Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia

BACKGROUND: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. MATERIALS AND METHODS: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (-1131T>C and S19W) were genotyped. RESULTS: Haplotype analysis of APOA5 showed an association with FCH (p=0.029), total cholesterol (p=0.031), triglycerides (p<0.001), apolipoprotein B (p=0.011), HDL-cholesterol (p=0.013), small dense LDL (p=0.010) and remnant-like particle cholesterol (p=0.001). Compared to S19 homozygotes, 19W carriers had an increased risk of FCH (OR=1.6 [1.0-2.6]; p=0.026) and a more atherogenic lipid profile, reflected by higher triglyceride (+22%) and apolipoprotein B levels (+5%), decreased HDL-cholesterol levels (-7%) and an increased prevalence of small dense LDL (16% vs. 26%). In carriers of the -1131C allele, small dense LDL was more prevalent than in -1131T homozygotes (29% vs. 16%). No association of the APOA5 gene with IMT and CVD was evident. CONCLUSION: In Dutch FCH families, variants in the APOA5 gene are associated with FCH and an atherogenic lipid profile.     

Plasma distribution of apoA-IV in patients with coronary artery disease and healthy controls

Recent studies showed lower apolipoprotein A-IV (apoA-IV) plasma concentrations in patients with coronary artery disease (CAD). The actual distribution of the antiatherogenic apoA-IV in human plasma, however, is discussed controversially and it was never investigated in CAD patients. We therefore developed a gentle technique to separate the various apoA-IV-containing plasma fractions. Using a combination of precipitation of all lipoproteins with 40% phosphotungstic acid and 4 M MgCl2, as well as immunoprecipitation of all apoA-I-containing particles with an anti-apoA-I antibody, we obtained three fractions of apoA-IV: lipid-free apoA-IV (about 4% of total apoA-IV), apoA-IV associated with apoA-I (LpA-I:A-IV, 12%), and apoA-I-unbound but lipoprotein-containing apoA-IV (LpA-IV, 84%). We compared these three apoA-IV fractions between 52 patients with a history of CAD and 52 age- and sex-matched healthy controls. Patients had significantly lower apoA-IV levels when compared to controls (10.28 +/- 3.67 mg/dl vs. 11.85 +/- 2.82 mg/dl, P = 0.029), but no major differences for the three plasma apoA-IV fractions. We conclude that our gentle separation method reveals a different distribution of apoA-IV than in many earlier studies. No major differences exist in the apoA-IV plasma distribution pattern between CAD patients and controls. Therefore, the antiatherogenic effect of apoA-IV has to be explained by other functional properties of apoA-IV (e.g., the antioxidative characteristics).     

Ciprofibrate therapy in patients with hypertriglyceridemia and low high density lipoprotein (HDL)-cholesterol: greater reduction of non-HDL cholesterol in subjects with excess body weight (The CIPROAMLAT study)

Background

Microalbuminuria and subsequent progression to proteinuria and nephropathy is associated with increased oxidative stress, increased inflammatory cytokines and increased cardiovascular (CVD) risk. The common functional IL-6 -174G>C gene variant is also associated with elevated levels of inflammatory cytokines and CVD risk.

Methods

The aim of this study was to examine the association between the IL-6 -174G>C gene variant with plasma total antioxidant status (TAOS) in 552 subjects with type 2 diabetes in relation to urinary protein excretion.

Results

In subjects free from CVD, there was a significant interaction between urinary protein excretion (normoalbuminuria/ microalbuminuria/proteinuria) and the -174C allele (compared to -174GG) in determining plasma TAOS (p value for interaction = 0.03). In the -174C allele carriers there was a significant association between plasma TAOS and urinary protein excretion: normalbuminuria v microalbuminuria v proteinuria: 44.30% ± 11.32 vs. 39.74% ± 14.83 vs. 37.93% ± 16.42, ANOVA p = 0.025. In those with CVD, no interaction or association was observed with the -174C allele (p = 0.246).

Conclusion

The IL-6 -174G>C gene variant is associated with differences in plasma oxidative stress in response to altered protein excretion in subjects with type 2 diabetes.     

Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans

We investigated the effect of the A-IV-2 allele, which encodes a Q360H substitution in apolipoprotein (apo) A-IV, and dietary fat on cholesterol absorption in humans. In three separate studies we compared fractional intestinal cholesterol absorption between groups of subjects heterozygous for the A-IV-2 allele (1/2) and homozygous for the common allele (1/1) receiving high cholesterol ( approximately 800 mg/day) diets with different fatty acid compositions. All subjects had the apoE 3/3 genotype. There was no difference in cholesterol absorption between the two genotype groups receiving a high saturated fat diet (33% of total energy as fat; 18% saturated, 3% polyunsaturated, 12% monounsaturated) or a low fat diet (22% of total energy as fat; 7% saturated, 7% polyunsaturated, 8% monounsaturated) diet. However, on a high polyunsaturated fat diet (32% of total energy as fat; 7% saturated, 13% polyunsaturated, 12% monounsaturated) mean fractional cholesterol absorption was 56. 7% +/- 1.9 in 1/1 subjects versus 47.5% +/- 2.1 in 1/2 subjects (P = 0.004). A post hoc analysis of the effect of the apoA-IV T347S polymorphism across all diets revealed a Q360H x T347S interaction on cholesterol absorption, and suggested that the A-IV-2 allele lowers cholesterol only in subjects with the 347 T/T genotype.We conclude that a complex interaction between apoA-IV genotype and dietary fatty acid composition modulates fractional intestinal cholesterol absorption in humans.     

The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes

Common variants in APOA5 and APOC3 have been associated with differences in plasma triglyceride (TG) levels in healthy individuals. The aim of this study was to examine the association of APOA5 (-1131T>C, S19W) and APOC3 (-482C>T, 1100C>T) polymorphisms in patients with type 2 diabetes (T2D) of European White (EW) (n=931), Indian Asian (IA) (n=610) and Afro-Caribbean (AC) (n=167) origin, with lipid and T2D parameters. Rare allele frequencies and linkage disequilibrium differed significantly amongst ethnic groups. Compared to APOA5 -1131T and 19S homozygotes, -1131C and 19W carriers had higher TGs in all groups, but this effect was only statistically significant for the -1131C in the EWs (P=0.04) and 19W in the IAs (P<0.001). APOC3 SNPs showed no significant association with lipid levels in any ethnic group. While haplotypes carrying -1131C allele showed significant TG-raising in the EWs only, the 19W defined haplotype showed significant TG-raising in both IAs and EWs. Comparing all four SNPs in EW T2D subjects with healthy EWs (n=2579), the APOC3 1100C>T frequency was significantly higher in T2D [0.26 (0.24, 0.28)] vs. healthy EWs [0.22 (0.20, 0.23)], P=0.001. While the variable size effects of the two APOA5 SNPs on TG levels may result from ethnically different gene-gene or gene-environment interactions, APOA5 and APOC3 variants did not affect parameters of T2D. However, comparison between EWs with T2D and healthy EWs suggest APOC3 1100C>T is associated with increased risk of diabetes probably through mechanisms other than direct effects on TG.     

Role of the kidney in the metabolism of apolipoprotein A-IV: influence of the type of proteinuria

Increased plasma concentrations of apolipoprotein A-IV (apoA-IV) in chronic renal disease suggest a metabolic role of the kidney for this antiatherogenic protein. Therefore, we investigated patients with various forms of proteinuria and found increased serum concentrations of apoA-IV in 124 nephrotic patients compared with 274 controls (mean 21.9 +/- 9.6 vs. 14.4 +/- 4.0 mg/dl; P < 0.001). Decreasing creatinine clearance showed a strong association with increasing apoA-IV levels. However, serum albumin levels significantly modulated apoA-IV levels in patients with low creatinine clearance, resulting in lower levels of apoA-IV in patients with low compared with high albumin levels (21.4 +/- 8.6 vs. 29.2 +/- 8.4 mg/dl; P = 0.0007). Furthermore, we investigated urinary apoA-IV levels in an additional 66 patients with a wide variety of proteinuria and 30 controls. Especially patients with a tubular type of proteinuria had significantly higher amounts of apoA-IV in urine than those with a pure glomerular type of proteinuria and controls (median 45, 14, and 0.6 ng/mg creatinine, respectively). We confirmed these results in affected members of a family with Dent's disease, who are characterized by an inherited protein reabsorption defect of the proximal tubular system. In summary, our data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. From this investigation of apoA-IV in urine as well as earlier immunohistochemical studies, we conclude that apoA-IV is filtered through the normal glomerulus and is subsequently reabsorbed mainly by proximal tubular cells.     

