An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients

Apolipoprotein A-V (apoA-V) is an important regulator of plasma levels of triglyceride (TG) in mice. In humans, APOA5 genetic variation is associated with TG in several populations. In this study, we determined the effects of the p.185Gly>Cys (c.553G>T; rs2075291) polymorphism on plasma TG levels in subjects of Chinese ancestry living in the United States and in a group of non-Chinese Asian ancestry. The frequency of the less common cysteine allele was 4-fold higher (15.1% vs. 3.7%) in Chinese high-TG subjects compared with a low-TG group (Chi-square = 20.2; P < 0.0001), corresponding with a 4.45 times higher risk of hypertriglyceridemia (95% confidence interval, 2.18-9.07; P < 0.001). These results were replicated in the non-Chinese Asians. Heterozygosity was associated, in the high-TG group, with a doubling of TG (P < 0.001), mainly VLDL TG (P = 0.014). All eleven TT homozygotes had severe hypertriglyceridemia, with mean TG of 2,292 +/- 447 mg/dl. Compared with controls, carriers of the T allele had lower postheparin lipoprotein lipase activity but not hepatic lipase activity. In Asian populations, this common polymorphism can lead to profound adverse effects on lipoprotein profiles, with homozygosity accounting for a significant number of cases of severe hypertriglyceridemia. This specific apoA-V variant has a pronounced effect on TG metabolism, the mechanism of which remains to be elucidated.     

Increased concentration of plasma cholesteryl ester transfer protein in nephrotic syndrome: role in dyslipidemia.

Hyperlipidemia is a prominent feature of the nephrotic syndrome. Lipoprotein abnormalities include increased very low and low density lipoprotein (VLDL and LDL) cholesterol and variable reductions in high density lipoprotein (HDL) cholesterol. We hypothesized that plasma cholesteryl ester transfer protein (CETP), which influences the distribution of cholesteryl esters among the lipoproteins, might contribute to lipoprotein abnormalities in nephrotic syndrome. Plasma CETP, apolipoprotein and lipoprotein concentrations were measured in 14 consecutive untreated and 7 treated nephrotic patients, 5 patients with primary hypertriglyceridemia, and 18 normolipidemic controls. Patients with nephrotic syndrome displayed increased plasma concentrations of apoB, VLDL, and LDL cholesterol. The VLDL was enriched with cholesteryl ester (CE), shown by a CE/triglyceride (TG) ratio approximately twice that in normolipidemic or hypertriglyceridemic controls (P < 0.001). Plasma CETP concentration was increased in patients with untreated nephrotic syndrome compared to controls (3.6 vs. 2.3 mg/l, P < 0.001), and was positively correlated with the CE concentration in VLDL (r = 0.69, P = 0.004) and with plasma apoB concentration (r = 0.68, P = 0.007). Treatment with corticosteroids resulted in normalization of plasma CETP and of the CE/TG ratio in VLDL. An inverse correlation between plasma CETP and HDL cholesterol was observed in hypertriglyceridemic nephrotic syndrome patients (r = -0.67, P = 0.03). The dyslipidemia of nephrotic syndrome includes increased levels of apoB-lipoproteins and VLDL that are unusually enriched in CE and likely to be atherogenic. Increased plasma CETP probably plays a significant role in the enrichment of VLDL with CE, and may also contribute to increased concentrations of apoB-lipoproteins and decreased HDL cholesterol in some patients.     

Apolipoprotein A-IV genetic polymorphism and its impact on quantitative traits in normoglycemic and non-insulin-dependent diabetic Hispanics from the San Luis Valley, Colorado.

