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: ObjectivesWe investigated associations between single nucleotide polymorphisms (SNPs) in the hepatic lipase promoter, levels of high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). Our primary hypothesis was that these SNPs associate with IHD after adjustment for HDL levels.: BackgroundHepatic lipase influences HDL metabolism, and may thus affect reverse cholesterol transport and consequently risk of IHD.: MethodsWe genotyped 9,121 white subjects aged 20 to 93 years from the Copenhagen City Heart Study, 456 of whom had incident IHD, as well as 921 Danish patients with IHD for the −216, −480, and −729 SNPs in the hepatic lipase promoter.: ResultsFrequencies of wild-type, triple heterozygotes, and triple mutation homozygotes in the general population were 61%, 33%, and 5%, respectively. Compared with wild-type, HDL cholesterol levels were 4% (0.06 mmol/l) and 10% (0.15 mmol/l) higher in heterozygotes and mutation homozygotes; the equivalent values for apolipoprotein A1 were 3% and 7% higher. In prospective and case-control studies, mutation homozygotes versus wild-type had relative risk (RR) and odds ratio (OR) for IHD of 1.5 (95% confidence interval [CI]: 1.0 to 2.2) and 1.4 (CI: 1.1 to 1.9) when adjusted for age, gender, and HDL cholesterol. In individuals with the ∊43 apolipoprotein E genotype, RR and OR for IHD in mutation homozygotes versus wild-type was 2.9 (CI: 1.5 to 5.6) and 2.0 (CI: 1.2 to 3.2).: ConclusionsHepatic lipase promoter SNPs are associated with increased HDL cholesterol and, paradoxically, an increased risk of IHD after adjustment for HDL cholesterol, and particularly in individuals with apolipoprotein E ∊43 genotype. Implications are that increased HDL levels may in certain situations be not protective, but rather associated with increased IHD risk. [Copyright &y& Elsevier]