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.     

Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults

The common apolipoprotein E (apoE) gene (APOE) epsilon2/epsilon3/epsilon4 polymorphism explains part of serum lipid variation, and polymorphisms in the APOE promoter region have been proposed to participate in the regulation of serum lipid levels within the most common APOE epsilon3/epsilon3 genotype group. We determined APOE -219G/T and +113G/C promoter genotypes and estimated APOE haplotypes in 525 participants of the Cardiovascular Risk in Young Finns Study. We studied the associations of the APOE promoter polymorphisms and their haplotypes with cross-sectional and longitudinal serum lipid and apolipoprotein concentrations as well as with flow-mediated dilatation (FMD), carotid artery compliance (CAC), and intima-media thickness (IMT) within the APOE epsilon3/epsilon3 carriers. We found no significant association between the APOE promoter genotypes and serum lipids [low density lipoprotein-cholesterol (LDL-C), HDL-C, and triglycerides], apolipoproteins (apoA-I and apoB), or brachial artery FMD, CAC, or carotid IMT in either men or women. In longitudinal analyses in males, the carriers of heterozygous genotypes (-219G/T or +113G/C) and, furthermore, carriers of the -219T/+113C/epsilon3 haplotype had significantly higher LDL-C and total cholesterol concentrations throughout the 21 year follow-up period compared with homozygous G allele carriers or noncarriers of the -219T/+113C/epsilon3 haplotype. Such associations were not found in females. In summary, the APOE promoter polymorphisms -219G/T and +113G/C as well as their haplotype are associated with longitudinal changes in LDL-C and total cholesterol concentrations in young Finnish males but do not seem to be major determinants for FMD, CAC, or carotid IMT in males or females.     

ABCA1 gene promoter DNA methylation is associated with HDL particle profile and coronary artery disease in familial hypercholesterolemia

High-density lipoproteins cholesterol (HDL-C) level, a strong coronary artery disease (CAD) clinical biomarker, shows significant interindividual variability. However, the molecular mechanisms involved remain mostly unknown. ATP-binding cassette A1 (ABCA1) catalyzes the cholesterol transfer from peripheral cells to nascent HDL particles. Recently, a differentially methylation region was identified in ABCA1 gene promoter locus, near the first exon. Therefore, we hypothesized that DNA methylation changes at ABCA1 gene locus is one of the molecular mechanisms involved in HDL-C interindividual variability. The study was conducted in familial hypercholesterolemia (FH), a monogenic disorder associated with a high risk of CAD . Ninety-seven FH patients (all p.W66G for the LDLR gene mutation and not under lipid-lowering treatment) were recruited and finely phenotyped for DNA methylation analyses at ABCA1 gene locus. ABCA1 DNA methylation levels were found negatively correlated with circulating HDL-C (r = -0.20; p = 0.05), HDL2-phospholipid levels (r = -0.43; p = 0.04), and with a trend for association with HDL peak particle size (r = -0.38; p = 0.08). ABCA1 DNA methylation levels were also found associated with prior history of CAD (CAD = 40.2% vs. without CAD = 34.3%; p = 0.003). These results suggest that epigenetic changes within the ABCA1 gene promoter contribute to the interindividual variability in plasma HDL-C concentrations and are associated with CAD expression. These findings could change our understanding of the molecular mechanisms involved in the pathophysiological processes leading to CAD.     

Promoter polymorphisms of hepatic lipase gene influence HDL(2) but not HDL(3) in African American men: CARDIA study

