Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity.

Low levels of HDL cholesterol have been clearly demonstrated to be associated with an increased incidence of coronary heart disease, strongly suggesting that HDL particles have an antiatherogenic function. However, little information has been available concerning the atherogenicity of a marked hyperalphalipoproteinemia (HALP). There is no agreement about whether plasma cholesteryl ester transfer protein (CETP) deficiency is associated with an antiatherogenic state or not, although this disorder was reported to be one of the major causes of marked HALP. In the current study, we have found a unique area (Omagari City, Akita Prefecture, Japan) where CETP deficiency caused by a G-to-A mutation at the 5' splice donor site of intron 14 in the CETP gene is extremely frequent. In Omagari City, the mutation was detected more than 20 times more frequently and the prevalence of a marked HALP with plasma HDL cholesterol > or = 2.58 mmol/L (100 mg/dL) was 5 to 10 times higher than in other areas of Japan. This discovery has made it possible to perform a large population-based study concerning the atherogenicity of a marked elevation of HDL cholesterol in a genetically more homogeneous population. There was a statistically significant U-shaped relationship between HDL cholesterol levels and the incidence of ischemic changes in electrocardiograms. In cases of HDL cholesterol < 1.81 mmol/L (70 mg/dL), the incidence increased in proportion to the levels of HDL cholesterol. The frequency of the CETP gene mutation was higher in patients with coronary heart disease than in healthy control subjects. In subjects aged > 80 years, the prevalence of both marked HALP and the intron 14 splicing defect was significantly lower than in the younger generation. The current study indicated for the first time that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome, suggesting the importance of reevaluation of the clinical significance and pathophysiology of a marked HALP.

[1]  S. Yamashita,et al.  Marked hyper-HDL2-cholesterolemia associated with premature corneal opacity. A case report. , 1984, Atherosclerosis.

[2]  A. Tall,et al.  Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. , 1990, The New England journal of medicine.

[3]  B. Philipson,et al.  Fish eye disease: a new familial condition with massive corneal opacities and dyslipoproteinaemia Clinical and laboratory studies in two afflicted families , 1982, European journal of clinical investigation.

[4]  S. Yamashita,et al.  A novel nonsense mutation (G181X) in the human cholesteryl ester transfer protein gene in Japanese hyperalphalipoproteinemic subjects. , 1996, Journal of lipid research.

[5]  G. Miller,et al.  PLASMA-HIGH-DENSITY-LIPOPROTEIN CONCENTRATION AND DEVELOPMENT OF ISCHÆMIC HEART-DISEASE , 1975, The Lancet.

[6]  N. Miller,et al.  Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism. , 1989, Arteriosclerosis.

[7]  A. Tall,et al.  Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins , 1989, Nature.

[8]  Charles R.scriver,et al.  The Metabolic basis of inherited disease , 1989 .

[9]  S. Yamashita,et al.  Detection of two species of low density lipoprotein particles in cholesteryl ester transfer protein deficiency. , 1991, Arteriosclerosis and thrombosis : a journal of vascular biology.

[10]  S. Yamashita,et al.  Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity. , 1988, Atherosclerosis.

[11]  S. Yamashita,et al.  Polydisperse low-density lipoproteins in hyperalphalipoproteinemic chronic alcohol drinkers in association with marked reduction of cholesteryl ester transfer protein activity. , 1992, Metabolism: clinical and experimental.

[12]  M C Hjortland,et al.  High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. , 1977, The American journal of medicine.

[13]  R. Knapp,et al.  Electrocardiographic Abnormalities and 30‐Year Mortality Among White and Black Men of the Charleston Heart Study , 1993, Circulation.

[14]  W. Jb,et al.  Very high values of serum high-density lipoprotein cholesterol. , 1992 .

[15]  J. Sasaki,et al.  Detection of a point mutation in cholesteryl ester transfer protein gene by polymerase chain reaction-mediated site-directed mutagenesis. , 1993, Biochimica et biophysica acta.

[16]  E. Rubin,et al.  Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. , 1995, The Journal of clinical investigation.

[17]  S. Yamashita,et al.  Very High Density Lipoproteins Induced by Plasma Cholesteryl Ester Transfer Protein (CETP) Have a Potent Antiatherogenic Function a , 1994, Annals of the New York Academy of Sciences.

[18]  N. Ernst,et al.  Alcohol and High‐density Lipoprotein Cholesterol , 1981, Circulation.

[19]  R. Elston,et al.  Familial hyper-alpha-lipoproteinemia: studies in eighteen kindreds. , 1975, Metabolism: clinical and experimental.

[20]  L. Colomo,et al.  Reference intervals for serum lipids, lipoproteins, and apoproteins in the elderly. , 1984, Clinical chemistry.

[21]  S. Yamashita,et al.  Accumulation of apolipoprotein E-rich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency. , 1990, The Journal of clinical investigation.

[22]  G. Franceschini,et al.  Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients , 1991, European journal of clinical investigation.

[23]  D. McGee,et al.  Alcohol and Cardiovascular Disease: The Hawaiian Experience , 1981, Circulation.

[24]  Y. Matsuzawa,et al.  Determination by the SRID Method of Normal Values of Serum Apolipoproteins (A-I, A-II, B, C-II, C-III, and E) in Normolipidemic Healthy Japanese Subjects , 1986 .

[25]  H. Hobbs,et al.  Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia. , 1987, The New England journal of medicine.

[26]  S. Yamashita,et al.  Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. , 1995, Atherosclerosis.

[27]  S. Yamashita,et al.  Frequency of intron 14 splicing defect of cholesteryl ester transfer protein gene in the Japanese general population--relation between the mutation and hyperalphalipoproteinemia. , 1993, Atherosclerosis.

[28]  S. Yamashita,et al.  A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins. , 1993, The Journal of clinical investigation.

[29]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[30]  S. Yamashita,et al.  Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency can not protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. , 1994, Journal of biochemistry.

[31]  S. Kihara,et al.  Atherosclerotic disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[32]  A. Tall,et al.  Cholesteryl ester transfer proteins, reverse cholesterol transport, and atherosclerosis , 1995, Current opinion in lipidology.

[33]  D. Thelle,et al.  THE TROMSØHEART-STUDY HIGH-DENSITY LIPOPROTEIN AND CORONARY HEART-DISEASE: A PROSPECTIVE CASE-CONTROL STUDY , 1977, The Lancet.

[34]  S. Yamashita,et al.  Low-density lipoproteins in hyperalphalipoproteinemic heavy alcohol drinkers have reduced affinity for the low-density lipoprotein receptor. , 1992, Clinical biochemistry.

[35]  H. Arai,et al.  Purification, microheterogeneity, and stability of human lipid transfer protein. , 1989, The Journal of biological chemistry.

[36]  S. Yamashita,et al.  Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency , 1995, European journal of clinical investigation.

[37]  M. Nikkilä,et al.  High-density lipoprotein cholesterol and longevity. , 1990, Age and ageing.

[38]  S. Yamashita,et al.  Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyperHDL2 cholesterolemia with abnormal cholesteryl ester transfer. , 1988, The American journal of cardiology.