Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle-aged men

The effects of common variants of cholesteryl ester transfer protein ( CETP ) ( Taq IB), hepatic lipase ( HL ) (−514C>T), lipoprotein lipase ( LPL ) (S447X) and lecithin cholesterol acyl transferase ( LCAT ) (S208T) on the determination of high density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoAI) levels were examined in 2773 healthy middle-aged men participating in the second Northwick Park Heart Study. The extent of gene:gene, gene:smoking and gene:alcohol interactions were determined. For HDL-C levels, only CETP genotype was associated with significant effects ( p <0·0001), with the B2 allele being associated with higher levels in both smokers and non-smokers. This interaction was significant at the lowest tertile of TG, suggesting that TG levels were rate limiting. As previously reported, CETP , LPL and HL genotypes were all associated with significant effects on apoAI levels (all p <0·01), with carriers of the rare alleles having higher levels and with no evidence of heterogeneity of effects in smokers and non-smokers. LCAT genotype was not associated with significant effects on either trait. There was no significant interaction between any of the genotypes and alcohol consumption on either HDL-C or apoAI levels. All genotypic effects were additive for HDL-C and apoAI. Environmental and TG levels explained more than 20% and 5·5% of the variance in HDL-C and apoAI, respectively. The novel aspect of this finding is that genetic variation at these loci explained in total only 2·5% of the variance in HDL-C and 1·89% of the variance in apoAI levels. Thus despite the key roles played by these enzymes in HDL metabolism, variation at these loci, at least as detected by these common genotypes, contributes minimally to the variance in HDL-C and apoAI levels in healthy men, highlighting the polygenic and multifactorial control of HDL-C.     

Cholesteryl Ester Transfer Protein (CETP) genotype and cognitive function in persons aged 35 years or older

Common polymorphisms of the Cholestryl Ester Transfer Protein (CETP) gene may predict lower risk of cognitive decline. We investigated the association of cognitive function with CETP genotype in a population-based cohort of 4135 persons aged 35-82 years. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points) and CETP I405V and Taq1B genotypes were determined by polymerase chain reaction. RFFT score was not associated with I405V genotype in persons aged 35-64 years. Remarkably, beyond age 65, homozygous valine carriers had higher RFFT scores than heterozygous carriers and noncarriers: RFFT (SD), 52 (21), 49 (18), and 47 (17) points, respectively (p = 0.005). There also was a statistically significant interaction between I405V genotype and age. Beyond age 65, the difference between homozygous valine carriers and noncarriers increased by 0.11 point per year (p = 0.005). RFFT score was not associated with Taq1B genotype. In conclusion, CETP I405V valine homozygosity was associated with better cognitive function in persons aged 65 years or older.     

Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction

BACKGROUND: A polymorphism in the gene for alcohol dehydrogenase type 3 (ADH3) alters the rate of alcohol metabolism. We investigated the relation among the ADH3 polymorphism, the level of alcohol consumption, and the risk of myocardial infarction in a nested case-control study based on data from the prospective Physicians' Health Study. METHODS: We identified 396 patients with eligible newly diagnosed cases of myocardial infarction among men in the Physicians' Health Study. Of these patients, 374 were matched with 2 randomly selected control subjects each and the remaining 22 with 1 control each (total, 770 controls). The ADH3 genotype (gamma1gamma1, gamma1gamma2, or gamma2gamma2) was determined in all subjects. We examined the relations among the level of alcohol intake, the ADH3 genotype, and plasma high-density lipoprotein (HDL) levels in this study population and in a similar cohort of women. RESULTS: As compared with homozygosity for the allele associated with a fast rate of ethanol oxidation (gamma1), homozygosity for the allele associated with a slow rate of ethanol oxidation (gamma2) was associated with a reduced risk of myocardial infarction (relative risk, 0.65; 95 percent confidence interval, 0.43 to 0.99). Moderate alcohol consumption was associated with a decreased risk of myocardial infarction in all three genotype groups (gamma1gamma1, gamma1gamma2, and gamma2gamma2); however, the ADH3 genotype significantly modified this association (P=0.01 for the interaction). Among men who were homozygous for the gamma1 allele, those who consumed at least one drink per day had a relative risk of myocardial infarction of 0.62 (95 percent confidence interval, 0.34 to 1.13), as compared with the risk among men who consumed less than one drink per week. Men who consumed at least one drink per day and were homozygous for the gamma2 allele had the greatest reduction in risk (relative risk, 0.14; 95 percent confidence interval, 0.04 to 0.45). Such men also had the highest plasma HDL levels (P for interaction = 0.05). We confirmed the interaction among the ADH3 genotype, the level of alcohol consumption, and the HDL level in an independent study of postmenopausal women (P=0.02). CONCLUSIONS: Moderate drinkers who are homozygous for the slow-oxidizing ADH3 allele have higher HDL levels and a substantially decreased risk of myocardial infarction.     

