on November 4, 2004
Published online before print November 4, 2004, doi: 10.1161/01.ATV.0000149380.94984.f0
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Submitted on August 4, 2004
Accepted on October 7, 2004
Phenotype of Heterozygotes for Low-Density Lipoprotein Receptor Mutations Identified in Different Background Populations
Anne Tybjærg-Hansen *;
From the Department of Clinical Biochemistry (A.T.-H., M.B.), Rigshospitalet, Copenhagen University Hospital, the Department of Cardiology (H.K.J.), Skejby University Hospital, the Department of Medicine B (R.S.), Hillerød Hospital, the The Copenhagen City Heart Study (A.T.-H., G.J., B.G.N.), Bispebjerg University Hospital, and the Department of Clinical Biochemistry (B.G.N.), Herlev University Hospital, Denmark.
* To whom correspondence should be addressed. E-mail: at-h{at}rh.dk.
Background--The effect of mutations on phenotype is often overestimated because of ascertainment bias. We determined the effect of background population on cholesterol phenotype associated with specific mutations in the low-density lipoprotein (LDL) receptor and the relative importance of background population and type of mutation (LDL receptor [LDLR] or APOB R3500Q) for cholesterol phenotype.
Methods and Results--We studied 9255 individuals from the general population, 948 patients with ischemic heart disease (IHD), and 63 patients with clinical familial hypercholesterolemia (FH) for 3 common LDL receptor mutations. Average increase in cholesterol in LDL receptor heterozygotes identified in the general population or among patients with IHD or FH compared with noncarriers was 2.9 mmol/L, 4.1 mmol/L, and 4.9 mmol/L, respectively (P=0.02). Background population and type of mutation determined cholesterol phenotype; average increase in LDL cholesterol from carriers in the general population to carriers with clinical FH was 1.6 mmol/L (P=0.03). The average increase for carriers of LDLR mutations compared with carriers of APOB R3500Q was 1.2 mmol/L (P=0.05).
Conclusion--The phenotype associated with a given mutation should not be determined in patients, but rather in unselected individuals in the general population.
Key words: atherosclerosis • epidemiology • genetics • cardiovascular disease • hypercholesterolemia
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