Ⅱ型糖尿病患者APOA5-1131T/C基因多态性与血脂代谢和胰岛素抵抗的关系研究

为了探讨载脂蛋白A5基因(APOA5)-1131T/C多态性在中国镇江地区的频率分布及其与血浆脂质代谢和Ⅱ型糖尿病患者胰岛素抵抗的关系, 采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)结合琼脂糖凝胶电泳技术检测152例健康人及71例Ⅱ型糖尿病患者APOA5 -1131T/C基因型及等位基因频率分布, 同时采用生化方法测定所有研究对象的血脂、血糖和胰岛素水平。结果显示: 糖尿病组APOA5 -1131C等位基因频率显著高于对照组(0.430 vs 0.296, P = 0.006)。CC纯合子患糖尿病的风险是TT纯合子的3.75倍(OR = 3.75, 95% CI: 1.57~8.92), 且经Logistic回归分析, 校正年龄、BMI和血浆HDL-c、LDL-c及ApoB水平等其他混杂因素影响后, 这种差异仍具有显著性意义(OR = 2.70, 95%CI: 1.24 ~ 5.86)。糖尿病组C等位基因携带者TG水平显著高于非C等位基因携带者(P < 0.01), TC水平和LDL-c水平亦明显升高(P < 0.05)。但是在两组中, 不同基因型患者 胰岛素抵抗相关指标均无显示差异。提示APOA5-1131T/C单核苷酸多态性对人群血浆TG水平有影响, -1131C等位基因与血浆TG、TC和LDL-c水平增高有关, 但是与糖尿病患者胰岛素相关指标无关; APOA5 -1131C等位基因可能与人群糖尿病的发生相关联。     

Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study

Several polymorphisms in the APOA5 gene have been associated with increased plasma triglyceride (TG) concentrations. However, associations between APOA5 and lipoprotein subclasses, remnant-like particles (RLPs), and cardiovascular disease (CVD) risk have been less explored. We investigated associations of five APOA5 single-nucleotide polymorphisms (SNPs; -1131T>C, -3A>G, 56C>G IVS3+ 476G>A, and 1259T>C) with lipoprotein subfractions and CVD risk in 1,129 men and 1,262 women participating in the Framingham Heart Study. Except for the 56C>G SNP, the other SNPs were in significant linkage disequilibria, resulting in three haplotypes (11111, 22122, and 11211) representing 98% of the population. SNP analyses revealed that the -1131T>C and 56C>G SNPs were significantly associated with higher plasma TG concentrations in both men and women. For RLP and lipoprotein subclasses, we observed gender-specific association for the -1131T>C and 56C>G SNPs. Female carriers of the -1131C allele had higher RLP concentrations, whereas in males, significant associations for RLPs were observed for the 56G allele. Moreover, haplotype analyses confirmed these findings and revealed that the 22122 and 11211 haplotypes exhibited different associations with HDL cholesterol concentrations. In women, the -1131C allele was associated with a higher hazard ratio for CVD (1.85; 95% confidence interval, 1.03-3.34; P = 0.04), in agreement with the association of this SNP with higher RLPs.     

Restriction isotyping of human apolipoprotein A-IV: rapid typing of known isoforms and detection of a new isoform that deletes a conserved repeat.

