Bile lipid composition and haemostatic variables in a case of high density lipoprotein deficiency (Tangier disease)

A 62-year-old man with clinical and biochemical findings consistent with homozygous Tangier disease is presented. Widespread atherosclerosis was present. Bile lipid analysis showed a low molar percentage of cholesterol with a low saturation index. The data suggest that high density lipoprotein cholesterol may act as a preferential precursor of biliary cholesterol. Coagulation and platelet studies indicated that the patient's platelets were hyper-responsive to aggregating agents and produced an increased amount of thromboxane B2. A platelet storage pool deficiency was also found.     

Ursodeoxycholic acid treatment in humans: effects on plasma and biliary lipid metabolism with special reference to very low density lipoprotein triglyceride and bile acid kinetics

Ursodeoxycholic acid reduces biliary saturation with cholesterol and may induce dissolution of cholesterol gallstones in man. In order to characterize the effects of this potentially useful bile acid on plasma lipid metabolism, we determined lipoprotein levels and very low density lipoprotein (VLDL) triglyceride kinetics in six hypertriglyceridaemic and three normolipidaemic subjects before and after 4-6 weeks of ursodeoxycholic acid treatment at a daily dose of 15 mg kg-1 body weight. The plasma levels of low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol were not significantly affected by therapy. Nor were the plasma level and apparent formation of VLDL triglycerides changed. In five subjects, the effects of a low dose (7.5 mg kg-1 body weight day-1 for 4-6 weeks) of ursodeoxycholic acid on biliary lipid composition and kinetics of cholic acid and chenodeoxycholic acid were determined. The relative concentration of cholesterol in bile was reduced to the same level as during treatment with a high dose of ursodeoxycholic acid. The synthesis rates of bile acids were not suppressed with ursodeoxycholic acid. It is concluded that, unlike chenodeoxycholic acid, ursodeoxycholic acid does not suppress endogenous bile acid production. The efficiency at lower doses, and the lack of effects on plasma lipid metabolism, may make ursodeoxycholic acid a more attractive alternative for clinical attempts of gallstone dissolution.     

Bile acid metabolism in heterozygous familial hypercholesterolaemia: a study comparing affected and unaffected siblings of four kindreds

Previous studies have indicated that quantitative as well as qualitative abnormalities of bile acid metabolism frequently occur in hypercholesterolaemia. In order to determine if this is a feature of familial hypercholesterolaemia, bile acid kinetics and biliary lipid composition were determined in 15 affected (heterozygous) and six unaffected siblings of four kindreds with familial hypercholesterolaemia. Furthermore, serum levels of cholic acid, chenodeoxycholic acid and deoxycholic acid were measured with a mass fragmentographic technique in 15 members of two of the kindreds, and secretion rates of biliary lipids were measured in six members of two kindreds. No differences with regard to these parameters between affected and unaffected siblings could be detected. There was a close resemblance between relatives of a given kindred concerning bile acid pool size and serum bile acid levels. No evidence for a defective bile acid metabolism in familial hypercholesterolaemia could be gained from the present study. It is concluded that the deficient receptor-mediated elimination of low density lipoprotein cholesterol in this disorder does not influence the maintenance of normal bile acid metabolism.     

Gemfibrozil in familial combined hyperlipidaemia: effect of added low-dose cholestyramine on plasma and biliary lipids

Gemfibrozil is frequently used for lipid-lowering in familial combined hyperlipidaemia (FCHL) and in other forms of combined hyperlipidaemia. This therapy increases biliary cholesterol saturation, enhancing the risk for gallstone formation. Furthermore, in hypertriglyceridaemia, LDL cholesterol levels often tend to rise. We have explored the possibility that addition of a low dose of cholestyramine to gemfibrozil therapy obliterates these phenomena. Eighteen gallstone-free patients with definite (n = 5) or probable (n = 10) FCHL, or combined hyperlipoproteinaemia (n = 3) were randomized to a 6 week treatment with gemfibrozil, 600 mg b.i.d., or gemfibrozil 600 mg b.i.d. plus 4 g cholestyramine o.d. After 6 weeks the patients were crossed over to the alternative treatment. Plasma lipoproteins and biliary lipids were determined at baseline and at the end of each period. Institution of gemfibrozil treatment resulted in a decrease in plasma cholesterol by 15% (P less than 0.05) and in plasma triglycerides by 47% (P less than 0.05); HDL cholesterol increased by 18% (P less than 0.05). Addition of cholestyramine further decreased plasma and LDL total cholesterol by 9% (P less than 0.05). Total triglycerides and HDL cholesterol did not change. Gemfibrozil treatment was associated with a rise in the relative biliary concentration of cholesterol from 5.6 +/- 0.4 to 6.9 +/- 0.5 molar percent (P less than 0.01), and a parallel decrease in the relative concentration of bile acids, resulting in an increased cholesterol saturation of the bile, from 77 +/- 5 to 90 +/- 6% (P less than 0.05). This change was not observed during the combined therapy (mean cholesterol saturation, 82 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)     