Apolipoprotein A-IV exhibits a common two-allele polymorphism in several human populations studied to date. Using isoelectric focusing and immunoblotting, we have analyzed plasmas from 188 non-insulin-dependent diabetic and 238 normoglycemic Hispanic individuals from the San Luis Valley, Colorado, to determine APOA4 genotype frequencies and to estimate the impact of the genotypes on quantitative traits. The frequencies of the two common alleles, APOA4*1 and APOA4*2, were 0.929 and 0.069, respectively, in normal subjects and 0.901 and 0.096, respectively, in diabetics. The third rare allele, APOA4*3, was detected sporadically in both groups. We studied the impact of APOA4 polymorphism on the levels of total plasma cholesterol, HDL cholesterol and its subfractions (HDL3 and HDL2), LDL cholesterol, triglycerides, glucose, and insulin. We observed no significant effect of the APOA4 polymorphism on any trait in diabetics. However, we did note a significant sex-specific effect in normoglycemic females on the level of total HDL cholesterol (p = 0.001) and its subfractions HDL2 (p = 0.043) and HDL3 (p = 0.001). The effect of the APOA4*2 allele in normal Hispanic females was to lower the total HDL, HDL2, and HDL3 cholesterol by 8.75 mg/dl, 2.37 mg/dl, and 5.36 mg/dl, respectively, compared to the common APOA4*1 allele.     

Genetic studies of human apolipoproteins. XI. The effect of the apolipoprotein C-II polymorphism on lipoprotein levels in Nigerian blacks

The human apolipoprotein C-II locus exhibits genetically determined structural polymorphism in United States and African blacks. In the present study, we have investigated the effect of the apoC-II polymorphism on quantitative serum levels of total cholesterol, total high density lipoprotein (HDL) cholesterol, cholesterol in high density lipoprotein subfractions, low density lipoprotein (LDL) cholesterol, and triglycerides (TG) in a sample of 368 unrelated Nigerian blacks. The frequencies of the APOC-II*1 and APOC-II*2 alleles in the samples were 0.947 and 0.053, respectively. In males, the effect of the APOC-II*2 allele was to lower the total serum cholesterol and LDL-cholesterol levels by 13.28 mg/dl and 10.55 mg/dl, respectively, relative to the common allele, APOC-II*1. In females, the effect was to lower total plasma cholesterol by 4.49 mg/dl and LDL-cholesterol by 3.21 mg/dl. The effect of apoC-II on quantitative lipoprotein levels is shown to be independent of variation at the linked apoE locus, but the products of the two loci interact in determining overall quantitative phenotypes.     

Polymorphisms in the lipoprotein lipase and hepatic lipase genes and plasma lipid values in the Czech population

We have determined the genotypes of two common polymorphisms in the lipoprotein lipase (S447X) and hepatic lipase (-480C/T) genes in a cohort of 285 representative selected Czech probands (131 male and 154 female), examined in 1988 and reinvestigated in 1996. The genotype distributions of both polymorphisms were in Hardy-Weinberg equilibrium and did not differ between male and female subjects. The rare allele frequency of the lipoprotein lipase polymorphism did not differ significantly from the other European populations. Compared to the German populations, the frequency of the hepatic lipase -480T allele was significantly higher in the Czech group (20% vs. 36%, p<0.0001). There were no significant associations between the lipoprotein lipase gene variants and lipid parameters measured either in 1988, or in 1996 or with changes of lipid parameters over the 8-year period. The carriers of the T-480 allele of the hepatic lipase polymorphism were found to have higher HDL cholesterol levels (p=0.02). However, this difference was confined to female subjects only. The male carriers of the -480T allele had higher concentrations of total cholesterol (p=0.03) as compared to CC-480 subjects. Both associations were observed in 1996 only. In the Slavic Czech population, a common polymorphism in the hepatic lipase gene (-480C/T), but not in the lipoprotein lipase gene (S447X), is a significant determinant of plasma HDL cholesterol in females and plasma total cholesterol in males and indicates the importance of gender-associated effects in the genetic determinations of plasma lipids.     