Genetic polymorphisms of apolipoprotein A-IV (apoA-IV) have been detected by isoelectric focusing of serum proteins. Because genetic variation in apoA-IV has significant effects on lipid risk factors, we used restriction enzyme isoform genotyping (restriction isotyping) to determine apoA-IV isoform genotypes at the DNA level for a large population (n = 509). In contrast to isoelectric focusing methods, restriction isotyping relies on nucleotide differences, enabling unambiguous typing of known isoforms and detection of new alleles that mimic other isoforms with shared charge properties. To determine genotypes for the common A-IV-1 isoform (Gln at aa position 360) and A-IV-2 isoform (360His), we used a mismatched primer for polymerase chain reaction (PCR) to introduce a restriction site (PvuII) that distinguishes each isoform. Using a portion of the same PCR reaction, we used HinfI to distinguish isoforms with Thr at position 347 (347Thr) versus Ser (347Ser). In surveys for these common genotypes, we detected heterozygotes for an allele with an insertion of 12 bp. Nucleotide sequencing showed that this allele is identical to the A-IV-0 isoform that inserts a hydrophilic repeat (Glu Gln Gln Gln) in a conserved region near the carboxy terminus. In addition, we discovered a new allele with a 12 bp deletion that removes a repeat (Glu Gln Gln Gln) from the same region. Nucleotide sequencing showed that this allele removes an acidic charge relative to A-IV-1, so we have named this isoform A-IV-2*. This isoform has not been discovered at the protein level, perhaps due to shared charge properties with A-IV-2 isoforms.     

The APOA4 Thr347→Ser347 Polymorphism Is Not a Major Risk Factor of Obesity

Objective: The goal of this study was to assess the association between the APOA4 Thr₃₄₇→Ser₃₄₇ polymorphism and BMI and obesity. Research Methods and Procedures: Men and women (n = 3320), randomly recruited in three independent population surveys from the north, east, and south of France, were genotyped for the APOA4 Thr₃₄₇→Ser₃₄₇ polymorphism. Results: There were 1327 overweight (825 men, 502 women) and 611 obese (313 men, 298 women) subjects. The prevalences of subjects carrying at least one Ser₃₄₇ allele (*/Ser₃₄₇) were 36.5%, 33.8%, and 34.3% in controls, overweight, and obese subjects, respectively (not significant), and those of the Ser₃₄₇/Ser₃₄₇ genotype were 4.5%, 3.0%, and 2.2%, respectively (not significant). In both men and women, mean BMI and body weight were not significantly different among APOA4 genotypes. There was no evidence of heterogeneity among centers, smoking status, alcohol intake, physical activity, and educational level categories. In men, mean waist girth was lower in Ser₃₄₇/Ser₃₄₇ (92.2 ± 9.4 cm) than in Thr₃₄₇ carriers (95.9 ± 10.9 cm; p = 0.01), and plasma triglycerides levels were lower in Ser₃₄₇ (1.41 ± 1.04 mM) than in Thr₃₄₇/Thr₃₄₇ carriers (1.55 ± 1.23 mM; p = 0.01). Discussion: These results suggest that the APOA4 347Ser allele is not a major risk factor for obesity or overweight.     

Structure and function of the apoA-IV T347S and Q360H common variants

Human apolipoprotein A-IV (apoA-IV) is involved in chylomicron assembly and secretion, and in reverse cholesterol transport. Several apoA-IV isoforms exist, the most common in Caucasian populations being apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). The objective of the present study was to investigate the impact of these common aminoacid substitutions on the ability of apoA-IV to bind lipids, to promote cell cholesterol efflux via ABCA1, and to maintain endothelial homeostasis. Recombinant forms of wild-type apoA-IV, apoA-IV Q360H, and apoA-IV T347S were produced in Escherichia coli. ApoA-IV Q360H and apoA-IV T347S showed a slightly higher α-helical content compared to wild-type apoA-IV, and associated with phospholipids faster than wild-type apoA-IV. The capacity to promote ABCA1-mediated cholesterol efflux was significantly greater for the apoA-IV T347S than the other apoA-IV isoforms. No differences were observed in the ability of apoA-IV isoforms to inhibit the production of VCAM-1 and IL-6 in TNFα-stimulated endothelial cells. In conclusion, the apoA-IV T347S common variant has increased lipid binding properties and cholesterol efflux capacity, while the apoA-IV Q360H variant has only slightly increased lipid binding properties. The two common aminoacid substitutions have no effect on the ability of apoA-IV to maintain endothelial homeostasis.     