DNA polymorphisms at the locus for human cholesteryl ester transfer protein (CETP) are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus

The effect of variation at the cholesteryl ester transfer protein (CETP) gene locus and in the apolipoprotein (apo) AI-CIII-AIV gene cluster on the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 136 male and 122 female patients with NIDDM. The prevalence of myocardial infarction was high (38%) in patients with the EcoNI genotype 2–2 of the CETP gene locus (= 2-2; subjects homozygous for the absence of the restriction site) compared with patients with the genotype 1–1 (=1–1; subjects homozygous for the presence of the restriction site) (18%, p < 0.02). The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was high in 2–2 (73%) compared with the genotype 1–2 (= 1–2; heterozygous for the presence of the restriction site) (52%, p < 0.02) and genotype 1–1 (p = 0.06). CHD was more prevalent in men with 2–2 (70%) than in those with 1–1 (42%, p < 0.05), but in women no significant differences were found in the prevalences of CHD between the EcoNI genotypes. Neuropathy was more often present in the patients with 2–2 (31%) than in those with 1–1 (12%, p < 0.02) or 1–2 (14%, p < 0.01). Plasma total cholesterol and total- and VLDL-triglycerides were higher in women with the EcoNI genotype 1–1 than in those with the genotype 1–2. In men no significant differences in plasma lipids were found. In addition, the prevalence of cerebrovascular disease was high (21%) in the patients with the genotype 1–1 of the TaqlB polymorphism compared with the genotype 2–2 (6%, p < 0.0–2). None of the alleles defined by four polymorphisms in the apo AI-CIII-AIV gene region were associated with an increased risk for macroangiopathy. The PstI polymorphism had an effect on plasma triglyceride levels. At the CETP locus one pair of loci (TaqlB and EcoNI) and three pairs of loci at the apo AI-CIII-AIV gene cluster (SacI and MspI, SapI and PvuII and MspI and PvuII) showed significant allelic association. In conclusion, the variation of CETP locus modulates the risk for diabetic complications in patients with NIDDM and the effect seems to be different between men and women. In contrast, the AI-CIII-AIV gene cluster polymorphisms seem not to be related to the risk of CHD in NIDDM. Long-term follow-up studies are needed to confirm the association of CETP gene polymorphism with diabetic complications.     

Cholesteryl ester transfer protein (CETP) I405V polymorphism and longevity in Italian centenarians

A common polymorphism (I405V) in exon 14 of the cholesteryl ester transfer protein (CETP) gene has been recently associated to healthy aging in Ashkenazi Jewish. In order to study this genetic effect in long-lived individuals with a different ethnicity, we analyzed the allele and genotype distributions of the CETP polymorphism a sample of Italian centenarians. Our result does not confirm the association between the I405V CETP variation and the healthy aging phenotype described in the Ashkenazi Jewish population and suggests that other gene environment interactions contribute to longevity.     

Effect of Microsomal Triglyceride Transfer Protein gene variants (−493G > T, Q95H and H297Q) on plasma lipid levels in healthy middle-aged UK men

