title: New MspI polymorphism at +83 bp of the human apolipoprotein AI gene: association with increased circulating high density lipoprotein cholesterol levels.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Prince Henry Hospital, University of New South Wales, Australia.
authors.forename: X L
authors.initials: XL
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Badenhop
authors.forename: K E
authors.initials: KE
authors.lastname: Humphrey
authors.forename: D E
authors.initials: DE
authors.lastname: Wilcken
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016632:Apolipoprotein A-I / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D008076:Cholesterol, HDL / Q000097:blood*; D004247:DNA; D019003:Deoxyribonuclease HpaII / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009517:New South Wales / Q000453:epidemiology; D011110:Polymorphism, Genetic; D017678:Sex Distribution
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D004247:DNA; D019003:Deoxyribonuclease HpaII