CLINICAL RESEARCH: GENETIC POLYMORPHISMS AND ISCHEMIC HEART DISEASE
Hepatic lipase mutations,elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease
The Copenhagen City Heart Study
Rolf V. Andersen, MSc, PhD*,
Hans H. Wittrup, MD, PhD*,
Anne Tybjærg-Hansen, MD, DMSc  ,
Rolf Steffensen, MD ,
Peter Schnohr, MD and
B.ørge G. Nordestgaard, MD, DMSc*,*
* Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark
Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark
Department of Medicine B, Division of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, Copenhagen, Denmark
Manuscript received April 12, 2002;
revised manuscript received September 19, 2002,
accepted October 31, 2002.
* Reprint requests and correspondence: Dr. Børge G. Nordestgaard, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
brno{at}herlevhosp.kbhamt.dk
OBJECTIVES: We 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.
BACKGROUND: Hepatic lipase influences HDL metabolism, and may thus affect reverse cholesterol transport and consequently risk of IHD.
METHODS: We 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.
RESULTS: Frequencies 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).
CONCLUSIONS: Hepatic 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.
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Abbreviations and Acronyms
| | ANOVA | | analysis of variance | | HDL | | high-density lipoprotein | | IHD | | ischemic heart disease | | LDL | | low-density lipoprotein | | PCR | | polymerase chain reaction | | SNPs | | single nucleotide polymorphisms |
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