Apolipoprotein A-I(Zavalla) (Leu159-->Pro): HDL cholesterol deficiency in a kindred associated with premature coronary artery disease.

We investigated the molecular defect causing high density lipoprotein cholesterol (HDL-C) deficiency in a male proband and his family members. Amplification and sequencing of genomic DNA disclosed a novel base-pair substitution at residue 159 in the apolipoprotein (apo) A-I gene. This substitution resulted in the loss of an AviII restriction site and a predicted substitution of leucine with proline at residue 159. Restriction enzyme analysis demonstrated absence of the AviII site in 19 of 40 biological family members. Compared with familial controls, subjects with the apoA-I(Zavalla) variant had reduced HDL-C (1.16 versus 0.27 mmol/L, P<0.0001), apoA-I (38.7 versus 124.4 mg/dL, P<0.0001), and apoA-II (14.3 versus 19.0 mg/dL, P<0.0001) levels. Two subjects who have developed coronary artery disease to date possess additional cardiovascular risk factors. Other heterozygotes for apoA-I(Zavalla) are presently without symptomatic coronary artery disease. This study identifies a monogenic cause of hypoalphalipoproteinemia, with the single base-pair substitution having a dominant effect on the low HDL-C phenotype. In addition, it extends recent observations that HDL-C deficiency states may be more prone to the development of premature coronary artery disease when accompanied by additional cardiovascular risk factors.