APOC3 and ABCA1 variants in unusual combined hypolipidaemia showing premature peripheral vascular disease (original) (raw)
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Atherosclerosis, 2004
Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with premature coronary artery disease (pCAD), had a combination of genetic defects. Besides being heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q substitution in apolipoprotein B and the third was a carrier of N291S substitution in lipoprotein lipase. By extending family studies we identified 17 heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these subjects were 38.3 and 36.9% lower than in unaffected family members and similar to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1 mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked and (ii) there may be a selection bias in genotyping towards carriers of ABCA1 mutations who have pCAD possibly related to a combination of genetic and environmental cardiovascular risk factors.
Genetic Epidemiology, 1995
Genetic variation at the apolipoprotein (apo) A-I/C-III/A-IV gene cluster on chromosome 11 has been associated with differences in occurrence of atherosclerosis and with variability in lipid levels among hypercholesterolemic-hypertriglyceridemic individuals. The functional cause of the association is not known, but polymorphisms of the apo A-IV gene are of interest because apo A-IV is involved in both triglyceride and cholesterol metabolism. Two mutations in the apo A-IV gene, 347T→S and 360Q→H, are known to cause amino acid substitutions in the mature protein. These polymorphisms were typed in a sample of 119 subjects with high cholesterol and high triglycerides in whom carotid artery wall thickness was previously shown to be strongly associated with silent polymorphic variation in the A-I/C-III/A-IV gene cluster.The relative allele frequencies were 0.83 and 0.17 for codon 347T→S, and 0.95 and 0.05 for codon 360Q→H. These polymorphisms did not show a statistically significant relationship with prevalent hypertension, diabetes, or cardiovascular disease or with plasma lipid levels. Most importantly, these amino acid substitutions in apo A-IV were not associated with carotid artery wall thickness. Therefore, the genetic cause of disease variability in a sample of mixed hyperlipidemics is not amino acid substitutions in codons 347 or 360 of the apolipoprotein A-IV gene. ©1995 Wiley-Liss, Inc.