New MspI polymorphism at +83 bp of the human apolipoprotein AI gene: association with increased circulating high density lipoprotein cholesterol levels.

We recently showed that loss of a MspI restriction site in the 5'-end (intron 1) of the apolipoprotein (apo) AI gene is due to a C to T transition (+83 bp) and/or a G to A transition (+84 bp). Since this region may be relevant to the regulation of apo AI gene expression and therefore to plasma high density lipoprotein cholesterol (HDL-C), we explored the association between this MspI polymorphic site and circulating HDL-C levels in 243 healthy Caucasians. There were 143 aged 18-67 years (60 males and 83 females) and 100 aged 6-12 years (58 males and 42 females). We also compared this association with a known MspI polymorphic site, a G to A transition at -75 bp of the apo AI gene. The rare allele (-) frequency for the polymorphism at +83 bp was 4.1% and 22.1% for the polymorphism at -75 bp. Subjects heterozygous for the loss of the MspI restriction site at +83 bp (genotype: M2+-, n = 20) had higher HDL-C levels than M2+2 subjects (mean +/- SD: 1.73 +/- 0.31 vs. 1.41 +/- 0.39 mmol/l, P < 0.05 for adults; 1.71 +/- 0.33 vs. 1.34 +/- 0.29 mmol/l, P < 0.01 for children). Adults with the G to A substitution at -75 bp also had higher HDL-C levels (1.56 +/- 0.36 mmol/l for AA, 1.53 +/- 0.38 mmol/l for GA, and 1.36 +/- 0.38 mmol/l for GG, P < 0.05); this difference was not observed in the children. The MspI polymorphisms at both sites were in linkage disequilibrium. Their joint effect on the HDL-C levels was also significant and individuals with rare alleles (-) at both sites had the highest HDL-C levels. In an analysis of variance, the MspI polymorphism at +83 bp, and at -75 bp and gender independently accounted for 6.5%, 1.7%, and 5.9%, respectively, of the variance in circulating HDL-C levels when age was controlled as a covariate. We conclude that loss of the MspI site by the C to T (+83 bp) and/or the G to A (+84 bp) transitions is highly associated with increased HDL-C levels. The association appears to be more significant than that of the G to A transition at -75 bp.