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

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

Patients with apoE3 deficiency (E2/2, E3/2, and E4/2) who manifest with hyperlipidemia have increased frequency of an Asn 291-->Ser mutation in the human LPL gene

Approximately 1% to 2% of persons in the general population are homozygous for a lipoprotein receptor-binding defective form of apoE (apoE2/2). However, only a small percentage (2% to 5%) of all apoE2/2 homozygotes develop type III hyperlipoproteinemia. Interaction with other genetic and environmental factors are required for the expression of this lipid abnormality. We sought to investigate the possible role of LPL gene mutations in the development of hyperlipoproteinemia in apoE2/2 homozygotes and in apoE2 heterozygotes. As a first step, we performed DNA sequence analysis of all 10 LPL coding exons in 2 patients with the apoE2/2 genotype who had type III hyperlipoproteinemia and identified a single missense mutation (Asn 291-->Ser) in exon 6 of the LPL gene. The mutation was then found in 5 of 18 patients with type III hyperlipoproteinemia who had the apoE2/2 genotype (allele frequency = 13.9%; P Ser mutant LPL had approximately 60% of LPL catalytic activity and approximately 70% of specific activity compared with wild-type LPL. The heparin-binding affinity of the mutant LPL was not impaired. Our data suggest that the Asn 291-->Ser substitution is likely to be a significant predisposing factor contributing to the expression of different forms of hyperlipidemia when associated with other genetic factors such as the presence of apoE