Compromised LCAT function is associated with increased atherosclerosis

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