Association of Two CETP Polymorphisms With HDL Levels in the Chinese Obese Population

The association of two cholesterol ester transfer protein (CETP) polymorphisms, D442G and TAQIB (B1→B2), with high‐density lipoprotein (HDL) levels in 932 Chinese obese individuals (BMI ≥ 27) was investigated in comparison with normal controls (BMI ≤ 24). Independent association was demonstrated for TAQIB minor allele B2 and CETP442 minor allele G with elevated HDL levels. The CETP D442G polymorphism was associated with a much greater increase in HDL levels in subjects with BMI exceeding 27 kg/m² (+5.42 mg/dl, P = 0.0007) compared to normal controls (+1.97 mg/dl, P = 0.275), and the increase in HDL reached the highest level among subjects with BMI exceeding 30 kg/m² (+6.80 mg/dl, P = 0.016). TAQIB showed significant association with HDL levels only in normal BMI subgroup (P = 0.0017). TAQIB significantly interacted with serum triglyceride (TG) on modulating HDL levels (P = 0.027). The TAQIB–TG interaction effect remained marginally significant after controlling for BMI (P = 0.057). We conclude that D442G polymorphism is associated with more HDL elevation in obesity. TAQIB interacts with serum TG on modulating HDL levels, and the interaction is partly independent of BMI.     

A study of the metabolism of apolipoprotein B100 in relation to insulin resistance in African American males.

The purpose of this study was to determine the relationship between insulin resistance and apoB100 metabolism in African American males. Fifteen subjects, 33 +/- 7.6 years old, were divided into two groups, insulin-resistant (IR) or insulin-sensitive (IS), based on the sum of the plasma insulin concentrations during an oral glucose tolerance test. The IR group (n = 8) differed significantly from the IS group (n = 7) with respect to body mass index (BMI) (30.1 vs 23.1 kg/m2; P = 0.0003), fasting triglycerides, (118 vs 54 mg/dl, P = 0. 013), and total plasma apolipoprotein B100 (80 vs 59 mg/dl, P = 0.014). Significantly elevated apoB100 levels in the IR group were seen in very low density lipoprotein (VLDL) (5.1 vs 3.4 mg/dl, P = 0.045) and intermediate density lipoprotein (IDL) (18 vs 12 mg/dl, P = 0.017) but not in low density lipoprotein (LDL) (57 vs 46 mg/dl, P = 0.19). Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A-I, and blood pressure were not significantly different between the two groups. There was a high correlation between the sum of insulins during the oral glucose tolerance test and the BMI (rho = 0.88, P = 0.0001). In five IR and five IS subjects, apoB100 kinetics were determined in the fasting state using a bolus dose of deuteroleucine and multicompartmental modeling. IR subjects had significantly lower fractional catabolic rates (FCR) in the larger VLDL1 (-70%), the smaller VLDL2 (-71%), and the IDL (-53%) fractions. No significant differences in production rates were observed for any lipoprotein class. There was a significant correlation between the sum of insulins and the FCR of the apoB100 of VLDL1 (rho = -0.65, P = 0.05) and of IDL (rho = -0.85, P = 0.004). The correlation coefficient of the sum of insulins and the FCR of VLDL2 was -0.61 with P = 0.067. We conclude that in this population of African American males, IR is correlated with a decreased FCR of apoB100 in VLDL and IDL and elevated plasma levels of apoB and triglycerides (TG). These changes might be explained by decreased clearance of the TG-rich lipoproteins. We postulate that this may reflect decreased lipoprotein and/or hepatic lipase activity related to insulin resistance and its association with obesity.     

Acute inhibition of hepatic lipase and increase in plasma lipoproteins after alcohol intake

Chronic alcohol intake is associated with an increase in fasting plasma high density lipoproteins (HDL). To study alcohol's acute effects on plasma lipoproteins, we measured plasma lipoprotein concentrations and activities of postheparin plasma lipases in nine normolipemic males after ingestion of 40 g of ethanol (as whiskey). After alcohol there was no change in lipoprotein lipase activity but hepatic lipase was decreased to 67% of baseline at 6 hr. There were associated increases in HDL phospholipids (12 mg/dl) and cholesterol (10 mg/dl) resulting in prominence of larger, lipid-enriched HDL particles. Changes were most pronounced in the HDL3 and HDL2a subclasses. Very low density lipoprotein (VLDL) phospholipids and cholesterol were also increased by 13 and 9 mg/dl, respectively, with no significant change in triglycerides. Changes in lipoproteins and lipase were largely reversed 10 hr after alcohol intake. The transient increases in VLDL and HDL lipids after alcohol may result in part from acute inhibition of hepatic lipase activity. The results suggest a role of hepatic lipase in the catabolism of phospholipids of VLDL and possibly HDL.     

Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia

Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 +/- 0.9 to 4.3 +/- 0.2 mg/dl (-38 +/- 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 +/- 0.8 vs. 1.7 +/- 0.2 mg/dl; -42 +/- 11%) and IDL/LDL apoE (1.9 +/- 0.3 vs. 0.8 +/- 0.1 mg/dl; -57 +/- 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 +/- 0.39 to 3.04 +/- 0.51 mg/kg/day (-34 +/- 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 +/- 0.67 to 2.26 +/- 0.42 mg/kg/day (-36 +/- 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.     

Plasma kinetics of VLDL and HDL apoC-I in normolipidemic and hypertriglyceridemic subjects

ApoC-I has several different lipid-regulating functions including, inhibition of receptor-mediated uptake of plasma triglyceride-rich lipoproteins, inhibition of cholesteryl ester transfer activity, and mediation of tissue fatty acid uptake. Since little is known about the rate of production and catabolism of plasma apoC-I in humans, the present study was undertaken to determine the plasma kinetics of VLDL and HDL apoC-I using a primed constant (12 h) intravenous infusion of deuterium-labeled leucine. Data were obtained for 14 subjects: normolipidemics (NL, n = 4), hypertriglyceridemics (HTG, n = 4) and combined hyperlipidemics (CHL, n = 6). Plasma VLDL triglyceride (TG) levels were 0.59 +/- 0.03, 4.32 +/- 0.77 (P < 0.01 vs. NL), and 2.20 +/- 0.39 mmol/l (P < 0.01 vs. NL), and plasma LDL cholesterol (LDL-C) levels were 2.34 +/- 0.22, 2.48 +/- 0.26, and 5.35 +/- 0.48 mmol/l (P < 0.01 vs. NL), respectively. HTG and CHL had significantly (P < 0.05) increased levels of total plasma apoC-I (12.5 +/- 1.2 and 12.4 +/- 1.3 mg/dl, respectively) versus NL (7.9 +/- 0.6 mg/dl), due to significantly (P < 0.01) elevated levels of VLDL apoC-I (5.8 +/- 0.8 and 4.5 +/- 0.8 vs. 0.3 +/- 0.1 mg/dl). HTG and CHL also had increased rates of VLDL apoC-I transport (i.e., production) versus NL: 2.29 +/- 0.34 and 3.04 +/- 0.53 versus 0.24 +/- 0.11 mg/kg.day (P < 0.01), with no significant change in VLDL apoC-I residence times (RT): 1.16 +/- 0.12 versus 0.69 +/- 0.06 versus 0.74 +/- 0.17. Although HDL apoC-I concentrations were not significantly lower in HTG and CHL versus NL, HDL apoC-I rates of transport were inversely related to plasma and VLDL-TG levels (r = -0.63 and -0.62, respectively, P < 0.05). Our results demonstrate that increased levels of plasma and VLDL apoC-I in hypertriglyceridemic subjects (with or without elevated LDL-C levels) are associated with increased levels of plasma VLDL apoC-I production.     

