Compromised LCAT function is associated with increased atherosclerosis

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 leve...

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Published in:	Circulation (New York, N.Y.) Vol. 112; no. 6; pp. 879 - 884
Main Authors:	HOVINGH, G. Kees, HUTTEN, Barbara A, HOLLEBOOM, Adriaan G, PETERSEN, Wilma, ROL, Patrick, STALENHOEF, Anton, ZWINDERMAN, Aeilko H, DE GROOT, Eric, KASTELEIN, J. P, KUIVENHOVEN, Jan Albert
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 09-08-2005
Subjects:	Adult Atherosclerosis (general aspects, experimental research) Atherosclerosis - enzymology Atherosclerosis - epidemiology Biological and medical sciences Blood and lymphatic vessels Blood coagulation. Blood cells C-Reactive Protein - metabolism Cardiology. Vascular system Cardiovascular Diseases - enzymology Cardiovascular Diseases - epidemiology Carotid Arteries - pathology Cholesterol, HDL - blood Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Female Fundamental and applied biological sciences. Psychology Genetic Carrier Screening Humans Male Medical sciences Middle Aged Molecular and cellular biology Mutation Phosphatidylcholine-Sterol O-Acyltransferase - genetics Phosphatidylcholine-Sterol O-Acyltransferase - metabolism Platelet Reference Values Tunica Intima - pathology Tunica Media - pathology Vascular disease genetics Atherosclerosis Lipids Cardiovascular disease Lipoprotein cardiovascular diseases Cholesterol lipoproteins
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Summary:	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. 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). 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-7322 1524-4539
DOI:	10.1161/CIRCULATIONAHA.105.540427