High density lipoprotein infusion and partial plasma exchange in Tangier disease

High density lipoprotein (HDL) infusion and partial plasma exchange were undertaken in two patients homozygous for Tangier disease. Serum samples and ultracentrifugally isolated serum fractions were analysed over a period of 7 days post infusion by agarose electrophoresis, two-dimensional immunoelectrophoresis (employing antibodies to HDL, HDL3, Apoprotein A-I, and Apoprotein A-II), Apoprotein A radioimmunoassay, and analytical polyacrylamide electrophoresis. The following observations were made: (a) immediately after HDL substitution the broad-beta band, normally visible upon agarose electrophoresis of Tangier plasma, resolved into a distinct beta and pre-beta band; (b)as HDL was catabolized, an abnormal alpha-migrating lipoprotein was generated which contained Apoprotein A-II as protein constituent; and (c) there was a proferential loss of Apoprotein A-I from HDL and the plasma compartment in the course of HDL catabolism. The results suggest that the defect in Tangier disease resides with enhanced catabolism or defective synthesis of Apoprotein A-I.     

Effect of adiposity on plasma lipid transfer protein activities: a possible link between insulin resistance and high density lipoprotein metabolism

Abstract. The mechanisms responsible for the decreased high density lipoprotein (HDL) cholesterol levels associated with obesity and insulin resistance are not well understood. Lecithin: cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) are key factors in the esterification of cholesterol in HDL and the subsequent transfer of cholesteryl ester towards apolipoprotein B-containing lipoproteins. Phospholipid transfer protein (PLTP) may be involved in the regulation of HDL particle size. We therefore measured the activities of LCAT, CETP and PLTP using exogenous substrate assays, as well as lipids, lipoproteins, insulin and C-peptide in fasting plasma from eight healthy obese men (body mass index >27 kg m^-2) and 24 non-obese subjects. The obese men had lower levels of HDL cholesterol (P<0·05) and higher levels of plasma triglycerides (P<0·05), insulin (P<0·05) and C-peptide (P<0·01), as compared to the quartile of subjects with the lowest body mass index (BMI <22·4 kg m^-2). CETP and PLTP activities were elevated in the obese men by 35% (P<0·01) and by 15% (P<0·05), respectively. LCAT activity was comparable among the quartiles. Linear regression analysis showed that CETP activity was positively correlated with body mass index (P<0·02), fasting blood glucose (P7lt;0·05) and plasma C-peptide (P<0·05). PLTP activity was positively related to body mass index (P<0·01), waist to hip circumference ratio (P<0·001), as well as to fasting blood glucose (P<0·05) and plasma C-peptide (P<0·05) It is concluded that the activities of CETP and PLTP are influenced by adiposity and possibly by insulin resistance. Elevated lipid transfer protein activities may provide a mechanism that contributes to alterations in HDL in insulin resistant states.     

Fish eye disease: a new familial condition with massive corneal opacities and dyslipoproteinaemia Clinical and laboratory studies in two afflicted families

Abstract. Fish eye disease (FED) is characterized by severe corneal opacities, causing impaired vision, and dyslipoproteinaemia: hypertriglyceridaemia, raised levels of very low density lipoproteins (VLDL), triglyceride enrichment of low density liproteins (LDL) and reduction of high density lipoproteins (HDL). The disease is described in two unrelated families. In both there was a high proportion of low HDL in relatives without eye disease.
VLDL, LDL and HDL had normal electrophoretic mobilities. The concentrations of VLDL cholesterol and triglycerides were increased fivefold. LDL cholesterol levels were normal but LDL triglycerides markedly increased. HDL cholesterol was reduced by 90% as were the levels of HDL apolipoproteins. The major part of HDL cholesterol was in the HDL₃ fraction. FED HDL were smaller than normal with molecular weights of 115,000 daltons.
Lecithin: cholesterol acyltransferase activity and amount of cholesterol esters in serum were normal. Postheparin lipoprotein and hepatic lipases showed normal or subnormal values.
Clinically FED differs from other familial conditions with deficiency of HDL such as Tangier disease, LCAT-deficiency and Milano-AI-apoprotein disease. In spite of the extremely low HDL cholesterol FED is not characterized by premature atherosclerosis. Mechanisms for the dyslipoproteinaemia are discussed.     

