Compound heterozygosity for a structural apolipoprotein A-I variant, apo A-I(L141R)(Pisa), and an apolipoprotein A-I null allele in patients with absence of HDL, cholesterol, corneal opacifications, and coronary heart disease

Background The concentration of HDL cholesterol is inversely correlated with the risk of coronary heart disease (CHD). Some rare mutations in the apolipoprotein (apo) A-I gene are associated with low levels of HDL cholesterol. Their association with cardiovascular risk is controversial. Methods and Results We studied the molecular defects underlying corneal opacities and absence of HDL cholesterol in three brothers and a sister. In a family study, the importance of these defects for lipid metabolism and manifestation of coronary heart disease was investigated. The frequency of these apo A-I defects was assessed by genotype and phenotype analysis of 477 DNA(-) and plasma samples, respectively, from the population. The four patients were compound heterozygotes for a null allele and a missense mutation in the apo A-I gene that leads to a leucine-->arginine substitution at residue 141 [apo A-I(L141R)(Pisa)]. Heterozygotes for either the null allele or the structural variant had half-normal concentrations of HDL cholesterol and apo A-I compared with unaffected family members, Apo A-I(L141R)(Pisa) was detected in one more unrelated subject. Coronary angiography of the four compound heterozygotes revealed the presence of CHD in all male patients, whose ages ranged between 45 and 52 years. They presented with additional risk factors, including elevated LDL cholesterol levels, obesity, and arterial hypertension. Despite complete HDL deficiency and hypercholesterolemia, CHD was absent in the 51-year-old premenopausal sister. Conclusions Apo A-I deficiency may lead to premature atherosclerosis if present in conjunction with additional cardiovascular risk factors.