Hepatic lipase encoded by the hepatic lipase gene (LIPC) is involved in the metabolism of several lipoproteins. Four promoter polymorphisms in LIPC have been found to be in complete disequilibrium and associated with high density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo)A-I levels in both white and black populations. We investigated the association between the promoter polymorphism and lipid profiles as well as anthropometric phenotypes in African American men in the Coronary Artery Risk Development in Young Adults study. We performed serial cross-sectional analyses and longitudinal analyses of lipids from 578 subjects in five examinations over 10 years of follow-up. Results showed that the allele frequency (0.52) in our black population was consistent with that reported in black subjects but much higher than that reported (approximately 0.2) in white populations. Analysis of covariance tests of the three genotypic means in each examination showed that the P values ranged from 0.01 to 0.08 for HDL-C (except P = 0.54 in the fourth examination), from 0.006 to 0.01 for HDL(2)-C, and from 0.06 to 0.07 for apoA-I. Mean HDL(3)-C levels were essentially identical among the three genotypes. Total cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides, and apoB, which are mainly involved in the very low density lipoprotein-LDL pathway, were not significantly different according to the promoter polymorphism, except for triglycerides in the third examination (P = 0.01). No significant association was found between anthropometric phenotypes and the LIPC polymorphism in any of five examinations. The change of the anthropometric variables was not significantly associated with genotypes. In conclusion, our results indicated that the LIPC promoter polymorphism has exclusive effects on HDL(2)-C but not HDL(3)-C levels.     

APOE ?491 T allele may reduce the risk of atherosclerotic lesions among middle-aged women

Genetic variability of the APOE gene confers susceptibility to coronary artery disease (CAD). Beyond variability on the coding region, polymorphisms in the regulatory region of the APOE gene have been associated with variation on plasma cholesterol levels. It has also been demonstrated a complex and multifactorial association between, APOE gene polymorphisms, gender, plasma lipids levels and risk of CAD. In the present case-control study, we examined polymorphisms -427 T/C and -491 A/T in the promoter region of APOE in relation to lipid profile and the coronary atherosclerosis, in a sample of Argentinean adults with (cases) and without (controls) atherosclerotic injuries regarding gender and age. In females below 60 years APOE -491 T allele was less prevalent in cases than in controls (OR 0.12, 95% CI 0.04-0.76). Among females cases the T allele was more frequent with increasing age (OR 0.49, 95% CI 0.27-0.90). Female up to 45 years who were carriers of the T allele showed lower levels of total (P = 0.01) and LDL cholesterol (P = 0.02) compared with non-carriers. Levels of total and LDL cholesterol increased with the age only in female carriers (P < 0.01 and P < 0.01). No differences were observed for HDL and TG levels. Allele C of polymorphism APOE -427 was associated with higher levels of triglycerides (P < 0.01). We conclude that, in middle-aged women, APOE -491 T allele contributes keeping lower levels of LDL cholesterol in the population studied, and would have a putative protective effect for the development of CAD.     

Association between promoter variants of interleukin-18 and schizophrenia in a Han Chinese population

An increasing amount of evidence suggests that interleukin-18 (IL-18) plays a pivotal role in the pathophysiology of schizophrenia. However, association between single nucleotide polymorphism of IL-18 and the risk of schizophrenia has not been clarified. This study examined whether two promoter polymorphisms -137 G/C (rs187238) and -607 C/A (rs1946518) of IL-18 were associated with schizophrenia and six clinical symptoms (disorder of perception, thought disorder, disturbance of emotion, disorder of behavior and volition, suicide action, and aggressive action) to provide data for screening high-risk Han Chinese individuals. Three hundred seventy-two schizophrenic patients and 353 healthy controls from a Han Chinese population were examined to assess their genotype and allele frequencies of the two promoter polymorphisms of IL-18. The genotype distributions in both patients and controls were within Hardy-Weinberg equilibrium. No significant differences were observed in the genotype or the allele frequencies of the two single-nucleotide polymorphisms between patients and controls. However, genotype frequencies of -607 C/A showed significant differences between patients and controls in the appearance of perception disorder (χ2 = 6.153, p = 0.046). A significant difference was detected in -137 G/C between patients and controls in the appearance of aggressive action (χ2 = 3.909, p = 0.048). In conclusion, IL-18 gene promoter polymorphisms may not contribute to the susceptibility of schizophrenia in a Han Chinese population, but two single-nucleotide polymorphisms, -137 G/C and -607 C/A, may play a role in the development of perception disorder and aggressive action, respectively.     

