Abstract 1691: Mutations in LCAT Cause Low HDL Cholesterol Levels but in the General Population LCAT Concentration is not Associated with HDL Cholesterol
Lecithin:cholesterol acyltransferase (LCAT) is long-known to play a key role in high-density lipoprotein (HDL) metabolism but its association with atherosclerosis remains to be defined. We studied
the prevalence of LCAT mutations among people with low HDL cholesterol levels, and
the relationship between plasma LCAT concentration and risk of coronary heart disease (CHD) among apparently healthy men and women.
Seventy-five individuals referred to our outpatient clinic with low HDL cholesterol levels and a suspicion of an hereditary trait associated with this phenotype were selected for LCAT gene sequencing. Point mutations known to result in loss of LCAT function were identified in 16 of these patients. In 4 additional patients, new LCAT mutations were identified. Average lipid concentrations were: total cholesterol 4.01 mmol/l, LDL cholesterol: 2.78 mmol/l, HDL cholesterol: 0.54 mmol/l, triglycerides: 1.51 mmol/l. LCAT concentration was measured in a nested case-control study in the prospective EPIC-Norfolk cohort. Cases (n = 933) were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CHD during a mean follow-up of 6 years. Controls (n = 1852) remained free of CHD during follow-up, and were matched by age, gender, and enrolment time. LCAT concentration was not associated with HDL cholesterol but was positively associated with TC, LDL cholesterol and TG. After adjustment for the Framingham Risk Score, higher LCAT concentrations were associated with decreased risk of future CHD in men. LCAT gene sequencing in low HDL subjects revealed that partial LCAT deficiency may not be as rare a condition as previously anticipated. These data also indicate that loss of LCAT causes low HDL. By contrast, plasma LCAT concentration was not associated with HDL cholesterol levels in the general population. Clinical relevance The data provided by this first ever prospective LCAT study may help to define whether LCAT is a feasible target for drug development to increase HDL cholesterol levels and reduce atherosclerosis.