Serum lipids, biliary lipid composition, and bile acid metabolism in vegetarians as compared to normal controls

Since dietary factors have been implicated in various diseases, such as coronary heart disease, gallstone formation and colonic cancer, possibly by affecting cholesterol and bile acid metabolism, we studied serum lipid levels, biliary lipid composition, cholic acid and deoxycholic acid kinetics in a group of young healthy male vegetarians and in age, sex and weight matched control subjects. Daily intake of nutrients was higher with respect to polyunsaturated fatty acids, carbohydrates and dietary fibre in the vegetarian group. Although mean serum lipid levels in the vegetarian were 8-28% lower than in the control subjects, differences were not statistically significant. Biliary lipid and biliary bile acid composition were similar in both groups. Bile acid kinetics, measured after simultaneous injection of [3H]cholic acid and [14C]deoxycholic acid, showed a slightly lower output of cholic acid and a slightly higher input of deoxycholic acid in the vegetarians, this causing a significantly (P less than 0.025) higher 7 alpha-dehydroxylation fraction (input deoxycholic acid divided by synthesis of cholic acid) in the vegetarians. Our results in young males suggest that bile acid conservation is associated with a vegetarian diet, but do not support the supposition that a vegetarian diet reduces deoxycholate formation.     

Influence of cholic and chenodeoxycholic acid on biliary cholesterol secretion in man

The interrelationships between biliary bile acid, lecithin and cholesterol secretion rates were studied druing depletion of the bile acid pool and during duodenal administration of cholic or chenodeoxycholic acid in thirteen patients 7-12 days after operation for uncomplicated gallstone disease. The mean lecithin secretion rate was signigicantly higher during cholic acid than during chenodeoxycholic acid infusion. The relationship between bile acid and cholesterol secretion rates was curvilinear, y = x/(a + bx) during bile acid pool depletion and during duodenal cholic acid infusion. At low bile acid secretion rates, during bile acid pool depletion and during cholic acid infusion, the lecithin secretion rate was significantly correlated to the cholesterol secreation rate. The bile acid and cholesterol secretion rates were not significantly correlated during chenodeoxycholic acid infusion. However, under this experimental condition a significant curvilinear relationship between lecithin and cholesterol secretion rates was found. The hepatic bile became unsaturated in cholesterol at significantly lower bile acid secretion rate during chenodeoxycholic acid infusion (10.7 +/- 0.3 mumol min-1) than during cholic acid infusion (15.6 +/- 0.5 mumol min-1).     

Oxidized low density lipoproteins, statin therapy and severity of coronary artery disease

BACKGROUND: The impact of statin therapy on the association between circulating levels of oxidized low density lipoproteins (OxLDL) and severity of coronary artery disease (CAD) has not been studied. METHODS: OxLDLs were measured in 687 patients with angiographically proven CAD (320 patients, 46.6% on statin therapy and 367 patients, 53.4% not on statin therapy on admission) using the Mercodia Oxidized LDL Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Patients on statin therapy had lower levels of OxLDL (median [interquartile range]; 63.9 U/L [53.9; 79.8] versus 72.3 U/L [58.4; 86.1], P<0.001) and C-reactive protein (3.0 mg/L [1.2; 6.6] versus 4.0 mg/L [1.7; 13.1], P<0.001) than patients not on statins. Multivariable analysis showed that statin therapy was an independent predictor of lower levels of OxLDL (P=0.0001). In univariate analysis, OxLDL level did not differ significantly among the patients with 1-, 2-or 3-vessel disease (70.5 U/L [57.5; 85.6], 66.3 U/L [53.8; 82.6] and 68.2 U/L [57.0; 83.4], respectively, P=0.26). Multivariable logistic regression analysis showed that OxLDL was an independent correlate of angiographic severity of CAD (P=0.04) and that there was an interaction (P=0.038) between statins and OxLDL in that the increased levels of OxLDL were associated with more extensive CAD. CONCLUSION: Patients with CAD who receive statins have lower levels of OxLDL and an attenuation of the relationship between circulating levels of OxLDL and CAD severity compared with patients who do not receive statins.     