Storage of human plasma samples leads to alterations in the lipoprotein distribution of apoC-III and apoE

The effect of frozen storage on lipoprotein distribution of apolipoprotein C-III (apoC-III) and apoE was investigated by measuring apoC-III and apoE by ELISA in HDL and apoB-containing lipoproteins of human plasma samples (n = 16) before and after 2 weeks of frozen storage (-20 degrees C). HDLs were separated by heparin-manganese precipitation (HMP) or by fast-protein liquid chromatography (FPLC). Total plasma apoC-III and apoE levels were not affected by frozen storage. HDL-HMP apoC-III and apoE levels were significantly higher in frozen versus fresh samples: 7.7 +/- 0.7 versus 6.7 +/- 0.7 mg/dl (P < 0.05) and 2.0 +/- 0.1 versus 1.2 +/- 0.1 mg/dl (P < 0.001), respectively. HDL-FPLC apoC-III and apoE, but not triglyceride (TG) or cholesterol, levels were also higher in frozen samples: 12.0 +/- 1.2 versus 7.5 +/- 0.6 mg/dl (P < 0.001) and 2.7 +/- 0.2 versus 1.6 +/- 0.2 mg/dl (P < 0.001), respectively. Frozen storage led to a decrease in apoC-III (-17 +/- 9%) and apoE (-19 +/- 9%) in triglyceride-rich lipoprotein. Redistribution of apoC-III and apoE was most evident in samples with high TG levels. HDL apoC-III and apoE levels were also significantly higher when measured in plasma stored at -80 degrees C. Our results demonstrate that lipoprotein distribution of apoC-III and apoE is affected by storage of human plasma, suggesting that analysis of frozen plasma should be avoided in studies relating lipoprotein levels of apoC-III and/or apoE to the incidence of coronary artery disease.     

Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Phospholipid transfer protein (PLTP) participates in key processes in lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. The impact of PLTP on reverse cholesterol transport suggests that the gene may harbor sequence anomalies that contribute to disorders of HDL metabolism. The human PLTP gene was screened for sequence anomalies by DNA melting analysis in 276 subjects with hypoalphalipoproteinemia (HA) and 364 controls. The association with plasma lipid parameters was evaluated. We discovered 18 sequence variations, including four missense mutations and a novel polymorphism (c.-34G > C). In healthy controls, the c.-34G > C minor allele was associated with higher high density lipoprotein-cholesterol (HDL-C) and was depleted in subjects with HA. Linear regression models predict that possession of the rare allele decreases plasma triglyceride (TG) and TG/HDL-C and increases HDL-C independent of TG. Decreased PLTP activity was observed in one (p.R235W) of four (p.E72G, p.S119A, p.S124Y, and p.R235W) mutations in an in vitro activity assay. These findings indicate that PLTP gene variation is an important determinant of plasma lipoproteins and affects disorders of HDL metabolism.     

Structural peculiarities of the binding of very low density lipoproteins and low density lipoproteins to the LDL receptor in hypertriglyceridemia: role of apolipoprotein E

