Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes

Evidence suggests that lead and selected genes known to modify the toxicokinetics of lead--namely, those for the vitamin D receptor (VDR) and delta-aminolevulinic acid dehydratase (ALAD)--may independently influence blood pressure and hypertension risk. We report the relations among ALAD and VDR genotypes, three lead dose measures, and blood pressure and hypertension status in 798 Korean lead workers and 135 controls without occupational exposure to lead. Lead dose was assessed by blood lead, tibia lead measured by X-ray fluorescence, and dimercaptosuccinic acid (DMSA)-chelatable lead. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele, and there were no ALAD(2) homozygotes; 11.2% (n = 89) had at least one copy of the VDR B allele, and 0.5% (n = 4) had the BB genotype. In linear regression models to control for covariates, VDR genotype (BB and Bb vs. bb), blood lead, tibia lead, and DMSA-chelatable lead were all positive predictors of systolic blood pressure. On average, lead workers with the VDR B allele, mainly heterozygotes, had systolic blood pressures that were 2.7-3.7 mm Hg higher than did workers with the bb genotype. VDR genotype was also associated with diastolic blood pressure; on average, lead workers with the VDR B allele had diastolic blood pressures that were 1.9-2.5 mm Hg higher than did lead workers with the VDR bb genotype (p = 0.04). VDR genotype modified the relation of age with systolic blood pressure; compared to lead workers with the VDR bb genotype, workers with the VDR B allele had larger elevations in blood pressure with increasing age. Lead workers with the VDR B allele also had a higher prevalence of hypertension compared to lead workers with the bb genotype [adjusted odds ratio (95% confidence interval) = 2.1 (1.0, 4.4), p = 0.05]. None of the lead biomarkers was associated with diastolic blood pressure, and tibia lead was the only lead dose measure that was a significant predictor of hypertension status. In contrast to VDR, ALAD genotype was not associated with the blood pressure measures and did not modify associations of the lead dose measures with any of the blood pressure measures. To our knowledge, these are the first data to suggest that the common genetic polymorphism in the VDR is associated with blood pressure and hypertension risk. We speculate that the BsmI polymorphism may be in linkage disequilibrium with another functional variant at the VDR locus or with a nearby gene.     

The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study

Recent research has indicated that a polymorphic variant of delta-aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP). Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter), cortical bone (tibia) lead (micrograms per gram), and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1), 22.1 (13.5), and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1), and 5.7 (4.2), 21.2 (10.9), and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2). In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 microg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 microg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone.     

Association of pro12Ala polymorphism in the peroxisome proliferative-activated receptor gamma2 gene with obesity and hypertension in Korean women

This study examined whether the Pro12Ala polymorphism of the PPARgamma2 gene is associated with obesity, hypertension and cardiovascular risk profiles in Korean adult women. We studied 129 Korean women (aged 42.71 +/- 8.56 y) who were divided into 2 groups as a Pro12Pro homozygous group and a Pro12Ala heterozygous or Ala12Ala homozygous group based upon PPARy2 genotype. Anthropometric parameters, blood pressure, abdominal fat area and blood lipid profiles were compared between the 2 groups, and the association of Ala allele frequency in PPARgamma2 gene with obesity or hypertension was evaluated. Most anthropometric parameters and blood lipid profiles did not differ significantly between the genotypes. However, all variables of skinfold thickness, body circumference and abdominal fat area of Pro12Ala heterozygous were consistently higher compared to the Pro12Pro homozygous subjects without a significance differences. The hypertensive group had significantly higher (p = 0.004) Ala12 allele frequency than the normotensive group whereas allele frequencies did not differ significantly between the obese group and non-obese group. Ala allele carriers had a significantly higher risk of hypertension than non-carriers in logistic regression analysis. There was no evidence that the Ala allele can be regarded as an independent risk factor for obesity. In conclusion, all variables related to obesity showed a consistently higher trend in Pro12Ala heterozygous subjects compared to Pro12Pro homozygous subjects. Pro12Ala heterozygous subjects showed an increasing trend of elevated blood pressure compared to Pro12Pro homozygous subjects. Ala12 variant as well as BMI and TG were regarded as independent risk factors for hypertension in our subjects.     

Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes

A cross-sectional study was performed to evaluate the influence of polymorphisms in the [delta]-aminolevulinic acid dehydratase (ALAD) and vitamin D receptor (VDR) genes on blood lead, tibia lead, and dimercaptosuccinic acid (DMSA)-chelatable lead levels in 798 lead workers and 135 controls without occupational lead exposure in the Republic of Korea. Tibia lead was assessed with a 30-min measurement by (109)Cd-induced K-shell X-ray fluorescence, and DMSA-chelatable lead was estimated as 4-hr urinary lead excretion after oral administration of 10 mg/kg DMSA. The primary goals of the analysis were to examine blood lead, tibia lead, and DMSA-chelatable lead levels by ALAD and VDR genotypes, controlling for covariates; and to evaluate whether ALAD and VDR genotype modified relations among the different lead biomarkers. There was a wide range of blood lead (4-86 microg/dL), tibia lead (-7-338 microg Pb/g bone mineral), and DMSA-chelatable lead (4.8-2,103 microg) levels among lead workers. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele and there were no homozygotes. For VDR, 10.7% (n = 85) had the Bb genotype, and 0.5% (n = 4) had the BB genotype. Although the ALAD and VDR genes are located on different chromosomes, lead workers homozygous for the ALAD(1) allele were much less likely to have the VDR bb genotype (crude odds ratio = 0.29, 95% exact confidence interval = 0.06-0.91). In adjusted analyses, subjects with the ALAD(2) allele had higher blood lead levels (on average, 2.9 microg/dL, p = 0.07) but no difference in tibia lead levels compared with subjects without the allele. In adjusted analyses, lead workers with the VDR B allele had significantly (p < 0.05) higher blood lead levels (on average, 4.2 microg/dL), chelatable lead levels (on average, 37.3 microg), and tibia lead levels (on average, 6.4 microg/g) than did workers with the VDR bb genotype. The current data confirm past observations that the ALAD gene modifies the toxicokinetics of lead and also provides new evidence that the VDR gene does so as well.     

eNOS第7外显子894G→T及第四内含子基因多态性与脑梗死关系的研究

目的探讨内皮型一氧化氮合酶（endothelial NOS,eNOS）第7外显子894G→T及第四内含子基因多态性在中国粤北地区汉族人群中的分布规律,并研究两组基因多态性与脑梗死（Cerebral infarction,CI）的关系及两种基因的连锁关系。方法本研究采用病例一对照研究,选择中国粤北地区汉族人群130例健康体检者（对照组）和148例经CT或MRI证实的脑梗死患者（cI组）为研究对象,用聚合酶链反应一限制性酶切片段长度多态性分析方法（PCR—RFLP）和核苷酸序列测定技术相结合的分子流行病学研究方法,对内皮型一氧化氮合酶第7外显子894G→T及第四内含子基因多态性进行检测及分析。结果脑梗死组eNOS基因外显子7处第894位T等位基因频率为10．5％,对照组为5．8％,两组比较差异有统计学意义（P〈0．05）,T等位基因纯合子携带者发生脑梗死的风险是GT或者GG纯合子携带者的1．757倍（χ^2=3．89,P=0．049,OR=1．757,95％CI=0．990～3．117）。第四内含子基因脑梗死组a等位基因频率为12．5％,对照组为6．6％,两组比较差异有统计学意义（P〈0．05）,4a基因纯合子携带者发生脑梗死的风险是464a或者4b纯合子携带者的1．8倍（χ^2=4．97,P=0．026,OR=1．860,95％CI=1．099～3．149）。结论研究显示,eNOS第7外显子894G→T及第四内含子与脑梗死的发病有关,而且两个基因位点之间并没有连锁不平衡的关系,提示eNOS第7外显子894G—T及第四内含子可能单独作用或和其他位点协同作用对脑梗死的发病产生影响,是脑梗死遗传危险因素。     

东乡族居民内皮型一氧化氮合酶基因G894T多态性和食盐量与原发性高血压的关系

目的探讨内皮型一氧化氮合酶(eNOS)基因G894T多态性和食盐量与东乡族居民原发性高血压(EH)的关系。方法于2007年6月—2008年3月在甘肃省东乡自治县开展调查,选取年龄在40～70岁之间、未服用过降压药物的东乡族居民为研究对象,其中高血压患者349例(EH组),正常血压者214例(NT组)。应用聚合酶链反应-限制性内切酶片段长度多态分析法(PCR-RLFP)对eNOS第7外显子894位碱基进行基因多态性分型;测定血浆胆固醇、甘油三酯、空腹血糖水平和体质指数,并调查其半年内食盐摄入量的平均水平;基因型频率、等位基因频率和组间计数资料间比较采用χ2检验;应用秩和检验结合趋势性检验分析G→T变异和食盐量与高血压分级的相关性。结果 EH组的平均食盐量高于NT组(P=0.003),EH组GT+TT基因型和T等位基因频率均高于NT组(分别为P=0.036,P=0.008)。在EH组中,T等位基因的变异对高血压的分级有一定影响(P=0.039),食盐量与高血压的分级呈正相关(rs=0.261,P=0.000)。结论 eNOS基因第7外显子G894T多态性的T等位基因影响东乡族EH的患病情况,并与EH的分级存在某种关联;同时EH的患病情况和分级也受高盐饮食的影响。     

