ATHEROSCLEROTIC DISEASE IN MARKED HYPERALPHALIPOPROTEINEMIA - COMBINED REDUCTION OF CHOLESTERYL ESTER TRANSFER PROTEIN AND HEPATIC TRIGLYCERIDE LIPASE

Hyperalphalipoproteinemia (HALF) has been regarded as a beneficial state accompanied by a longevity syndrome. However, we reported the cases of markedly hyperalphalipoproteinemic subjects with juvenile corneal opacification. These patients had reduced postheparin hepatic triglyceride lipase (HTGL) activities, and one of them has recently been identified to be homozygous for a missense mutation in exon 15 (D442: G) in the cholesteryl ester transfer protein (CETP) gene. In the current study, to elucidate the clinical significance of and atherogenicity in marked HALF, we determined the incidence of atherosclerotic cardiovascular disease (ACD) in patients with marked HALF and characterized the lipoprotein abnormalities in those who had ACD, focusing especially on CETP and HTGL. The subjects were 201 patients (111 males and 90 females) with marked HALF (greater than or equal to 2.58 mmol/L [100 mg/dL]), 67% of whom were demonstrated to have the CETP gene mutations in the intron 14 splice donor site or in exon 15. Their mean age was 54 +/- 15 years. Plasma levels of total cholesterol, HDL cholesterol, and triglyceride in all subjects were 6.28 +/- 1.78, 3.15 +/- 0.90, and 1.08 +/- 0.53 mmol/L, respectively. Ten of the male patients (9.0%) and two of the female patients (2.2%) had apparent ACD such as myocardial infarction, angina pectoris, and peripheral vascular diseases. Ten patients with HALF who had ACD were identified to be heterozygotes for CETP deficiency. To further clarify the characteristics of marked HALF in patients with ACD. we compared the plasma lipids, lipoproteins, CETP, and HTGL activities between heterozygotes for CETP deficiency who were with and without ACD. There was no significant difference in plasma lipids, lipoproteins, and CETP between the two groups, whereas HTGL activities were significantly lower in the heterozygotes for CETP deficiency with ACD than in the heterozygotes without ACD and in control subjects. These results suggest that marked HALF may not always be a beneficial state and that people who are heterozygotes for CETP deficiency and who have low HTGL may be susceptible to ACD.