The yin and yang of cholesteryl ester transfer protein in cardiovascular disease.

Cholesteryl ester transfer protein (CETP) is a 79-kDa glycoprotein, present in humans, rabbits, primates, and hamsters but absent in rodents, dogs, horses, cows, and pigs, that facilitates transfer of cholesteryl ester from high-density lipoprotein (HDL) particles to low-density lipoprotein (LDL)–very-low-density lipoprotein (vLDL) particles in exchange for triglycerides, thereby participating in reverse cholesterol transport and regulating circulating HDL cholesterol (HDL-C) levels.1,2 In 1989, Brown et al3 described 2 Japanese subjects with markedly elevated HDL-C levels who were homozygous for a point mutation in the 5 -splice donor site of intron 14 of the CETP gene, a change that was shown to be incompatible with normal splicing of pre–messenger RNA. The following year, Inazu et al4 reported that 4 of 11 additional families from 3 different regions of Japan with elevated HDL-C were homozygous or heterozygous for the same mutation with gene-dose– dependent increases in HDL-C levels. Because epidemiological studies had generally shown an inverse relationship between circulating HDL-C levels and coronary heart disease (CHD), loss-offunction CETP mutations associated with increased HDL-C levels were thus thought to confer protection against CHD. This view is further supported by studies that have shown that increased CETP activity is associated with increased atherosclerosis progression and/or cardiovascular risk.5,6 A prospective 7-year follow-up study of American men of Japanese descent from the Honolulu Heart Program suggested that CETP mutations associated with reduced CETP activity and markedly elevated HDL-C ( 60 mg/dL) may confer a lower risk of CHD,7 although an earlier cross-sectional analysis had suggested the opposite.8 Contrary to these observations, other studies have shown that reduced CETP activity is associated with paradoxically increased CHD despite elevated HDL-C levels.9–12 A deleterious CETP haplotype was shown to be associated with a 6-fold increase in myocardial infarction risk independent of HDL-C levels.13 Similarly, carriers of CETP Taq1B B2 allele were shown to have increased CHD events over a 10-year follow-up period.14 A recent meta-analysis involving subjects genotyped for 3 common CETP variants provided inconclusive results showing a very weak association between CETP deficiency and lower relative risk of CHD.15 Thus, the inconsistent and often contradictory relationship between CETP activity and CHD risk has created uncertainty as to whether CETP is a friend or foe in atherosclerosis (Figure).