Associations of renal function with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers

We analyzed data from 798 lead workers to determine whether polymorphisms in the genes encoding delta-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR) were associated with or modified relations of lead exposure and dose measures with renal outcomes. Lead exposure was assessed with job duration, blood lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and tibia lead. Renal function was assessed with blood urea nitrogen (BUN), serum creatinine, measured creatinine clearance, calculated creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG), and retinol-binding protein. Mean (+/- SD) tibia lead, blood lead, and DMSA-chelatable lead levels were 37.2 +/- 40.4 microg/g bone mineral, 32.0 +/- 15.0 microg/dL, and 767.8 +/- 862.1 microg/g creatinine, respectively. After adjustment, participants with the ALAD(2) allele had lower mean serum creatinine and higher calculated creatinine clearance. We observed effect modification by ALAD on associations between blood lead and/or DMSA-chelatable lead and three renal outcomes. Among those with the ALAD(1-2) genotype, higher lead measures were associated with lower BUN and serum creatinine and higher calculated creatinine clearance. Participants with the eNOS variant allele were found to have higher measured creatinine clearance and BUN. In participants with the Asp allele, longer duration working with lead was associated with higher serum creatinine and lower calculated creatinine clearance and NAG; all were significantly different from relations in those with the Glu/Glu genotype except NAG (p = 0.08). No significant differences were seen in renal outcomes by VDR genotype, nor was consistent effect modification observed. The ALAD findings could be explained by lead-induced hyperfiltration.     

beta(3) Adrenergic receptor polymorphism and obesity-related phenotypes in hypertensive patients

OBJECTIVES: Obesity is a complex trait that is affected by both environmental and genetic risk factors. The beta(3) adrenergic receptor (ADRB3) is expressed in adipose tissue and plays a role in energy metabolism. A missense mutation on codon 64 of this gene (W64R) is associated with receptor malfunction. Previous studies examining the relation between this polymorphism and obesity produced inconsistent findings. The current study assessed the association between the W64R genotype and obesity-related phenotypes, including body weight, BMI, and serum triglycerides, cholesterol, and glucose. RESEARCH METHODS AND PROCEDURES: We determined the ADRB3 W64R genotypes and fasting serum lipid and glucose concentrations for 695 hypertensive adults (336 men,359 women) from a rural county in Anhui Province, China. Multivariate linear regression models were fit to detect associations between the genetic polymorphism and obesity-related phenotypes. RESULTS: The ADRB3 W64R polymorphism was significantly associated with body weight and BMI in men but not in women. After controlling for potential confounding variables, men who were homozygous for the R64 allele were 11.8 kg heavier (p < 0.001) and had a BMI that was 3.7 kg/m(2) greater (p = 0.001) than men who were homozygous for the W64 allele. Serum concentrations of lipids and glucose were found not associated with the genetic polymorphism. DISCUSSION: The ADRB3 R64 allele was associated with increased body weight and BMI in men but not in women. The genetic association was not modified by triglyceride, cholesterol, blood glucose, or blood pressure levels of the subjects.     

中国人内皮型一氧化氮合酶基因G894T多态性与原发性高血压关系的Meta分析

目的 综合评价中国不同地区人群内皮型一氧化氮合酶基因G894T(Glu298Asp)多态性与原发性高血压的关系.方法 以高血压组和对照组基因型和等位基凼分布的OR值为统计最,检索相关文献;应用MIX软件对各研究结果进行一致性检验和分析,并进行数据合并,评估发表偏倚的影响.结果 共10篇文献纳入Meta分析,包括1900例原发性高血压患者和1216例对照者,10篇文献中高血压组与对照组(GT+TT)/GG基因型频率和T/G等位基因频率OR值效应量的一致性检验结果均显著(P=0.013;P=0.011),并存在发表偏倚(P=0.049;P=0.038).高血压组与对照组(GT+TT)/GG基因型频率的合并OR值(95%CI)为1.79(1.33～2.42),显著性检验Z=3.83,P<0.001.高血压组与对照组T/G等位基因频率的合并OR值(95%CI)为1.73(1.32～2.27),显著性检验Z=3.92,P<0.001.结论 中国人(汉族为主)内皮型一氧化氮合酶基因894G→T多态性与原发性高血压相关.     

