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(Circulation. 2002;106:3031.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Low-Density Lipoprotein Receptor Gene Mutations and Cardiovascular Risk in a Large Genetic Cascade Screening Population

From the Department of Vascular Medicine (M.A.W.U.-E., J.J.P.K., J.C.D.), Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands; the Foundation for the Identification of Persons with Inherited Hypercholesterolemia (M.A.W.U.-E., J.J.P.K.), Amsterdam, the Netherlands; and the Department of Internal Medicine (E.J.G.S.), Erasmus Medical Center, Rotterdam, the Netherlands.

Correspondence to Dr Ir J.C. Defesche, Department of Vascular Medicine, G1–146, Academic Medical Center at the University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail j.defesche{at}amc.uva.nl

Background— A large cohort of patients with familial hypercholesterolemia (FH), free from selection for cardiovascular disease (CVD), and their unaffected relatives was collected by genetic cascade screening and examined for the influence of different mutations of the LDL receptor gene on lipoprotein levels and the risk of CVD. Multivariate analyses with adjustment for age, sex, and specific family ties were performed.

Methods and Results— Significant variation of LDL levels was observed among 399 patients with FH with different mutations. Null alleles were associated with more severely elevated LDL cholesterol, whereas the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol. The type of mutation did not influence HDL cholesterol levels. Patients with FH had CVD 8.5 times more often compared with their unaffected relatives (RR, 8.54; 95% CI, 5.29 to 13.80). The N543H/2393del9 mutation was associated with a smaller increase of risk compared with other mutations (P<0.0001). After exclusion of families with the N543H/2393del9 mutation, null alleles and other allele mutations no longer differed with regard to LDL cholesterol levels and CVD risk.

Conclusions— LDL receptor mutations only partly contributed to the variation of LDL cholesterol levels and cardiovascular burden in FH. Additional, so far unidentified, familial risk factors must underlie the differences of CVD risk, most likely independent of lipids and lipoproteins.

Key Words: atherosclerosis • cardiovascular diseases • genetics • lipoproteins • risk factors

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