Very low (VLDL) and low density lipoproteins (LDL) were isolated from plasma of patients with the E3/3 phenotype which were divided into three groups based on their plasma triglyceride content: low (TG<200 mg/dl, TG(l)), intermediate (200<300 mg/dl, TG(i)300 mg/dl, TG(h)). The protein density (PD) on the VLDL and LDL surface was calculated from lipoprotein composition and protein location was studied by tryptophan fluorescence quenching by I(-) anions at 25 degrees C and 40 degrees C. A comparison of the TG(h) with the TG(l) group revealed a significant (<0.05) increase of the PD parameter as much as 21% for VLDL, but not for LDL where this parameter did not change for any group; generally, PD(LDL) values were 3.2-3.8-fold lower than PD(VLDL). In accordance with this difference, the tryptophan accessibility f in VLDL vs. LDL was lower at both temperatures. There were temperature-induced changes of the f parameter in opposite directions for these lipoproteins. The difference in f value gradually decreased for VLDL in the direction TG(l)TG(i)TG(h) while for LDL there was a U-shaped dependence for these groups. The Stern-Volmer quenching constant K(S-V) which is sensitive to both temperature and viscosity, did not change for VLDL, but K(S-V)(LDL) was 2-3-fold higher for the TG(i) group compared to the other two. The efficiencies of VLDL and LDL binding to the LDL receptor (LDLr) in vitro were compared by solid-phase assay free of steric hindrance observed in cell binding. The maximal number of binding sites did not change for either type of particles and between groups. The association constant K(a) and apolipoprotein (apo) E/apoB mole ratio values all increased significantly for VLDL, but not for LDL, in comparison of the TG(i+h) with the TG(l) group. Based on VLDL and LDL concentrations in serum and on the affinity constant values obtained in an in vitro assay, VLDL concentrations corresponding to 50% inhibition of LDL binding (IC(50)) were calculated in an assumption of the competition of both ligands for LDLr in vivo; the mean values of IC(50) decreased 2-fold when plasma TG exceeded 200 mg/dl. The functional dependences of K(a)(VLDL), IC(50) and apoE content in VLDL (both fractional and absolute) and in serum on TG content in the whole concentration range studied were fitted to a saturation model. For all five parameters, the mean half-maximum values TG(1/2) were in the range 52-103 mg/dl. The efficiency of protein-protein interactions is suggested to differ in normolipidemic vs. HTG-VLDL and apoE content and/or protein density on VLDL surface may be the primary determinant(s) of the increased binding of HTG-VLDL to the LDL receptor. ApoCs may compete with apoE for the binding to the VLDL lipid surface as plasma triglyceride content increases. The possible competition of VLDL with LDL for the catabolism site(s) in vivo, when plasma TG increases, could explain the atherogenic action of TG-rich lipoproteins. Moreover, the 'dual action' hypothesis on anti-atherogenic action of apoE-containing high density lipoproteins (HDL) in vivo is suggested: besides the well-known effect of HDL as cholesteryl ester catabolic outway, the formation of a transient complex of apoE-containing discs appearing at the site of VLDL TG hydrolysis by lipoprotein lipase with VLDL particles proposed in our preceding paper promotes the efficient uptake of TG-rich particles; in hypertriglyceridemia due to the diminished HDL content this uptake seems to be impaired which results in the increased accumulation of the remnants of TG-rich particles. This explains the observed increase in cholesterol and triglyceride content in VLDL and LDL, respectively, due to the CETP-mediated exchange of cholesteryl ester and triglyceride molecules between these particles.     

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN studyboxs

Chronically elevated interleukin-6 (IL-6) affects lipid and lipoprotein metabolism. Individuals genetically predisposed to higher IL-6 secretion may be at risk of dyslipidemia, especially during the postprandial phase. We investigated the effect of genetic variants at the IL6 locus on postprandial lipemia in US Whites participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Subjects were given a single fat load composed of 3% of calories as protein, 14% as carbohydrate, and 83% as fat. Blood was drawn at 0 h, 3.5 h, and 6 h to determine plasma triglyceride (TG), TG-rich lipoprotein (TRL) and lipoprotein particle size. Homozygotes (GG) and heterozygotes (CG) of the -174C/G variant displayed higher plasma IL-6 concentrations compared with major allele homozygotes (CC) (P = 0.029). GG and CG subjects showed higher fasting plasma TG (P = 0.025), VLDL (P = 0.04), and large VLDL (P = 0.02) concentrations than did CC subjects. Moreover, GG and CG subjects experienced greater postprandial response of TG (P = 0.006) and TRL, including chylomicrons (P = 0.005), total VLDL (P = 0.029), and large VLDL (P = 0.017) than did CC subjects. These results suggest that the functional polymorphism -174C>G at the IL6 locus determines the difference in both fasting and postprandial TG metabolism. This phenomenon could be responsible for the observed association of this genetic variant with cardiovascular disease risk.     