Relation of alleles of the sodium-potassium adenosine triphosphatase alpha 2 gene with blood pressure and lead exposure

Lead is associated with elevated blood pressure, although the mechanism of action is unknown. Genetic differences in sodium-potassium adenosine triphosphatase (Na(+)-K(+)ATPase) could explain some of the variation in the strength of the blood pressure-blood lead relation that has been observed in previous studies. In 1996-1997, the authors studied the association of blood pressure, hypertension prevalence, and polymorphisms in the gene for the alpha 2 subunit of Na(+)-K(+)ATPase (ATP1A2) among 220 former organolead manufacturing workers from New Jersey. Subjects were genotyped for a restriction fragment length polymorphism (RFLP) on the ATP1A2 gene. The association between blood lead and blood pressure was stronger among persons who were homozygous for the variant allele. Genotype was also associated with hypertension (adjusted odds ratio = 7.7; 95% confidence interval: 1.9, 31.4). Finally, the variant allele was 1.8 times more common among African Americans than among Caucasians. The RFLP may indicate susceptibility to the effect of lead on blood pressure. Moreover, the alpha 2 gene (or a closely linked gene) may contribute to the pathophysiology of hypertension. However, because the number of subjects (especially African Americans) with the susceptible genotype in this study was small, these observations should be considered preliminary.     

一氧化氮合酶基因G894T变异与高血压病关系的研究

目的：探讨内皮型一氧化氮酶（eNOS）基因第7外显示G894T变异（Glu298Asp）与高血压病的关系。方法：以人群中筛检出的，未经药物治疗的116例高血压病患者及136名血压正常者为研究对象，运用聚合酶链反应－限制性片段长度多态性（PCR－RFLP）检测G894T变异。结果：G894T变异与高血压病显著相关，894T等位基因频率高血压病组显著高于血压正常组（16．0％：8．8％，P＝0．019），OR＝1．96，95％CI：1．14－3．37。在病例组，对照组及两组合计中，G894T变异基因型的收缩压及舒张压水平皆显著升高（P＜0．05）。用多元协方差分析调整年龄，性别、吸烟，饮酒，体重指数，甘油三酯，总胆固醇，高密度脂蛋白胆固醇后，在病例与对照合计中，G894T变异基因型对收缩压及舒张压水平仍具有正显著影响（P＜0．01）。结论：eNOS基因第7外显子G894T变异可能是该研究人群中高血压病发病的重要危险因素之一。     

Associations of uric acid with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers

Recent research suggests that uric acid may be nephrotoxic at lower levels than previously recognized and that it may be one mechanism for lead-related nephrotoxicity. Therefore, in understanding mechanisms for lead-related nephrotoxicity, it would be of value to determine whether genetic polymorphisms that are associated with renal outcomes in lead workers and/or modify associations between lead dose and renal function are also associated with uric acid and/or modify associations between lead dose and uric acid. We analyzed data on three such genetic polymorphisms: delta-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR). Mean (+/- SD) tibia, blood, and dimercaptosuccinic acid-chelatable lead levels were 37.2 +/- 40.4 microg/g bone mineral, 32.0+/- 15.0 g/dL, and 0.77+/- 0.86 microg/mg creatinine, respectively, in 798 current and former lead workers. Participants with the eNOSAsp allele had lower mean serum uric acid compared with those with the Glu/Glu genotype. Among older workers (age > or = median of 40.6 years), ALAD genotype modified associations between lead dose and uric acid levels. Higher lead dose was significantly associated with higher uric acid in workers with the ALAD1-1 genotype; associations were in the opposite direction in participants with the variant ALAD1-2 genotype. In contrast, higher tibia lead was associated with higher uric acid in those with the variant VDRB allele; however, modification was dependent on participants with the bb genotype and high tibia lead levels. We conclude that genetic polymorphisms may modify uric acid mediation of lead-related adverse renal effects.     