Microsomal triglyceride transfer protein (MTP) plays a central role in the synthesis of lipoproteins by shuttling lipids between phospholipid membranes to apoB. We have examined the effect of three MTP gene variants, −493G > T, Q95H and H297Q, in 2831 healthy UK middle-aged men. The rare allele frequencies were: 0.25 (95% CI 0.24–0.26) for −493T, 0.054 (95% CI 0.05–0.06) for 95H and 0.32 (95% CI 0.31–0.33) for 297Q. The three variants were in strong allelic association in all pairwise combinations ( p < 0.001). None of the variant sites were associated with significant differences in cholesterol, triglyceride, apoB or apoAI levels. When stratified by tertiles of triglycerides for the H297Q variant alone there was a significant effect on apoB levels in men in the top tertile ( p = 0.01). Considering the −493G > T and H297Q genotype in combination on baseline levels, individuals with three or four rare alleles had 6.6% higher mean apoB levels compared to the rest ( p = 0.007). Therefore, homozygosity for 297Q at higher triglyceride (Tg) levels, or in combination with −493G > T, is associated with a raising effect on apoB levels, suggesting the importance of modest differences in MTP activity in determining hepatic secretion of lipoproteins in healthy men.     

The A370T Variant (StuI Polymorphism) in the LDL Receptor Gene is not Associated with Plasma Lipid Levels or Cardiovascular Risk in UK Men

Over 800 different missense mutations in the low density lipoprotein (LDL) receptor gene ( LDLR ) have been identified in patients with familial hypercholesterolaemia (FH). Only two of them, including the Alanine to Threonine change at position 370 (A370T), have been discovered in FH patients but do not cause FH. The frequency of the 370T allele has been reported worldwide to be between 0.022 and 0.070, with no clear association with high cholesterol levels or risk for coronary heart disease (CHD) and stroke. To explore this relationship in more detail we have determined this genotype in 2,659 healthy middle-aged (50–61 years) men participating in the prospective Second Northwick Park Heart Study, with 236 CHD and 67 stroke incident events. The genotype distribution was in Hardy-Weinberg equilibrium and in the no-event group the frequency of 370T was 0.046 (95% CI 0.040–0.052). Overall, there was no significant association of the 370T allele with any measured plasma lipid trait, and there was no difference in genotype distribution or allele frequency between the no-event and CHD (0.059; 95% CI 0.040–0.085) or stroke (0.037; 95% CI 0.012–0.085) groups (  p = 0.18 and 0.65, respectively). There was evidence for significant interaction (  p = 0.006) between body mass index (BMI) and genotype on CHD risk, with 370A homozygotes showing the expected higher CHD risk for those with higher BMI, whilst risk for 370T allele carriers was highest in men in the lowest tertile of BMI. The explanation for this association is unclear, and may simply be chance. Thus, these data confirm the absence of a significant impact of the A370T polymorphism on LDL receptor function, at least as measured by the effect on plasma lipid levels and CHD risk.     

胆固醇酯转运蛋白基因突变及其与冠状动脉粥样硬化性心脏病易感性的关联研究

目的：确定胆固醇酯转运蛋白（cholesteryl ester transfer protein,CETP)基因4种突变在中国人群中的频率，并探讨这些突变与脂代谢和冠状动脉粥样硬化性心脏病（coronary atherosclerotic heart disease,CHD)易感性的关系。方法：对209名正常人和203例CHD患者CETP基因相应片段进行了限制性片段长度多态性分析，用HWE软件和SPSS软件分别进行遗传平衡检验和统计学分析。结果：在正常对照组和CHD患者组中均未检出IVS14A和451Q突变基因。405V突变基因频率在正常人和CHD患者中分别为0．443和0．413，442G突变基因频率在两组中分别为0．007和0．025，I405V和D442G突变的等位基因频率分布符合Hardy-Weinberg平衡。CHD患者组442G突变基因频率显著高于正常人群（P＝0．043）。与无D442G突变的CHD患者相比，442G突变杂合子CHD患者的总胆固醇和低密度脂蛋白胆固醇显著升高（P＝0．017；P＝0．041）。结论：CETP基因IVS14A和451Q突变在中国人群中非常罕见，442G突变基因可能是中国人CHD的易感因子之一。     

Association of 5HT2A receptor gene polymorphism and alcohol abuse with behavior problems