Frequencies of apolipoprotein A4 gene polymorphisms and association with serum lipid concentrations in two healthy Spanish populations

Apolipoprotein A4 (apoA4) plays a role in intestinal lipid absorption. Several experimental interventions have shown that common variations at residues 347 (Thr --> Ser) and 360 (Gln --> His) on apoA4 are associated with differences in plasma lipid response to dietary fat; however, association studies between these variants and plasma lipid concentrations in populations reveal mixed results. We examined the effects of these polymorphisms in 758 randomly selected subjects (mean age 36.7+/-9.5 years) from 2 Spanish regions differing in latitude and fat intake: Aragón and Comunidad Valenciana. Subjects were matched one to one by sex and age. Frequencies for the less common alleles were similar in both regions: 0.096 (95% CI: 0.111-0.081) for codon 360 and 0.196 (95% CI: 0.216-0.176) for codon 347. In men and women there was no association between the codon 360 polymorphism and total cholesterol or triglyceride levels. However, subjects carrying the 360His allele had low-density lipoprotein (LDL) cholesterol concentrations statistically lower than homozygotes for the 360Gln allele, even after further adjustment for sex, age, region, body mass index, and APOE polymorphism (p = 0.043). The less common allele at codon 347 (the 347Ser allele) was associated with increased LDL-cholesterol concentrations with a clear gene-dosage effect after multivariate adjustment (p = 0.029). Although these polymorphisms showed no heterogeneity by geographic region, the magnitude of the effect was higher in subjects from Aragón compared with the Comunidad Valenciana, suggesting a possible influence of the higher fat intake in Aragón. In the combined association analysis subjects with the 360Gln/347Ser pseudohaplotype had the highest LDL-cholesterol concentrations, supporting the antagonistic effect between the 360His and the 347Ser alleles on this trait.     

Positive Association between APOA5 rs662799 Polymorphism and Coronary Heart Disease: A Case-Control Study and Meta-Analysis

Objective

Apolipoprotein A5 (APOA5) is associated with plasma triglyceride (TG) levels, a risk factor for coronary heart disease (CHD). This study explored the association between CHD and the APOA5 rs662799 polymorphism.

Methods

We collected 1,521 samples (783 CHD patients and 738 controls) for this case-control study. Meta-analysis was performed using Review Manager Software and Stata Software.

Results

Significant differences were observed between CHD cases and controls at the level of both genotype (χ² = 8.964, df = 2, P = 0.011) and allele (χ² = 9.180, df = 1, P = 0.002, OR = 1.275, 95% CI = 1.089–1.492). A breakdown analysis by gender showed a significant association of APOA5 rs662799 with CHD in males (χ² = 7.770, df = 1, P = 0.005; OR = 1.331, 95% CI = 1.088–1.628). An additional meta-analysis using 21378 cases and 28428 controls established that rs662799 is significantly associated with CHD (P < 0.00001).

Conclusion

Both our case-control study and meta-analysis confirm a significant association between APOA5 rs662799 and CHD. In addition, our results suggest a male-specific association between the APOA5 rs662799 polymorphism and CHD.     

Apolipoprotein A5 polymorphisms in Turkish population: association with serum lipid profile and risk of ischemic stroke

Atherosclerosis, a major cause of ischemic stroke, may be associated with variability of triglyceride (TG) levels. Apolipoprotein A5 (APOA5) genetic polymorphisms are associated with altered TG levels. The objective of this study was to investigate the coding region polymorphisms S19W (rs3135506) and G185C (rs2075291) and the promoter region polymorphism ?1131T>C (rs662799) of the APOA5 gene as risk factors for ischemic stroke in Turkish population. Study group consisted of 272 ischemic stroke patients and 123 controls. Genotypes were determined by real-time polymerase chain reaction (PCR) for S19W and PCR-restriction fragment length polymorphism analysis (PCR–RFLP) for ?1131T>C and G185C. 19W allele frequency was 0.090 in stroke patients and 0.062 in controls (P = 0.191). Minor allele frequencies of ?1131T>C and G185C in patients were 0.106 and 0.004, respectively, and were nearly the same in controls. Total cholesterol and LDL-cholesterol levels were significantly higher for stroke patients having at least one 19W allele compared to non-carriers. A significant difference was also found for LDL-cholesterol levels of stroke patients; higher in ?1131C allele carriers compared to wild type patients. There was a trend for higher frequency of ischemic stroke among ?1131C allele carrier hypertensive, diabetic or obese subjects compared to non-carriers. However, APOA5 genotypes were not associated with the risk of ischemic stroke by logistic regression analysis. The present study demonstrated that carrying rare alleles of APOA5 S19W, ?1131T>C and G185C alone do not constitute a risk for ischemic stroke in the studied Turkish subjects.     