Associations of patella lead with polymorphisms in the vitamin D receptor, delta-aminolevulinic acid dehydratase and endothelial nitric oxide synthase genes

A cross-sectional analysis was performed to evaluate associations of polymorphisms in the vitamin D receptor (VDR), delta-aminolevulinic acid dehydratase (ALAD), and endothelial nitric oxide synthase (eNOS) genes with patella lead concentrations in 652 lead workers in the Republic of Korea. There was a wide range of patella lead (from below detection limit to 946 microg Pb/g bone mineral), with a mean (standard deviation) of 75.2 (101.0). There were no associations of ALAD or eNOS genotypes with patella lead, but workers with the VDR B allele had significantly (P value < 0.05) higher patella lead (on average, 25% or approximately 6.6 microg Pb/g bone mineral) than lead workers with the VDR bb genotype. There was evidence that the relation between age and patella lead was modified by both the VDR and eNOS genotypes.     

重庆市部分高血压患者一氧化氮合酶基因G894T多态性与相关危险因素的研究

目的 了解重庆市部分高血压病患者内皮一氧化氮合酶(eNOS)基因G894T多态性和高血压相关危险因素的关系。方法 高血压患者226例,设对照组。取血标本提取DNA,用聚合酶链反应(PCR)方法扩增目的基因,用限制性内切酶(Ban Ⅱ)酶切PCR产物用于基因分型,同时按照流行病学方法制作规范的调查表,调查内容包括体重指数、膳食、精神心理、疾病家族史等方面情况。结果 eNOS各基因型(GG、GT或TT)在高血压组与对照组中的分布差异无显著性(P>0.05),但在高血压相关的危险因素中(钠盐摄入、性格、打鼾等)分布有差别,T等位基因携带者高血压相关危险因素较多。logistic回归分析显示894T等位基因与高血压发病无关联。结论 eNOS基因G894T多态性在重庆市高血压发病中不起直接重要作用,但可能通过影响相关危险因素参与高血压发病机制。     

A delta-aminolevulinic acid dehydratase (ALAD) polymorphism may modify the relationship of low-level lead exposure to uricemia and renal function: the normative aging study

In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.     

内皮型一氧化氮合酶基因多态性与神经管畸形的关系

目的:探讨内皮型一氧化氮合酶基因第4内含子27bp长度的可变数目串联重复序列(VNTR)4a/bVNTR基因多态性和第7外显子单核苷酸多态性G894T与神经管畸形的关系。方法:提取2008年1月～2009年9月间生育神经管畸形儿的30名妇女和同期生育正常儿的60名健康妇女基因组DNA,用PCR-RFLP方法测定G894T和4a/bVNTR的多态性。结果:①eNOS基因G894T位点在本次研究中有3种基因型,即野生型GG、纯合突变型TT和杂合突变型GT。其基因型频率(GG、GT、TT)在病例组中的构成分别为46.67%、40.00%、13.33%,在对照组中的构成分别为73.33%、21.67%、5.00%,两组间的差异有统计学意义(χ2=6.413,P0.05);其等位基因G的频率在病例组和对照组中的构成分别为66.7%和84.2%,T等位基因的频率分别为33.3%和15.8%,差异有统计学意义(χ2=7.218,P0.01);②eNOS基因4a/bVNTR位点在本次研究中有两种基因型,即bb型和ab型。其基因型频率(bb、ab)在病例组中的构成分别为63.33%和36.67%,在对照组中的分布频率分别为80.00%和20.00%,在两组中的差异无统计学意义(P0.05);其等位基因b的频率在病例组和对照组中的构成分别为81.7%和90.0%,a等位基因在病例组和对照组中的分布频率分别为18.3%和10.0%,差异无统计学意义(P0.05);结论:母亲eNOS基因894位点G→T突变是出生神经管畸形儿的独立遗传学因素,而第4内含子27bpVNTR基因突变不足以构成导致神经管畸形发生的独立遗传学因素。     

