Genetics
Combined CETP and hepatic lipase deficiency drives atherosclerotic disease in some patients with marked high HDL (Arterioscler Thromb Vasc Biol 1995)
Original title: Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase
Researchers studied 201 patients (111 men, 90 women) with marked hyperalphalipoproteinemia (HDL cholesterol 100 mg per dL or higher), a state often regarded as part of a longevity syndrome, of whom 67 percent carried CETP gene mutations in intron 14 or exon 15. Despite the generally protective reputation of high HDL, 9.0 percent of male patients and 2.2 percent of female patients had apparent atherosclerotic cardiovascular disease including myocardial infarction, angina, or peripheral vascular disease, and all ten of these patients with disease were heterozygotes for CETP deficiency. The study, building on earlier case reports of markedly hyperalphalipoproteinemic patients with reduced hepatic triglyceride lipase activity and a CETP exon 15 missense mutation, characterises combined CETP and hepatic lipase reduction as a driver of atherogenic risk within this ostensibly protective lipid state.
Original abstract
Hyperalphalipoproteinemia (HALP) 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. The 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 HALP, we determined the incidence of atherosclerotic cardiovascular disease (ACD) in patients with marked HALP 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 HALP ( > or = 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 HALP who had ACD were identified to be heterozygotes for CETP deficiency. To further clarify the characteristics of marked HALP 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.