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.


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.
Hovingh
G Kees
GK
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Hutten
Barbara A
BA
Holleboom
Adriaan G
AG
Petersen
Wilma
W
Rol
Patrick
P
Stalenhoef
Anton
A
Zwinderman
Aeilko H
AH
de Groot
Eric
E
Kastelein
John J P
JJ
Kuivenhoven
Jan Albert
JA
D000328:Adult; D050197:Atherosclerosis / Q000201:enzymology / Q000453:epidemiology*; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000453:epidemiology*; D002339:Carotid Arteries / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism*; D012016:Reference Values; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D008076:Cholesterol, HDL; D002097:C-Reactive Protein; D007862:Phosphatidylcholine-Sterol O-Acyltransferase