This study investigated the association between T/C polymorphism, at position 102, of the 5-hydroxytryptamine 2A receptor gene and alcoholism with and without behavior problems. Eighty-five subjects (45 men, 40 women) with alcohol abuse, 75 subjects (51 men, 24 women) with alcohol dependence, and 70 normal control subjects (21 men, 49 women) participated in the study. The results show that the frequency of the homozygous T102 genotype was significantly lower in the group of male alcohol abuse with behavior problems than in the female group (chi(2) = 4.072, df = 1, P < 0.05) and the allele frequency of T102 was also lower in the male group than in the female group (chi(2) = 4.187, df = 1, P < 0.05). Of the male alcohol abuse subjects, the group with behavior problems was found to have lower frequencies of the T102 allele than the group without behavior problems (chi(2) = 4.328, df = 1, P < 0.05). In conclusion, this study demonstrates that alcoholism is heterogeneous and male alcohol abuse with behavioral problems was associated with T/C 102 polymorphism of the 5HT2A receptor gene. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:797-800, 2000.     

Cholesterol ester transfer protein,apolipoprotein E and lipoprotein lipase genotypes in patients with coronary artery disease in the Turkish population

The aim of this study was to compare patients with coronary artery disease (CAD) to healthy objects, in order to explore a possible association between CAD and the variants in the gene encoding cholesterol ester transfer protein (CETP), apolipoprotein E (Apo E) and lipoprotein lipase (LPL). The relationship between CETP MspI, apo E and LPL PvuII gene polymorphisms and serum lipids were investigated in 173 patients with CAD and 111 healthy controls. The frequency of Apo epsilon4 (p < 0.05) and CETP M1 (p < 0.01) alleles were higher in the CAD group than in the control group. In the CAD group, those with the Msp M1 allele had higher levels of total cholesterol (TC) (p = 0026) and low-density lipoprotein cholesterol (LDL-C) than those with the Msp M2 allele. Subjects with an epsilon2 allele had the lowest levels of TC and LDL-C, while subjects with the epsilon4 allele had the highest. In the control group, CETP, the Msp M2 allele was associated with a higher level of high-density lipoprotein cholesterol (HDL-C) (p = 0.012) than the Msp M1 allele. The distributions of LPL genotype and allele did not differ between the CAD and control groups. The present study demonstrates that the CETP Msp1 and Apo E gene polymorphisms are associated with variations in lipids in patients with CAD and healthy controls in Turkish population.     

The effects of genotype and infant weight on adult plasma levels of fibrinogen, factor VII, and LDL cholesterol are additive.

High circulating levels of cholesterol, particularly low density lipoprotein (LDL) cholesterol and the clotting factors fibrinogen and factor VII, are associated with increased risk of myocardial infarction. Variations in the plasma levels of these factors are determined in part by polymorphisms in the genes concerned and also by weight at 1 year (infant weight). We have looked at the possibility of interactions between these genetic factors and infant weight in a sample of 290 men and 192 women from Hertfordshire using the beta-fibrinogen G/A-455, factor VII R353Q, and ApoE polymorphisms. The rare allele frequencies of the three polymorphisms were 0.19 for beta-fibrinogen, 0.10 for factor VII, and 0.07 and 0.13 for the 2 and 4 alleles of ApoE, and these frequencies were not different in subjects of different infant weight. In this sample, the polymorphisms showed the expected effects on plasma levels of fibrinogen, factor VII, and LDL cholesterol. The A-455 allele was associated with higher fibrinogen levels but the effect was only statistically significant in women (p = 0.003). The R353 allele was associated with higher factor VII activity in both men and women (p < 0.0001 for both). The ApoE2 allele was associated with lower levels of LDL cholesterol (p = 0.03 in men, p = 0.006 in women), while the ApoE4 allele was associated with higher levels (p < 0.001 in men, not significant in women). In this sample of men and women the effect of low infant weight was only associated with significant effects on fibrinogen and LDL cholesterol in the group of men (p = 0.005 and p = 0.008 respectively). Compared with the E3E3 subjects, the LDL lowering effect of the E2 allele and the raising effect of the E4 allele was greater in those with low infant weight compared with those with high infant weight (low v high infant weight for E2: 12.7% v 9.4%; for E4 12.7% v 8.5%). Although in this sample the interactive effect did not reach statistical significance, the additive effect of ApoE genotype and low infant weight on determining plasma LDL cholesterol levels, if confirmed, may be of relevance in determining a person's future risk of atherosclerosis.     