APOC3基因SstⅠ单核苷酸多态性与冠心病、Ⅱ型糖尿病合并高甘油三酯血症的关联性研究

对许多人群研究表明 ,位于APOA1/C3/A4 /A5基因簇上的载脂蛋白C3基因 (APOC3)SstⅠ多态性与高甘油三酯血症 (Hypertriglyceridaemia ,HTG)密切相关 ,高甘油三酯是冠心病和糖尿病的独立危险因素。为探讨中国人群APOC3基因SstⅠ单核苷酸多态性与冠状动脉粥样硬化性心脏病 (coronaryatheroscleroticheartdisease,CHD)合并高甘油三酯血症 (HTG)、Ⅱ型糖尿病 (non insulin dependentdiabetesmellitus,NIDDM)合并高甘油三酯血症 (HTG)患者的相关性 ,应用聚合酶链反应 限制性片段长度多态性 (PCR RFLP)的方法 ,分析了 2 6 7例CHD患者、2 4 6例NIDDM患者及 4 91例健康对照APOC3基因SstⅠ位点 (S1/S2 )多态性。CHD组、NIDDM组和对照组的APOC3基因SstⅠ多态位点S2等位基因频率分别为 0 30 1、0 30 7和 0 2 86 ,其基因型频率和等位基因频率分布与对照组比较均无显著性差异 (P >0 0 5 )。以TG >1 90mmol/L为标准将CHD组、NIDDM组分为正常甘油三酯组 (NTG)和高甘油三酯组(HTG)发现 ,在CHD患者 ,HTG亚组S1S2基因型频率显著高于NTG亚组 (0 5 4 2 >0 35 7,χ2 =8 77,P =0 0 12 4 ) ;在NIDDM患者 ,HTG亚组S2S2基因型频率显著高于NTG亚组 (0 2 0 0 >0 0 5 5 ,χ2 =2 0 2 1,P =0 0 0 0 0 ) ,两亚组间等位基因频     

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.     

Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease: the Veterans Affairs HDL Intervention Trial

Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; < or =40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of >40, who had corresponding values of 3.2% (P = 0.06), 1.5% (P < 0.01), and 18.2% (P < 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL (-32%; P < 0.01) but higher levels of small, dense LDL (+59%; P < 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 +/- 0.87 vs. 20.63 +/- 0.80 nm; P < 0.003). In men with low HDL-C and CHD: 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil.     

Effect of the apolipoprotein A-IV Q360H polymorphism on postprandial plasma triglyceride clearance

Apolipoprotein (apo)A-IV is synthesized in the small intestine during fat absorption and is incorporated onto the surface of nascent chylomicrons. In circulation, apoA-IV is displaced from the chylomicron surface by high density lipoprotein-associated C and E apolipoproteins; this exchange is critical for activation of lipoprotein lipase and chylomicron remnant clearance. The variant allele A-IV-2 encodes a Q360H polymorphism that increases the lipid affinity of the apoA-IV-2 isoprotein. We hypothesized that this would impede the transfer of C and E apolipoproteins to chylomicrons, and thereby delay the clearance of postprandial triglyceride-rich lipoproteins. We therefore measured triglycerides in plasma, S(f) > 400 chylomicrons, and very low density lipoproteins (VLDL) in 14 subjects heterozygous for the A-IV-2 allele (1/2) and 14 subjects homozygous for the common allele (1/1) who were fed a standard meal containing 50 gm fat per m(2) body surface area. All subjects had the apoE-3/3 genotype. Postprandial triglyceride concentrations in the 1/2 subjects were significantly higher between 2;-5 h in plasma, chylomicrons, and VLDL, and peaked at 3 h versus 2 h for the 1/1 subjects. The area under the triglyceride time curves was greater in the 1/2 subjects (plasma, P = 0.045; chylomicrons, P = 0.027; VLDL, P = 0.063). A post-hoc analysis of the frequency of the apoA-IV T347S polymorphism suggested that it had an effect on triglyceride clearance antagonistic to that of the A-IV-2 allele. We conclude that individuals heterozygous for the A-IV-2 allele display delayed postprandial clearance of triglyceride-rich lipoproteins.     