<Emphasis Type="Italic">ABCA1</Emphasis> gene polymorphisms and their associations with coronary artery disease and plasma lipids in males from three ethnic populations in Singapore

Mutations in the ATP-binding cassette transporter ABCA1 underlie Tangier disease and familial hypoalphaliproteinemia (FHA), disorders that are characterised by reduced high-density lipoprotein-cholesterol (HDL-C) concentration and cholesterol efflux, and increased coronary artery disease (CAD). We explored if polymorphisms in the ABCA1 gene are associated with CAD and variations in plasma lipid levels, especially HDL-C, and whether the associations may depend on ethnicity. Male cases and controls from the Singapore Chinese, Malay and Indian populations were genotyped for five ABCA1 single nucleotide polymorphisms. Various single-locus frequency distribution differences between cases and controls were detected in different ethnic groups: the promoter -14C>T in Indians, exon 18 M883I in Malays, and 3'-untranslated (UTR) region 8994A>G in Chinese. For the Malay population, certain haplotypes carrying the I825- A (exon 17) and M883- G alleles were more frequent among cases than controls, whereas the converse was true for the alternative configuration of V825- G and I883- A, and this association was reinforced in multi-locus disequilibrium analysis that utilized genotypic data. In the healthy controls, associations were found for -14C>T genotypes with HDL-C in Chinese; 237indelG (5'UTR) with apolipoprotein A1 (apoA1) in Malays and total cholesterol (TC) in Indians; M883I with lipoprotein(a) [Lp(a)] in Malays and apolipoprotein B (apoB) in Chinese; and 8994A>G with Lp(a) in Malays, and TC, low-density lipoprotein-cholesterol (LDL-C) as well as apoB in Indians. While genotype-phenotype associations were not reproduced across populations and loci, V825I and M883I were clearly associated with CAD status in Malays with no effects on HDL-C or apoA1.     

Protective effect of an endothelial lipase gene variant on coronary artery disease in a Chinese population

The aim of the present study was to assess the influence of the endothelial lipase (EL) gene 584C/T variant, which results in a change at codon 111 of the EL gene from threonine to isoleucine, on the risk of coronary artery disease (CAD) in a Chinese population. The study population consisted of 265 CAD patients and 265 age- and sex-matched control subjects. The T allele frequency was significantly lower among CAD patients than among control subjects (18.3% vs. 29.8%; P < 0.001). In both the CAD and control groups, the T allele carriers had higher high density lipoprotein cholesterol (HDL-C) levels than homozygote C allele carriers. In a multiple logistic regression model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, hyperlipidemia, and low density lipoprotein cholesterol, a significantly decreased risk of developing CAD was found in subjects carrying a variant CT or TT genotype (odds ratio = 0.496, 95% confidence interval = 0.341-0.723; P < 0.001), and the significance persisted after further adjustment for HDL-C. In conclusion, our observation that the EL 584T allele was associated with protection from CAD in this Chinese population replicates the findings in a Japanese study, which found a similar association of this allele with acute myocardial infarction, independent of HDL-C levels.     

Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations

The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.     

延边朝鲜族和汉族脂联素启动子SNPs与原发性高血压的相关性

为了探讨延边朝鲜族和汉族脂联素基因启动子单核苷酸多态性(SNPs)与原发性高血压(EH)的关系, 文章采用PCR产物直接测序方法检测了220例EH患者和268例对照个体的脂联素启动子5个SNPs位点: -11426A>G(rs16861194)、-11391G>A(rs17300539)、-11377C>G(rs62620185)、-11156insCA(rs60806105)、-11043C>T(rs76786086), 氧化酶法测定空腹血糖、甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白, 酶联免疫吸附法(ELISA)测定血浆脂联素和胰岛素。结果显示: (1) -11426A>G、-11377C>G 和-11156insCA 3个位点具有多态性, 且它们的基因型频率分布符合Hardy-Weinberg平衡定律(P>0.05), -11391G>A和-11043C>T位点无多态性; (2) -11426A>G和-11156insCA呈完全连锁不平衡(D’=1; r2=1); (3) -11426G基因频率比较, 朝鲜族(21.10%)高于汉族(12.05%), 汉族EH组高于对照组; -11377C>G的基因型和基因频率在朝鲜族和汉族间及同一民族内EH组和对照组间比较均无统计学意义(P>0.05); (4)单倍型?11426G -11377C的频率, 汉族EH组高于对照组(P<0.05), 朝鲜族EH组和对照组比较无统计学意义(P>0.05); (5)EH组的血浆脂联素水平明显低于对照组(P<0.001)。据此得出结论: (1)首次发现?11426A>G和?11156insCA呈完全连锁不平衡, -11426 A>G的多态性在朝鲜族和汉族中存在民族差异; (2) -11426 G和-11426G -11377C是延边汉族EH的危险因子和危险单倍型, 但不是朝鲜族的; (3)低血浆脂联素是延边朝鲜族和汉族EH的重要危险因素; (4)血浆脂联素水平与-11426A>G基因型无关。     