The methylenetetrahydrofolate reductase C677T polymorphism is a major determinant of coffee-induced increase of plasma homocysteine: a randomized placebo controlled study

Some methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms are associated with hyperhomocysteinemia. Trials have shown a plasma homocysteine raising effect of coffee. We determined the effect of a daily intake of 600 ml coffee and a supplementation of 200 microg folic acid or placebo on plasma homocysteine (tHcy) with respect to the MTHFR C677T and A1298C polymorphisms. One hundred and twenty healthy, non-smoking men (22%) and women (78%) aged 29-65 years, took part in a controlled, randomized, blinded study with two intervention periods: i) a coffee-free period of three weeks, ii) 600 ml coffee/day and a supplement of 200 microg folic acid/d or placebo for four weeks. The results showed that tHcy at baseline was significantly higher for the 677TT genotype group compared to the 677CC genotype group (p=0.0045) and that this group responded with significantly larger increase in tHcy upon coffee exposure than the 677CC and 677CT genotype groups (p=0.0045 and p=0.0041, respectively). Supplementation with 200 microg folic acid compared to placebo reduced the tHcy increasing effect of coffee in the 677TT genotype group. The A1298C polymorphism did not affect tHcy concentration significantly at any stage in the study. In conclusion, the homocysteine increasing effect of coffee is particularly seen in individuals with the homozygous 677TT genotype. Supplementation with 200 microg folic acid/d decreases this tHcy increment.     

中国人内源性高甘油三酯血症载脂蛋白E基因多态性的研究

目的 探讨中国人内源性高城油三酯血症（endogenous hypertriglyceridemia,HTG)患者载脂蛋白E（apolipoprotein E,apoE)基因多态性及其与血脂和载脂蛋白水平的关系。方法 采用聚合酶链反应－限制性片段长度多态性分析方法,分别对225例HTG患者及230名血脂正常者的apoE基因型、空腹血脂及载脂蛋白AⅠ、AⅡ、B100、CⅡ、CⅢ、E进行了分析。结果 HTG患者的体重指数(BMI)` 清甘油三酯（TG）、总胆固醇（TC）、非高密度脂蛋白胆固醇（nHDLC)水平较对照组显著升高,血清高密度脂蛋白胆固醇（HDLC）则显著降低（P＜0．001）,并伴有载脂蛋白水平的异常。HTG组与对照组apoE基因型及等位基因频率分布均以E3／3和ε3最高,HTG组的ε2等位基因有增高的趋势（P＞0．05）。对照组ε2等位基因携带者血清TG和apoE水平较ε3和ε4等位基因携带者显著升高（P＜0．001）,其低密度脂蛋白胆固醇（LDLC）水平及apoE/ApoC Ⅲ比值则显著降低（P＜0．001）。结论 ε2等位基因与血清TG和apoE水平升高及LDLC水平降低有关,apoE/apoC Ⅲ比值降低可能与HTG患者血TG水平升高有关。     

Apolipoproteins B and E, and angiotensin I-converting enzyme (ACE) genetic polymorphisms in Italian women with coronary artery disease (CAD) and their relationships with plasma lipid and apolipoprotein levels

The Xba I, Eco RI and the signal peptide insertion/deletion ( I/D ) polymorphic sites of APOB gene, the Cfo I polymorphic site of apolipoprotein E gene (APOE), and the insertion/deletion polymorphism of angiotensin I-converting enzyme (ACE) gene were studied using polymerase chain reaction (PCR) in 55 postmenopausal women with coronary artery disease (CAD) and in 119 control women of equivalent age. Patients and controls were recruited from the population of Rome, considered representative of Central and Southern Italy. There were no significant differences in allele frequencies between the two groups, though APOB X-, R- and I, APOE*3 , and ACE D alleles were slightly more frequent in the cases than in the controls. The patients did not differ from the controls for plasma total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, and apoAI values, while they presented significantly higher levels of triglycerides and apoB, and lower apoE levels. TC, apoE, and apoB quantitative values, adjusted for age, varied significantly among APOB Xba I and APOE genotypes. APOB X-X-genotype was associated in patients with a significantly lower mean TC concentration than the other two genotypes pooled together. APOE 3–2 genotype in the controls had significantly lower TC levels with respect to the other two pooled genotypic classes and higher apoE levels compared to 3–3 and 4–3 genotypes. In the patients, 3–2 genotype had significantly lower apoB levels than the pooled 3–3 and 4–3 class. We conclude that in the Italian women the DNA polymorphisms studied in this work do not seem to be important risk factors for CAD occurrence; that apoE quantitation could be another useful parameter to identify subjects at risk of CAD; and that APOB X -and APOE*2 are the alleles that most influence the interindividual plasma lipid variation among CAD female patients.     

