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.