Effects of a standardized wheat bran preparation on biliary lipid composition and bile acid metabolism in young healthy males

The effects of adding bran to the normal diet on biliary lipid composition and bile acid metabolism in a group of young healthy males was studied. A chemically standardized coarse wheat bran product, with serum lipid lowering properties, in a dose of 0.5 kg-1 body weight per day was used. Bran feeding for 4 or 8 weeks did not change biliary lipid and biliary bile acid composition. Faecal bile acid and neutral sterol composition was similar before and after 8 weeks of bran. Bile acid kinetics, measured by double isotope dilution after simultaneous injection of [3H]cholic acid and [14C]deoxycholic acid, showed only minor differences before and during bran ingestion. The most surprising finding was an increase in 7 alpha-dehydroxylation fraction (input of deoxycholic acid divided by synthesis of cholic acid) in six out of seven subjects after 4 weeks of brain and in all four subjects after 8 weeks of bran. In conclusion, the bran product we used is not effective in lowering the biliary cholesterol saturation in healthy young males. Nor does it reduce deoxycholate input in our subjects even after 8 weeks of bran.     

Effect of the composition of very low and low density lipoproteins on the rate of cholesterylester transfer from high density lipoproteins in man, studied in vitro

The process of cholesterylester (CE) transfer is supposed to be a regulatory factor in the distribution of CE between lipoproteins. In addition to the activity of CE transfer protein, this process may be affected by acceptor lipoprotein characteristics. In this study the effect of the composition of different very low density lipoproteins (VLDL) and low density lipoproteins (LDL) on the ability to accept CE from HDL in vitro was investigated. [3H]-CE high density lipoprotein (HDL) (100 nmol CE) from one batch was incubated with VLDL (75 nmol CE), isolated from fifteen subjects for 4 h and separately with LDL (250 nmol CE), isolated from thirteen subjects for 16 h, both in the presence of lipoprotein-free plasma providing a source of cholesterylester transfer protein. The CE transfer rate of VLDL (range 1.34-2.84% [3H]-CE transferred h-1) was correlated to the triacylglycerol (TG):CE molar ratio (r: 0.63, P less than 0.05), to the phospholipid (PL):CE molar ratio (r: 0.75, P less than 0.01), to the protein (Pr):CE ratio (expressed in g nmol-1) (r: 0.72, P less than 0.01) and to the free cholesterol (FC):CE molar ratio (r: 0.69, P less than 0.01), but not to the FC:PL molar ratio (r: -0.08, NS). The CE transfer rate to LDL (range 1.18-3.59 nmol CE h-1) was correlated to the Pr:CE ratio (r: 0.72, P less than 0.01) and inversely to the FRC:PL molar ratio (r: -0.88, P less than 0.001), but not to the TG:CE molar ratio (r: 0.40, NS), nor to the FC:CE molar ratio (r: -0.37, NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Variation at the cholesteryl ester transfer protein gene in relation to plasma high density lipoproteins cholesterol levels and carotid intima-media thickness

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a major role in lipoprotein metabolism. We have screened the CETP gene for mutations and polymorphisms regulating high density lipoproteins cholesterol (HDL-C) levels and the development of atherosclerosis, and found some polymorphisms (I405V and R451Q) to have minor effects. DESIGN: The purpose of this study was to investigate the combined effect of the several polymorphisms of the CETP gene so far found on HDL-C levels and carotid intima-media thickness (IMT), and, in addition, to study whether the recently found functional polymorphism in the promoter region of the CETP gene (C to A, - 629 relative to the first transcribed nucleotide) explains the previous associations due to linkage disequilibrium. The genotypes were determined in a population sample of 481 men and women. RESULTS: There were no significant differences in plasma CETP activity or carotid IMT between the genotypes of the promoter polymorphism. The women with the CC genotype of the promoter polymorphism had the lowest HDL-C levels (P < 0.001), but no such difference was seen in men. Detected polymorphisms of the CETP gene explained about 8% of the variation in HDL-C in women and about 7 and 10% of the variation in carotid IMT in women and men, respectively. The associations of the promoter, I405V and R451Q-A373P polymorphisms with HDL-C and carotid IMT seemed to be independent of each other. The associations with IMT were independent of total HDL-C levels, suggesting that HDL subfractions may have more effect on IMT. CONCLUSION: The CETP gene locus was found to be polymorphic and its polymorphisms explained a reasonable proportion of the variation in the degree of carotid atherosclerosis.     

