. Haplotypes of the apo AI gene, determined 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 segregation of the low HDL-C trait with either the apo AI or the AII gene. Sequence analysis of the promoter region of the apo AI gene reveals heterozygosity for guanine-to-adenine substitution at position 76 in two kindreds with no evidence of segregation with the low HDL trait. None of the patients had mutations of the lipoprotein lipase gene common in subjects of French-Canadian descent. Haplotype analysis of the lipoprotein lipase gene did not show segregation with the low HDL trait. Plasma 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 manifestations of Tangier disease. Two of the four cases examined, both men, had 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 of the families did the low HDL trait unequivocally cosegregate with CAD.(ABSTRACT TRUNCATED AT 400 WORDS)