No association of CETP genotype with cognitive function or age-related cognitive change

A cholesteryl ester transfer protein (CETP) genotype (V/V homozygosity for I405V, NCBI dbSNP rs5882) has been associated with preservation of cognitive function in old age, in addition to its associations with exceptional longevity and cardiovascular disease. We tested the hypotheses that this polymorphism was associated with either level of cognitive function or lifetime cognitive change in 525 participants who took part in the Scottish Mental Survey of 1932. Participants took the same well-validated mental ability test at ages 11 and 79. Scores were also available for several other mental ability tests at age 79, and history of cardiovascular disease was available. Frequency of the V/I genotype was slightly greater than expected in the sample, possibly consistent with some role for the V polymorphism in longevity, and the V/V genotype was associated with a lower rate of cardiovascular disease history. There were, however, no significant associations of CETP genotype with either childhood IQ or current cognitive function in old age, or with lifetime change in cognitive function.     

Effect of the StuI polymorphism in the LDL receptor gene (Ala 370 to Thr) on lipid levels in healthy individuals

We have examined the effect on plasma lipid levels of a single base change in exon 8 of the LDL receptor gene that causes an amino acid change Ala 370 to Thr in a sample of 318 Icelandic individuals selected at random from the general population. The change destroys a Stu I restriction site and was detected by digestion of pooled samples in groups of 5. The frequency of the loss of the cutting site was 0.05 (95%CI=0.014-0.054). In men, those with the Thr allele (n=18) had 8.3% higher total cholesterol, 11.8% higher LDL cholesterol and 10.3% higher apolipoprotein B than those with the common Ala allele, whereas in women those with the Thr allele (n=12) had levels lower by 7.4%, 13.3% and 10.1% respectively. These differences reached statistical significance only in the men (p<0.05). Functional analysis of CHO cells transfected with constructs of the LDL receptor cDNA carrying the Ala370 and Thr370 alleles showed that within the limits of the assays there was no difference in function of the LDL receptor protein as measured by uptake and degradation of LDL. The data raise the possibility that amino acid substitutions that could affect LDL receptor function below the limits of detection by conventional assays, may have an effect on plasma lipid levels in the general population.     

The association of cholesteryl ester transfer protein polymorphism with high-density lipoprotein cholesterol and coronary artery disease in Koreans

Cholesteryl ester transfer protein (CETP) is a key protein involved in high-density lipoprotein cholesterol (HDL-C) metabolism. It is known to affect plasma HDL-C levels, and its genetic regulation may be involved in the development of coronary artery disease (CAD). The aim of this study was to determine the frequency of the CETP Taq1B polymorphism in Koreans, and to investigate its relationship with plasma HDL-C levels and CAD. One-hundred and nineteen patients with significant CAD and 106 controls were examined with respect to their genotypes, lipid profiles and other risk factors of CAD. The genotype frequencies of B1B1:B1B2:B2B2 in males and females were 35.5%:50%:14.5% and 34.7%:42.6%:22.7%, respectively, which is comparable to previous reports in other ethnic groups. The B1B1 homozygote was associated with significantly lower HDL-C levels in females (p = 0.049) and non-smoking males (p = 0.037). After controlling for gender, body mass index (BMI) and smoking, the TaqIB polymorphism was still significantly associated with HDL-C levels (p = 0.046) and explained 5.4% of the HDL-C variation in this study. By univariate analysis, the B1B1 homozygote was a significant predictor of CAD (p = 0.043), and this was confirmed by multivariate analysis with traditional risk factors, i.e. the B1B1 homozygote was an independent predictor of CAD (p = 0.026, odds ratio = 1.97, 95% confidence interval: 1.08-3.57). In conclusion, the B1B1 homozygote of the CETP Taq1B polymorphism is associated with low HDL-C levels in females and non-smoking males, and may be an independent genetic risk factor of CAD in the Korean population.     