单核细胞与高密度脂蛋白比值在心血管疾病中的研究进展

心血管疾病的发生和发展与炎症反应和脂质沉积密切相关,单核细胞的积累和高密度脂蛋白胆固醇的减低在其中发挥了重要作用。单核细胞与高密度脂蛋白胆固醇比值(monocyte to high density lipoprotein cholesterol ratio,MHR)是一种结合了炎症和抗炎的新型炎症反应标志物,目前有研究报道其能够以实用、经济、快捷的方式评估心血管疾病(cardiovascular diseases,CVD)的发生、发展及预后。     

Lecithin: cholesterol acyl transfer rate and high density lipoproteins in plasma during dietary and cholestyramine treatment of type Ila hyperlipoproteinaemia

Abstract. Changes in the lecithin:cholesterol acyl transfer rate and the concentrations of lipids and high density lipoprotein lipids in plasma were studied during dietary and cholestyramine treatment of type IIa subjects. Samples were obtained from twenty subjects before and 2 months after the start of a cholesterol lowering diet. Sixteen subjects were studied 1 month after the addition of cholestyramine treatment to the dietary regimen.
During 2 months of dietary modification the mean concentrations of cholesterol, phospholipids and low density lipoprotein cholesterol were reduced by 10%. In the high density lipoprotein fraction there was a 10% mean increase of the cholesterol but no change of the mean phospholipid concentration. There were no changes of the mean triglyceride concentration or the mean fractional or molar lecithin:cholesterol acyl transfer rates in plasma.
One month after the addition of cholestyramine to the diet there were further reductions in the mean plasma concentrations of cholesterol by 22.5%, phospholipids by 12% and low density lipoprotein cholesterol by 32%. The mean triglyceride concentration and the mean concentration and composition of the high density lipoprotein fraction were unchanged. The mean fractional Iecithin _:cholesterol acyl transfer rate was increased by 30%. The type IIa subjects with high molar lecithin: cholesterol acyl transfer rates during the diet showed increments of molar lecithin:cholesterol acyl transfer rates during cholestyramine therapy.
Interpretations of these findings in relation to lipoprotein metabolism are discussed.     

血清总胆固醇与高密度脂蛋白胆固醇比值作为冠心病危险标志的意义

目的分析冠心病(CHD)患者的血脂水平,探讨血清总胆固醇(TC)与高密度脂蛋白胆固醇(HDL-C)比值作为CHD危险标志的临床意义。方法测定295例CHD患者的血清TC、三酰甘油(TG)、HDL-C及低密度脂蛋白胆固醇(LDL-C)水平,并计算TC/HDL-C比值。结果依据《中国成人血脂异常防治指南》颁布的血脂水平合适范围,CHD患者血清TC、TG及LDLC高于合适范围百分率分别为32.20%、34.24%及37.63%,血清HDL-C低于合适范围百分率为39.32%。血清TC/HDL-C比值高于合适范围百分率为57.29%。血清TC/HDL-C比值异常率显著高于血清TC、TG、HDL-C及LDL-C(χ2=37.540、31.576、19.066、22.866,P0.01)。结论与任一单项血脂检测相比,血清TC/HDL-C比值作为CHD危险标志可能更有临床意义,临床血脂检测报告单应增加TC/HDL-C比值。     

Amino acids and lipoproteins in plasma of duodenopancreatectomized patients: effects of glucagon in physiological amounts

Duodenopancreatectomy induces a severe glucagon deficiency and elevated plasma concentrations of alanine, aspartate, glycine, proline, serine, arginine, citrulline, ornithine, phenylalanine and tyrosine. Restoring high physiological plasma glucagon in six such patients by infusing 0.3 mg/24 h of exogenous glucagon reduced significantly (P less than 0.01 or 0.001) the mentioned amino acids (except phenylalanine) and further asparagine, glutamine, methionine and threonine. In six normal subjects the same infusion reduced significantly (P less than 0.05 to 0.001) plasma alanine, asparagine, glutamate, glutamine, glycine, proline, serine, threonine, arginine, ornithine, lysine and tyrosine. However, the effect was significantly (P less than 0.01 or 0.001) less marked for alanine, glutamine, glycine, methionine, serine, threonine and arginine. This particular glucagon sensitivity of duodenopancreatectomized patients suggests that glucagon deficiency is the cause of their hyperaminacidaemia. By contrast, lipoprotein concentrations were virtually unaffected by either glucagon deficiency or its replacement. In the light of the marked hypoaminacidaemia in glucagonoma patients these results attribute to glucagon a major role as a regulator of protein metabolism.     

