APOLIPOPROTEIN A-I-ZAVALLA (LEU(159)-]PRO) HDL CHOLESTEROL DEFICIENCYIN 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 member s. 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 a nd a predicted substitution of leucine with proline at residue 159. Re striction enzyme analysis demonstrated absence of the AviII site in 19 of 40 biological family members. Compared with familial controls, sub jects 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 h ave developed coronary artery disease to date possess additional cardi ovascular risk factors. Other heterozygotes for apoA-I-Zavalla are pre sently without symptomatic coronary artery disease. This study identif ies a monogenic cause of hypoalphalipoproteinemia, with the single bas e-pair substitution having a dominant effect on the low HDL-C phenotyp e. In addition, it extends recent observations that HDL-C deficiency s tates may be more prone to the development of premature coronary arter y disease when accompanied by additional cardiovascular risk factors.