Wittrup_1999_Arterioscler.Thromb.Vasc.Biol_19_1535

The aim of this study was to test the hypothesis that the Asp9Asn substitution and the T(-93)-->G mutation in the promoter of the lipoprotein lipase gene affect plasma lipid levels and thereby the risk of ischemic heart disease (IHD). We genotyped 9033 men and women from a general population sample and 940 patients with IHD. The frequency of both the G allele and the Asn9 allele in the general population sample was approximately 0.015 for both men and women. These 2 mutations appeared together in 95% of carriers. The average triglyceride-raising effect associated with double heterozygosity for the T(-93)-->G mutation and the Asp9Asn substitution was 0.28 mmol/L (P=0.004) and 0.16 mmol/L (P=0.10) in men and women, respectively. On logistic regression analysis allowing for age, the risk of IHD for double heterozygous men and women was increased 90% (95% confidence interval [CI], 20% to 200%) and 30% (95% CI, -40% to 170%), respectively, compared with noncarriers. When, in addition, other conventional cardiovascular risk factors were allowed for, the risk of IHD for double heterozygous men and women was increased 70% (95% CI, 0% to 190%) and 20% (95% CI, -50% to 180%), respectively. Of the overall risk of IHD in men in the general population, the fraction attributable to double heterozygosity was 3%, similar to the 5% attributable to diabetes mellitus. These results demonstrate that the Asp9Asn substitution is in linkage disequilibrium with the T(-93)-->G mutation and that the double-heterozygous carrier status is associated with elevated plasma triglycerides and an increased risk of IHD in men.