Acute dietary effects on plasma lipids, lipoproteins and lipolytic enzymes in healthy normal males

Diurnal plasma lipids and lipoproteins were studied in twelve healthy young males on corn oil and palm oil diets, respectively. The major triglyceridy. Lecithin-cholesterol acyl transferase, lipoprotein lipase and hepatic triglyceride lipase were also measured. diurnal changes of triglycerides and cholesterol were confined to lipoproteins of d less than 1.006 kg/l. There was a diurnal rise of lecithin-cholesterol acyl transferase activity with corn oil but not with palm oil. Fasting and postprandial postheparin lipoprotein lipase and hepatic triglyceride lipase were similar but there was a significant correlation of postprandial hepatic lipase with postprandial plasma triglycerides on palm oil. Marked diurnal changes of triglyceride fatty acids were observed not only in 'very low density lipoprotein' but also in high-density lipoprotein amounting to approximately one third of total high density lipoprotein triglyceride fatty acids.     

Effects of weight reduction on plasma lipoproteins and adipose tissue metabolism in obese subjects

The relationship between obesity and alterations in adipose tissue metabolism and lipid transport was studied in fourteen obese subjects before and after a weight reduction of 4-22 kg. Blood glucose and plasma insulin patterns after peroral glucose intake improved significantly, and plasma glucagon levels decreased markedly after treatment. Plasma triglyceride and total cholesterol levels were not altered, but there was a 20% (P less than 0.05) increase in HDL concentrations. Plasma free fatty acid and glycerol concentrations decreased, in parallel to a decrease in lipolysis rate in vitro. Lipoprotein lipase and hepatic lipase activities in postheparin plasma, as well as the intravenous fat tolerance test, were normal and did not change significantly after weight loss. Lipoprotein lipase activity in adipose tissue, expressed per cell, was elevated and did not change after weight reduction. Also, the enzyme activity did not increase after glucose intake before or after treatment. The lack of effect on lipoprotein lipase activity and regulation in combination with significant improvements of other aspects of lipid and glucose transport is consistent with the view that alterations in LPL activity and regulation may represent an early and possibly primary defect in the development of obesity.     

Polymorphism of the apolipoprotein A-IV gene and its significance in lipid metabolism and coronary heart disease in a Japanese population

Apolipoprotein A-IV (apo A-IV) is involved in the metabolism of both triglycerides and high-density lipoproteins (HDLs). Apo A-IV has been suggested as participating in several stages of reverse cholesterol transport. Uncertainty about the exact biochemical function of apo A-IV has made the use of genetic apo A-IV polymorphism (variants) attractive in evaluating its physiological role. To date, although some reports indicate that DNA polymorphisms at this locus play an important role in the metabolism of lipids and lipoproteins in western (Caucasian) populations, no similar comprehensive analysis has been performed in a distinct Japanese population. Using DNA sequencing and a restriction fragment length polymorphism (RFLP) study with polymerase chain reaction (PCR), the following allele frequencies were established: (a) codon ?8 (G→A, non-synonymous) allele 2=0 (n=105); (b) codon 9 (A→G, synonymous) allele 2=0.388 (n=152); (c) codon 347 (A→T, non-synonymous) allele 2=0 (n=900); (d) codon 360 (T→G, non-synonymous) allele 2=0 (n=800); (e) VNTR exon 3 [(CTGT)₃ and (CTGT)₄] (CTGT)₃=0.262 (n=105); and (f ) MspI (newly detected polymorphic site) polymorphism (C C/T GG) within intron 2, allele 2=0.096 (n=193). The frequencies of these polymorphisms, except for that of the newly identified MspI site, are completely different from those reported in western populations. Among the 900 subjects examined, we found one ACT (Thr) to ACG (Thr) synonymous mutation at codon 347, which does not change the primary structure of apo A-IV. The apo A-IV allele frequency in patients (166 men and 56 women) with angiographically proven coronary heart disease (CHD) was also studied [codon 9 allele 2=0.329 (n=217); VNTR exon 3 (CTGT)₃=0.262 (n=84); MspI within intron 2, allele 2=0.092 (n=222)]. Furthermore, we evaluated serum lipid and lipoprotein levels quantitatively in control subjects and Japanese CHD patients. These polymorphisms did not show any consistent and significant association with lipid and lipoprotein parameters. In addition, no gender-specific effects of apo A-IV polymorphisms on lipid parameters adjusted for confounding factors were observed in either CHD patients or control subjects. Our results indicate that the apo A-IV gene is not a major determinant of the risk for CHD in Japanese.