Fat energy use and plasma lipid changes associated with exercise intensity and temperature

The effect of 60 min of exercise at two intensities (50 and 60% VO2max) and temperatures (0 and 22 degrees C) on changes (delta) in plasma lipids [triglycerides (TG), glycerol (GLY), total cholesterol (TC), and HDL-cholesterol (HDL-C)] was examined. Subjects were 10 men aged 27 +/- 7 years (VO2max = 3.81 +/- 0.45 1 min, % fat = 12.2% +/- 7.1%). VO2 and respiratory exchange ratio results indicated that total energy and fat energy use were similar at the two temperatures. Changes in plasma volume (%delta PV) were different (P less than 0.05) at the two temperatures (22 degrees C: -2.3% vs 0 degrees C: 1.1%). Combining the data at each temperature revealed that the increases in concentrations were greater (P less than 0.05) at 22 degrees C (delta TG = 0.22, delta GLY = 0.20, delta TC = 0.14, delta HDL-C = 0.05 mmol l-1) vs 0 degrees C (delta TG = 0.10, delta GLY = 0.12, delta TC = 0.05, delta HDL-C = 0.02 mmol l-1). Combining the data for each intensity revealed that the increases in concentration were greater (P less than 0.05) at 60% VO2max for delta TG and delta HDL-C. The 60% VO2max/22 degrees C bout produced greater changes (P less than 0.05) than all other bouts for delta TC and delta HDL-C (0.21 and 0.08 mmol l-1, respectively). Only delta TG and delta GLY were greater at 22 degrees C when adjusted for %delta PV. These metabolic and plasma lipid results indicate that cold exposure does not act synergistically with exercise to further stimulate fat metabolism.     

Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol

Type A and B forms of Niemann-Pick disease (NPD) are lipid storage disorders caused by deficient activity of the enzyme acid sphingomyelinase (aSMase) and the resulting accumulation of sphingomyelin in tissues. In the present study, we investigated two family members who had been diagnosed with Type B NPD and who had a severe decrease in plasma high density lipoprotein cholesterol (HDL-C). The proband (a 48-year-old male) had an HDL-C of 0.30 mmol/l (12 mg/dl) and his sister had values of 0.45 mmol/l (17 mg/dl) with severe premature coronary artery disease (CAD). Hypertriglyceridemia was found in both cases. aSMase activity measured in skin fibroblasts appeared markedly depressed. The SMPD1 gene, coding for aSMase, was sequenced in affected subjects and all family members. Compound heterozygosity (DeltaR608 and R441X) was identified in both affected patients. Carriers of the DeltaR608 mutation tended to have moderately to severe decreased HDL-C levels, whereas carriers of the R441X mutation, although present only in young subjects (<20 years of age) had normal HDL-C levels. To investigate the cause of the low HDL-C level in these patients, we studied apoA-I-mediated cellular cholesterol efflux in fibroblasts. Unlike patients with Tangier disease, cholesterol efflux was found to be normal under the experimental conditions used in the present study. On the other hand, we observed a significant increase in the free cholesterol:esterified cholesterol ratio in HDL fraction from these patients and a decrease in endogenous lecithin-cholesterol acyltransferase (LCAT) activity, as determined by the fractional esterification rate. Taken together, these results suggest that (1) compound heterozygosity at the SMPD1 gene causes a severe decrease in aSMase activity and in HDL-C and increases the risk of CAD, (2) this lipoprotein abnormality is not attributable to defective cellular cholesterol efflux, (3) abnormal HDL composition might cause a decrease in LCAT activity and a lack of HDL maturation.