Genetic studies of human apolipoproteins

Summary Apolipoprotein H (APO H) has recently been identified as a structural component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Although the precise metabolic function of APO H in lipid metabolism is not certain, it has been suggested that APO H may be involved in triglyceride (TG) metabolism. In addition to the previously described quantitative polymorphism, we have recently detected a common qualitative polymorphism at the APO H structural locus. To test the role of APO H genetic variation in determining lipoprotein and lipid levels, we have estimated the allelic effects of APO H variation on TG, VLDL, LDL, HDL, HDL3, and total cholesterol on 356 Nigerian blacks(189 males, 167 females). While no significant effect of phenotype was observed on lipoprotein levels, the effect of interaction between phenotype and gender was significant. Therefore, data on males and females were analyzed separately using analysis of variance after adjusting for age and body mass index. Logarithmic transformation of pertinent variables was done to bring the distribution of the variables closer to normality. A statistically significant effect of phenotype was observed on triglyceride levels in females only (P<0.05). Further analysis of this phenotypic effect revealed that it is due to the impact of the APO H ^* 3 allele, which raises triglycerides by 9.92 mg/dl as compared to the common allele, APO H ^* 2. These findings are in accordance with the postulated role of APO H in triglyceride metabolism. On the basis of its sex-specific effect, we propose a hypothesis that may explain the combined influence of the quantitative and qualitative polymorphisms at the APO H locus on triglyceride levels in females.     

Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks.

Human apolipoprotein E exhibits genetic polymorphism in all populations examined to date. By isoelectric focusing and immunoblotting, three common alleles have been demonstrated in 365 unrelated Nigerian blacks. Furthermore, the APO E genetic polymorphism's effect on quantitative levels of lipids and lipoproteins has been determined. The respective frequencies of the APO E*2, APO E*3, and APO E*4 alleles are .027, .677, and .296. The effect of APO E polymorphism is significant only on total cholesterol and low-density lipoprotein cholesterol. The average excesses of the APO E*2 allele are to lower total cholesterol and low-density lipoprotein cholesterol by 9.19 mg/dl and 11.11 mg/dl, respectively. The average excesses of the APO E*4 allele are to increase total cholesterol and low-density lipoprotein cholesterol by 5.64 mg/dl and 6.18 mg/dl, respectively. On the basis of the differences in (a) the distribution of APO E allele frequencies between the Nigerians and other populations and (b) dietary lipids, we propose a model that shows that lipid metabolism is influenced by the combined effects of the APO E polymorphism and environmental factors.     

The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations.

Application of uniform methods for measuring the apolipoprotein (apo) E polymorphism and plasma cholesterol levels in nine populations (Tyrolean, Sudanese, Indian, Chinese, Japanese, Hungarian, Icelandic, Finnish, and Malay) revealed significant heterogeneity among them in apo E type frequencies and mean cholesterol levels. The major apo E types in all populations were E3/2 (frequency range from 7.0% in Indians to 16.9% in Malays), E3/3 (frequency range from 39.8% in Sudanese to 72.1% in Japanese), and E3/4 (frequency range from 11.3% in Japanese to 35.9% in Sudanese). Mean cholesterol levels ranged from 144.2 mg/dl in the Sudanese to 228.5 mg/dl in the Icelandics. Two-way analysis of variance of the effect of population and apo E type on cholesterol levels showed no significantly interaction effect, indicating that the effects of apo E type on cholesterol levels do not differ significantly among the populations. The overall average excess for the epsilon 2 allele was -14.12 mg/dl (range -31.63 to -8.82 mg/dl); for the epsilon 3 allele, 0.04 mg/dl (range -1.87 to 1.58 mg/dl; and for the epsilon 4 allele, 8.14 mg/dl (range -1.71 to 13.31 mg/dl). Despite the apparent heterogeneity in these values, especially for the epsilon 4 allele, comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations. These data indicate that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors.     

Apolipoprotein AV variants do not affect C-reactive protein levels in Caucasian males

The important role of APOAV gene variants in determination of plasma triglyceride levels has been shown in many population studies. Recently, an influence of APOAV T-1131>C polymorphism on C-reactive protein (CRP) in young Korean males has been reported. We have therefore analyzed a putative association between T-1131>C, Ser19>Trp and Val153>Met APOAV variants (PCR and restriction analysis) and CRP concentrations in 1119 Caucasian males, aged between 28 and 67 years (49.2+/-10.8 years). The frequency of C allele carriers was lower in Caucasians than in Koreans (15.5% vs. 46.2%). CRP levels did not differ between T/T homozygotes (n=946, 1.61+/-2.05 mg/l) and carriers of the C allele (n=173, 1.67+/-1.95 mg/l). Thus, in contrast to Korean males, T-1131>C APOAV variant has no effect on plasma concentrations of CRP in a large group of Caucasian males. Other APOAV variants (Ser19>Trp and Val153>Met) did not also influence plasma concentrations of CRP. APOAV variants are unlikely to be an important genetic determinant of plasma CRP concentrations in Caucasian males.     

