Published Online
on August 1, 2005

A more recent version of this article appeared on August 9, 2005

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Submitted on September 29, 2004
Revised on April 19, 2005
Accepted on April 26, 2005

Compromised LCAT Function Is Associated With Increased Atherosclerosis

G. Kees Hovingh MD, Barbara A. Hutten PhD, Adriaan G. Holleboom MD, Wilma Petersen BSc, Patrick Rol BSc, Anton Stalenhoef MD, PhD, Aeilko H. Zwinderman PhD, Eric de Groot MD, PhD, John J.P. Kastelein MD PhD, and Jan Albert Kuivenhoven PhD^*

From the Departments of Vascular Medicine (G.K.H., A.G.H., W.P., P.R., E.d.G., J.J.P.K., J.A.K.) and Clinical Epidemiology and Biostatistics (B.A.H., A.H.Z.), Academic Medical Center, Amsterdam, the Netherlands, and Department of Medicine (A.S.), University Medical Centre Nijmegen, Nijmegen, the Netherlands.

^* To whom correspondence should be addressed. E-mail: j.a.kuivenhoven{at}amc.uva.nl.

Background--Prospective epidemiological studies have shown that low plasma levels of HDL cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease (CVD). Despite nearly 40 years of research, however, it is unclear whether this also holds true for individuals with severely reduced levels of HDL-C due to mutations in the lecithin:cholesterol acyltransferase (LCAT) gene. Better insight into CVD risk in these individuals may provide clues toward the potential of LCAT as a pharmaceutical target to raise HDL-C levels.

Methods and Results--Lipids, lipoproteins, high-sensitivity C-reactive protein (CRP), and carotid artery intima-media thickness (IMT) were assessed in 47 heterozygotes for LCAT gene mutations and 58 family controls. Compared with controls, heterozygotes presented with a mean 36% decrease in HDL-C levels (P<0.0001), a 23% increase in triglyceride levels (P<0.0001), and a 2.1-fold increase in CRP levels (P<0.0001). Mean carotid IMT was significantly increased in heterozygotes compared with family controls (0.623±0.13 versus 0.591±0.08 mm). After adjustment for age, gender, and alcohol use, this difference proved statistically significant (P<0.0015).

Conclusions--The data show that heterozygosity for LCAT gene defects is associated with low HDL-C levels and elevated concentration of triglycerides and CRP in plasma. This phenotype underlies increased IMT in carriers versus controls, which suggests that LCAT protects against atherosclerosis. This in turn indicates that targeting LCAT to raise HDL-C may reduce CVD risk.

Key words: lipoproteins • atherosclerosis • cardiovascular diseases • cholesterol • genetics

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