A novel homozygous mutation in CETP gene as a cause of CETP deficiency in a Caucasian kindred.

Objective: To analyze the cholesteryl ester transfer protein (CETP) gene and the plasma HDL phenotype in a Caucasian subject with extremely elevated plasma high density lipoprotein-cholesterol (HDL-C).

Methods And Results: The proband, a 63-year-old male of Swedish ancestry with elevated HDL-C (208mg/dl) and apoA-I (and 272mg/dl), was found to be homozygous for a point mutation in exon 2 of CETP gene (c.109 C>T) resulting in a premature termination codon (R37X). Plasma CETP mass and activity were undetectable. Plasma HDL were characterized by predominance of large HDL with enhanced prebeta-HDL content. The proband's sons, heterozygotes for the mutation, had reduced plasma CETP activity and moderately elevated HDL-C. Serum of CETP deficient subjects showed a normal or enhanced cholesterol efflux capacity via ABCG1/SR-BI; cholesterol efflux via ABCA1 and macrophage cholesterol removal were lower than normal. The proband was healthy and had no atherosclerotic plaques in carotid or femoral arteries.

Conclusion: Complete CETP deficiency caused by mutations in CETP gene is exceedingly rare in Caucasians; the description of this single case indicates that CETP deficiency does not predispose to atherosclerosis in the absence of major cardiovascular risk factors.