Periodontitis decreases the antiatherogenic potency of high density lipoprotein

Periodontitis, a consequence of persistent bacterial infection and chronic inflammation, has been suggested to predict coronary heart disease (CHD). The aim of this study was to investigate the impact of periodontitis on HDL structure and antiatherogenic function in cholesterol efflux in vitro. HDL was isolated from 30 patients (age 43.6 +/- 6.1 years, mean +/- SD) with periodontitis before and after (3.2 +/- 1.4 months) periodontal treatment. The capacity of HDL for cholesterol efflux from macrophages (RAW 264.7), HDL composition, and key proteins of HDL metabolism were determined. After periodontal treatment, phospholipid transfer protein (PLTP) activity was 6.2% (P<0.05) lower, and serum HDL cholesterol concentration, PLTP mass, and cholesteryl ester transfer protein activity were 10.7% (P<0.001), 7.1% (P=0.078), and 19.4% (P<0.001) higher, respectively. The mean HDL2/HDL3 ratio increased from 2.16 +/- 0.87 to 3.56 +/- 0.48 (P<0.05). HDL total phospholipid mass and sphingomyelin-phosphatidylcholine ratio were 7.4% (P<0.05) and 36.8% (P<0.001) higher, respectively. The HDL-mediated cholesterol efflux tended to be higher after periodontal treatment; interestingly, this increase was significant (P<0.05) among patients whose C-reactive protein decreased (53.7% reduction, P=0.015) and who were positive by PCR for Actinobacillus actinomycetemcomitans. These results suggest that periodontitis causes similar, but milder, changes in HDL metabolism than those that occur during the acute-phase response and that periodontitis may diminish the antiatherogenic potency of HDL, thus increasing the risk for CHD.     

Increased plasma apoA-IV level is a marker of abnormal postprandial lipemia: a study in normoponderal and obese subjects.

Plasma apolipoprotein A-IV (apoA-IV) levels are found elevated in hypertriglyceridemic patients. However, the relationship between plasma apoA-IV level and postprandial lipemia is not well known and remains to be elucidated. Thus, our objective was to study the relationship between plasma apoA-IV and postprandial TG after an oral fat load test (OFLT). Plasma apoA-IV was measured at fast and during an OFLT in 16 normotriglyceridemic, normoglucose-tolerant android obese subjects (BMI = 34.6 +/- 2.9 kg/m(2)) and 30 normal weight controls (BMI = 22.2 +/- 2.3 kg/m(2)). In spite of not statistically different fasting plasma TG levels in controls and obese patients, the former group showed an altered TG response after OFLT, featuring increased nonchylomicron TG area under the curve (AUC) compared with controls (516 +/- 138 vs. 426 +/- 119 mmol/l x min, P < 0.05). As compared to controls, obese patients showed increased apoA-IV levels both at fast (138.5 +/- 22.4 vs. 124.0 +/- 22.8 mg/l, P < 0.05) and during the OFLT (apoA-IV AUC: 79,833 +/- 14,281 vs. 68,176 +/- 17,463 mg/l x min, P < 0.05). Among the whole population studied, as among the control and obese subgroups, fasting plasma apoA-IV correlated significantly with AUC of plasma TG (r = 0.60, P < 0.001), AUC of chymomicron TG (r = 0.45, P < 0.01), and AUC of nonchylomicron TG (r = 0.62, P < 0.001). In the multivariate analysis, fasting apoA-IV level constituted an independent and highly significant determinant of AUC of plasma TG, AUC of chymomicron TG, AUC of nonchylomicron TG, and incremental AUC of plasma TG. In conclusion, we show a strong link between fasting apoA-IV and postprandial TG metabolism. Plasma fasting apoA-IV is shown to be a good marker of TG response after an OFLT, providing additional information on post-load TG response in conjunction with other known factors such as fasting TGs.