Lipoprotein lipase and apoE polymorphisms: relationship to hypertriglyceridemia during pregnancy.

Pregnancy is associated with increases in plasma total cholesterol (TC) and triglycerides (TG). Individuals with decreased LPL activity have a mild form of hypertriglyceridemia. Variations in the apolipoprotein E (apoE) gene have been associated with increases in plasma TG in addition to differences in plasma TC, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C). Because of the overproduction of TG-rich VLDL, normal pregnancy challenges the lipolytic capacity of LPL and the clearance of remnants particles. During pregnancy, LPL and apoE polymorphisms may contribute to hypertriglyceridemia. This study investigated the impact of three LPL polymorphisms and the apoE genotypes on lipid levels during pregnancy. Fasting plasma lipids were measured and analyses of the LPL and apoE polymorphisms were performed in 250 women in the third trimester of pregnancy. S447X carriers had lower TG (P = 0.003), and N291S carriers had lower HDL-C (P < 0.02) and higher fractional esterification rate of HDL (FER(HDL)) (P = 0.007), a measure of HDL particle size, than the noncarriers. The E2 allele was associated with lower TC, LDL-C, and FER(HDL) (P < 0.05) compared to the E3/E3 genotype. These findings support that LPL and apoE polymorphisms play an important role in lipid metabolism in pregnancy. The relationship of these polymorphisms to risk of coronary heart disease in women requires further study.     

Hepatic lipase gene -514C>T variant is associated with exercise training-induced changes in VLDL and HDL by lipoprotein lipase

Our objective was to test the hypothesis that a common polymorphism in the hepatic lipase (HL) gene (LIPC -514C>T, rs1800588) influences aerobic exercise training-induced changes in TG, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) through genotype-specific increases in lipoprotein lipase (LPL) activity and that sex may affect these responses. Seventy-six sedentary overweight to obese men and women aged 50-75 yr at risk for coronary heart disease (CHD) underwent a 24-wk prospective study of the LIPC -514 genotype-specific effects of exercise training on lipoproteins measured enzymatically and by nuclear magnetic resonance, postheparin LPL and HL activities, body composition by dual energy x-ray absorptiometry and computer tomography scan, and aerobic capacity. CT genotype subjects had higher baseline total cholesterol, HDL-C, HDL(2)-C, large HDL, HDL particle size, and large LDL than CC homozygotes. Exercise training elicited genotype-specific decreases in VLDL-TG (-22 vs. +7%; P < 0.05; CC vs. CT, respectively), total VLDL and medium VLDL, and increases in HDL-C (7 vs. 4%; P < 0.03) and HDL(3)-C with significant genotype×sex interactions for the changes in HDL-C and HDL(3)-C (P values = 0.01-0.02). There were also genotype-specific changes in LPL (+23 vs. -6%; P < 0.05) and HL (+7 vs. -24%; P < 0.01) activities, with LPL increasing only in CC subjects (P < 0.006) and HL decreasing only in CT subjects (P < 0.007). Reductions in TG, VLDL-TG, large VLDL, and medium VLDL and increases in HDL(3)-C and small HDL particles correlated significantly with changes in LPL, but not HL, activity only in CC subjects. This suggests that the LIPC -514C>T variant significantly affects training-induced anti-atherogenic changes in VLDL-TG, VLDL particles, and HDL through an association with increased LPL activity in CC subjects, which could guide therapeutic strategies to reduce CHD risk.