Changes in systolic blood pressure associated with lead in blood and bone

BACKGROUND: Several studies have examined longitudinal associations of blood pressure change or hypertension incidence with lead concentration in blood or bone. It is not clear whether the observed associations reflect an immediate response to lead as a consequence of recent dose or rather are a persistent effect of cumulative dose over a lifetime. METHODS: We followed 575 subjects in a lead-exposed occupational cohort in South Korea between October 1997 and June 2001. We used generalized estimating equation models to evaluate blood pressure change between study visits in relation to tibia lead concentrations at each prior visit and concurrent changes in blood lead. The modeling strategy summarized the longitudinal association of blood pressure with cumulative lead dose or changes in recent lead dose. RESULTS: On average, participants were 41 years old at baseline and had worked 8.5 years in lead-exposed jobs. At baseline, the average +/- standard deviation for blood lead was 31.4 +/- 14.2 microg/dL, and for tibia lead, it was 38.4 +/- 42.9 microg/g bone mineral. Change in systolic blood pressure during the study was associated with concurrent blood lead change, with an average annual increase of 0.9 (95% confidence interval = 0.1 to 1.6) mm Hg for every 10-microg/dL increase in blood lead per year. CONCLUSION: The findings in this relatively young population of current and former lead workers suggest that systolic blood pressure responds to lead dose through acute pathways in addition to the effects of cumulative injury.     

The association between two common mutations C677T and A1298C in human methylenetetrahydrofolate reductase gene and the risk for diabetic nephropathy in type II diabetic patients

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes mellitus (DM). Both A1298C and C677T are highly prevalent in the diabetic population with allele frequencies of 0.35 and 0.36, respectively. The genotype frequency and allele frequency for these two polymorphisms in patients who are normoalbuminuric (n = 55) were compared with those of patients who had either micro- or macroalbuminuria (n = 43). For both polymorphisms, there were no significant differences in either the genotype distribution or allele frequency in patients with or without DN. However, in patients with serum folate <15.4 nmol/L, there was a greater incidence of DN in those patients who were homozygous or heterozygous for the C677T mutation. For the A1298C mutation, there is evidence suggesting that the homozygous state may be protective in patients with low-normal serum folate. Folate supplementation in diabetic patients with the C677T mutation and low-normal serum folate may prevent the onset or retard the progression of DN.     

Different associations of blood lead, meso 2,3-dimercaptosuccinic acid (DMSA)-chelatable lead, and tibial lead levels with blood pressure in 543 former organolead manufacturing workers

In this study, the authors' objective was to determine the influence of blood lead, meso 2,3-dimercaptosuccinic acid (DMSA)-chelatable lead, and tibial lead on systolic and diastolic blood pressures and on hypertension in 543 former organolead manufacturing workers. All workers had past exposure to inorganic and organic lead. The authors used linear regression to model systolic and diastolic blood pressure separately, and logistic regression was used for the modeling of hypertension status (i.e., systolic blood pressure > 160 mm Hg, diastolic blood pressure > or =96 mm Hg, or current use of antihypertensive medications). Blood lead, DMSA-chelatable lead, and tibial lead levels had means (standard deviations appear within parentheses) of 4.6 microg/dl (2.6 microg/dl), 19.3 microg (17.2 microg), and 14.4 microg/g (9.3 microg/g), respectively. The authors adjusted for covariates, and they found that blood lead was a predictor of (1) both systolic and diastolic blood pressures and (2) hypertension status in men < 58 y of age. DMSA-chelatable lead and tibial lead were not associated with any of the blood pressure measures. Systolic blood pressure was elevated by blood lead levels as low as 5 microg/dl. We speculate that lead may have a transient influence on blood pressure that is related to target dose levels obtained once release of lead from body stores has occurred.     

Dietary calcium as a potential modifier of the relationship of lead burden to blood pressure

BACKGROUND: Cumulative lead burden and low dietary calcium have been independently associated with increased risk of hypertension. There is evidence of an interaction between these factors. We tested the hypothesis that dietary calcium intake modifies the relationship between lead burden and hypertension. METHODS: A total of 471 men from the Normative Aging Study were evaluated. Bone lead was assessed using a K-x-ray fluorescence instrument, and information on dietary calcium intake was obtained with a self-administered semiquantitative food frequency questionnaire. RESULTS: We categorized 259 subjects (55%) as having low calcium intake (< or =800 mg/d) and 212 subjects (45%) as having higher calcium intake. In logistic regression models stratified by dietary calcium intake, tibia lead had a weak association with hypertension among subjects with low dietary calcium (odds ratio for 1-standard deviation increase in tibia lead = 1.30; 95% confidence interval = 0.97-1.74) but not in subjects with higher dietary calcium intake. Similarly, blood lead was associated with hypertension only in subjects with low calcium intake. We also found evidence of an interaction between dietary calcium intake and body mass index. CONCLUSIONS: High bone and blood lead increased the likelihood of hypertension, particularly among subjects with low dietary calcium intake. Dietary calcium may be helpful in prevention of hypertension induced by elevated lead burden.