海南汉、黎族正常人群胆固醇酯转运蛋白基因的多态性

 目的 了解海南汉、黎族正常人群CETP基因TaqIB、I405V、D442G、R451Q、A373P和I14A 6种多态位点频率的分布情况。方法 应用等位基因特异性PCR,分析海南汉、黎族正常人群CETP基因。结果 在海南汉、黎族正常人群中,TaqIB 、I405V和D442G多态位点可分别检测出B1B1、B1B2、B2B2 3种基因型,II、IV、VV 3种基因型和DD、DG 2种基因型,未检测到R451Q、A373P和I14A3种突变类型。I405V多态位点的基因型分布（P<0.0001）和等位基因频率（P<0.0001）在2组人群之间存在显著性差异,其余多态位点无统计学意义。结论 CETP基因TaqIB、I405V和D442G多态位点是海南汉、黎族正常人群中的常见突变位点,且I405V多态位点在2组人群之间存在明显的种族差异,R451Q、A373P和I14A 3种突变在海南汉、黎族人群中非常罕见。     

A polymorphism in the CYP17 gene and intrauterine fetal growth restriction

Intrauterine fetal growth restriction is a multifactorial disorder, and its aetiology includes both environmental and genetic components. We aimed to investigate whether maternal genetic polymorphisms of metabolic enzymes affects fetal growth and pregnancy duration. Genomic DNA was obtained from 134 women who experienced singleton deliveries beyond 24 weeks of gestation. Maternal age, birth weight, gestational age at birth and frequencies of fetal growth restriction, prematurity and pregnancy-induced hypertension were compared among genotypic subgroups of cytochrome p450 (CYP) and glutathione S-transferase (GST) genes. The polymorphisms of CYP1A1 (MspI), CYP17 (MspAI) and GSTP1 (BsmAI) genotypes, and the presence or absence of GSTM1 and GSTT1 genes were analysed by PCR-based methods. The frequency of fetal growth restriction (<10th percentile/<-1.5 SD; 22.7%/11.4%) in 44 women who were homozygous for the A1 allele (A1A1) of CYP17 was significantly higher than that (7.8%/2.2%) in 90 women who carried the A2 allele (A1A2/A2A2) of CYP17 (P < 0.05), with an odds ratio =3.41 (95% confidence interval = 1.18-9.84). The gestational age at birth (mean +/- SD, 37.5 +/- 3.1 weeks) in 67 women with GSTM1 null genotype was significantly lower than that (38.5 +/- 2.4 weeks) in 67 women who carried GSTM1 (P < 0.05). The polymorphism of CYP17 that encodes the cytochrome p450c17alpha enzyme might be associated with the pathophysiology underlying fetal growth restriction.     

PAI-1启动子区插入/缺失(5G/4G)多态性与脑血管病的相关性研究

目的 初步探讨人类纤溶酶原激活物抑制物－1（plasminogen ativator inhibhitor-1,PAI-1)启动子区基因多态性与脑血管病的关系,及其在脑血管病发病过程中的作用。方法 通过多聚酶链反应技术和发色底物法（ELISA）,测定了96例脑卒中患者和60名健康对照者的白细胞PAI－1启动子区4G／5G多态位点的基因型及血浆PAI－1活性。结果 脑梗死（cerebral infarction,CI)组血浆PAI－1活性明显高于脑出血（cerabral hemorrhage,CH)组及对照组,脑梗死和脑出血组中均以纯合子4G／4G基因型患者的PAI－1血浆活性水平最高,5G／5G基因型最低,杂合子4G／5G基因型居中;4G纯合子基因型与其它二型之间比较差异无有显著性,4G／5G与5G／5G基因型之间比较差异无显著性。CI组4G／4G纯合子基因型与对照组比较差异有显著性（P＜0．05）,CI组基因型与CH组及CH组与对照组基因型比较差异均无显著性（P＞0．05）。CI组女性4G纯合子基因型患者血浆PAI－1活性与同型男性患者比较差异有显著性（P＜0．05）。结论 纯合子4G／4G基因型可能是CI发病的危险因素之一,4G纯合子个体可能具有较高的CI发病倾向,尤其可能与女性CI发病相关。