title: The Asn9 variant of lipoprotein lipase is associated with the -93G promoter mutation and an increased risk of coronary artery disease. The Regress Study Group.
abstract: Two mutations in the lipoprotein lipase (LPL) gene, a T to G transition at position -93 of the proximal promoter region and an Asp9Asn substitution in exon 2, were examined in 762 Dutch males with angiographically-diagnosed coronary artery disease (CAD) and 296 healthy normolipidemic Dutch males. The two mutations exhibited strong linkage disequilibrium (D' = 0.975). A significantly higher proportion of cases (4.86%) than controls (1.37%) carried the -93G/Asn9 allele (p = 0.008). In the combined sample of cases and controls, adjusted mean plasma total cholesterol (TC) levels were significantly higher in -93G/Asn9 carriers (6.20+/-0.13 mmol/l) than in non-carriers (5.93+/-0.03 mmol/l; p = 0.048), while mean high-density lipoprotein cholesterol (HDL-C) levels were lower in carriers (0.88+/-0.03 mmol/l) than in non-carriers (0.98+/-0.01 mmol/l; p = 0.002). There was a trend towards higher triglyceride (TG) levels in carriers (1.96+/-0.14 mmol/l) compared with non-carriers (1.73+/-0.03 mmol/l) (p = 0.08). Additionally, carrier frequencies in tertiles of TC, HDL-C, TG, and LPL activity, suggested an association of the -93G/Asn9 variant with higher TC and TG levels, and with lower HDL-C and LPL activity levels. Logistic regression revealed a significant odds ratio (OR) for the combined -93G/Asn9 genotype in CAD cases relative to controls (OR: 5.36; 95% CI: 1.57-18.24), with age, body mass index (BMI), smoking, and plasma total- and HDL-cholesterol levels included in the model. In conclusion, we show that the LPL Asp9Asn mutation is in non-random association with a T G substitution at position -93 of the proximal promoter region and that the combined -93G/Asn9 genotype predisposes to decreased HDL-C levels and an increased risk of CAD.
authors.affiliation: Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: B E
authors.initials: BE
authors.lastname: Groenemeyer
authors.forename: D M
authors.initials: DM
authors.lastname: Hallman
authors.forename: H
authors.initials: H
authors.lastname: Henderson
authors.forename: P W
authors.initials: PW
authors.lastname: Reymer
authors.forename: S E
authors.initials: SE
authors.lastname: Gagné
authors.forename: H
authors.initials: H
authors.lastname: Jansen
authors.forename: J C
authors.initials: JC
authors.lastname: Seidell
authors.forename: D
authors.initials: D
authors.lastname: Kromhout
authors.forename: J W
authors.initials: JW
authors.lastname: Jukema
authors.forename: A V
authors.initials: AV
authors.lastname: Bruschke
authors.forename: E
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D001216:Asparagine / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics*; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012307:Risk Factors
chemical_list: D001216:Asparagine; D008071:Lipoprotein Lipase; D005998:Glycine