Complete and partial LCAT deficiency are differentially associated with atherosclerosis

Background—Lecithin:cholesterol acyltransferase (LCAT) is the sole enzyme that esterifies cholesterol in plasma. Its role in the supposed protection from atherogenesis remains unclear since mutations in LCAT causing Fish-Eye Disease (FED) or Familial LCAT Deficiency (FLD) have been reported to be associated with more or instead less carotid atherosclerosis, respectively. This discrepancy may be associated with the loss of cholesterol esterification on only apolipoprotein (apo) A-I (FED) or on both apoA-I and apoB-containing lipoproteins (FLD), an aspect that has thus far not been investigated. Methods—Seventy-four heterozygotes for LCAT mutations recruited from Italy and the Netherlands were assigned to FLD (n=33) or FED (n=41) groups and compared to 280 controls. Subclinical atherosclerosis was assessed using carotid intima-media thickness (IMT). Results—Compared to controls, total cholesterol was lower by 16% (-32.9 mg/dL) and 7% (-14.9 mg/dL), and HDL cholesterol was lower by 29% (-16.7 mg/dL) and 36% (-20.7 mg/dL) in the FLD and FED groups, respectively. FLD subjects displayed a significant 18% lower LDL cholesterol compared with FED (101.9±35.0 vs 123.6±47.4 mg/dL, P=0.047) and controls (122.6±35.0 mg/dL, P=0.003). Remarkably, all three IMT parameters were lower in FLD compared to FED and controls (accounting for age, sex, BMI, smoking, hypertension, family history of cardiovascular disease and plasma lipids). After additional correction for nationality and ultrasonographic methods, average and maximum IMT remained significantly lower when comparing FLD to FED (0.59mm vs 0.73mm, P=0.003, and 0.87mm vs 1.24mm, P<0.001, respectively). By contrast, the common carotid IMT (corrected for age, sex, BMI, smoking, hypertension, family history of cardiovascular disease, and plasma lipids) was higher in FED compared to controls (0.69mm versus 0.65mm, P=0.05), but this significance was lost after adjustment for nationality and ultrasonographic machine. Conclusions—In this head-to-head comparison, FLD and FED mutations were shown to be associated with decreased and increased atherosclerosis, respectively. We propose that this discrepancy is related to the capacity of LCAT to generate cholesterol esters on apoB-containing lipoproteins. While this capacity is lost in FLD, it is unaffected in FED. These results are important when considering LCAT as a target to decrease atherosclerosis.