Asp Allele Research Articles

An Evaluation of μ-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence

Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response. To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. Eleven academic sites in the COMBINE Study. Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI. These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options. clinicaltrials.gov Identifier: NCT00006206.

The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels

Genetic variants of the endothelial nitric oxide synthase (eNOS) gene, Glu298Asp and T-786C, have been reported to be associated with cardiovascular disease. Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and vascular protective effects; its levels are typically low in metabolic syndrome. Therefore, eNOS gene polymorphisms may also be associated with specific metabolic profiles, including plasma adiponectin levels and atherogenic lipids. We evaluated the functional significance of eNOS gene Glu298Asp and T-786C polymorphisms on endothelial function and metabolic profiles in 101 healthy young men (mean age 30.3 years) before the progression of atherosclerotic lesions. No linkage disequilibrium was found between the two genotypes. The Asp298 allele carriers of the eNOS gene presented significantly higher plasma low density lipoprotein (LDL) cholesterol, LDL particle size, malondialdehyde-modified LDL (MDA-LDL), and fasting insulin levels and lower plasma high density lipoprotein (HDL) cholesterol, apolipoprotein A-I levels, and endothelium-dependent vasodilation when compared with noncarriers. In spite of higher MDA-LDL levels, Asp298 carriers had significantly larger LDL particle size. By contrast, in C-786 allele carriers, systolic blood pressure was significantly higher, and plasma high-molecular-weight adiponectin levels and endothelium-dependent vasodilation were significantly lower than those in non-carriers. Although both eNOS polymorphisms induced endothelial dysfunction, the eNOS T-786C polymorphism may be associated with adiponectin levels, whereas the Glu298Asp polymorphism may be associated with atherogenic lipid levels.

Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation

Studies in European Americans (EAs) have shown that the hypothalamic-pituitary-adrenal (HPA)-axis activation by the opioid blockade is moderated by the single nucleotide polymorphism (SNP) A118G (Asn40Asp) at the mu-opioid receptor locus (OPRM1). We examined the effect of this, and of five intronic OPRM1 SNPs, on adrenocorticotropic hormone and cortisol concentrations, following the placebo-controlled administration of naloxone to healthy individuals who were of EA or Asian ancestry. We used a balanced, within-participant design with two test sessions to examine the hormonal responses to intravenous naloxone (an opioid antagonist) (125 microg/kg) or placebo in 29 healthy participants (62% men, 59% of Asian ancestry). DNA isolated from whole blood was PCR amplified and genotyped using a fluorogenic 5 nuclease assay (TaqMan) method. Consistent with earlier reports, participants with one or two Asp40 alleles (n=16) had a significantly greater cortisol response to naloxone than Asn40 homozygotes, but the effect was limited to EAs. Asians with the Asp40 allele did not show a greater increase in cortisol response compared with Asn40 homozygotes. None of the intronic SNPs was associated with cortisol response either directly or via an interaction effect with Asn40Asp. Effects of the Asn40Asp polymorphism at OPRM1 on HPA-axis activation seem to be population-specific. The association between the Asn40Asp and the HPA-axis response to naloxone cannot, therefore, be explained with reference only to the amino acid substitution encoded by that polymorphism. Further research to understand the basis for the observed association is warranted.

Glu298Asp polymorphism of the eNOS gene is associated with coronary collateral development

Objective We examined the endothelial nitric oxide (eNOS) gene Glu298Asp polymorphism to assess its possible association with the extent of coronary collaterals. Methods A total of 473 consecutive patients who had high grade coronary stenosis or occlusion were evaluated for the extent of coronary collaterals by using Rentrop classification. Patients with grade 0 or 1 collaterals were identified as having poor collaterals. The relation between collateral status and eNOS Glu298Asp polymorphism was studied by multivariate logistic regression analysis. Results Subjects with poor collaterals were more likely to have diabetes mellitus ( p < 0.001) and unstable angina pectoris as clinical presentation ( p = 0.014) and more likely to carry Asp298 variant ( p = 0.02) but they were less likely to have received statins ( p = 0.031). Multivariate analysis demonstrated that Asp298 allele carriers were 1.7 times more likely to have poor collaterals than patients with GluGlu genotype (95% CI: 1.09–2.69, p = 0.024). There was a significant interaction between diabetes mellitus and eNOS Glu298Asp polymorphism in the analysis of collateral development. Among 145 diabetic patients Asp298 allele was the only predictor of poor collateral development with OR of 5.38 (95% CI: 2.41–11.98, p < 0.001). Once diabetic patients were excluded from the analysis Asp298 allele was no longer a significant correlate of poor collateral formation. Conclusions The present study suggests that the Asp298 allele of the eNOS gene is significantly associated with impaired collateral development, especially in patients with diabetes mellitus. Treatment strategies that modulate eNOS activity and/or NO production may improve coronary collateral development.

Mcp-1, eNOS, tPA and PAI-1 Gene Polymorphism and Correlation of Genotypes and Phenotypes in Hepatopulmonary Syndrome

The aim of this case-control study was to investigate both the distribution of MCP-1, eNOS, tPA and PAI-1 gene polymorphism and correlation of genotypes and phenotypes. Between September 1997-January 2005, 20 patients with HPS (group 1) were compared with a group of cirrhotic patients (group 2, n = 19) as well as unrelated healthy controls (group 3, n = 59) in respect to MCP1, eNOS, tPA and PAI-1 gene polymorphism frequency distribution. MCP1-2518G allele carriage in patients with HPS was higher than in controls (P = 0.01). In non-HPS cirrhotic patients, eNOS Glu298Asp, Asp gene carriers and frequency of Asp alleles were detected to be considerably higher than in patients with HPS and healthy controls (P < 0.05). HPS is more common in patients with MCP-1 2518G gene carriage; conversely it is less frequent in patients with high frequency of eNOS 298Asp allele and eNOS 298Asp carriage.

The zinc cluster transcription factor Tac1p regulates PDR16 expression in Candida albicans

The Candida albicans PDR16 gene, encoding a putative phosphatidylinositol transfer protein, is co-induced with the multidrug transporter genes CDR1 and CDR2 in azole-resistant (A(R)) clinical isolates and upon fluphenazine exposure of azole-susceptible (A(S)) cells, suggesting that it is regulated by Tac1p, the transcriptional activator of CDR genes. Deleting TAC1 in an A(R) isolate (5674) overexpressing PDR16, CDR1 and CDR2 decreased the expression of the three genes and fluconazole resistance to levels similar to those detected in the matched A(S) isolate (5457), demonstrating that Tac1p is responsible for PDR16 upregulation in that strain. Deleting TAC1 in the A(S) strain SC5314 abolished CDR2 induction by fluphenazine and decreased that of PDR16 and CDR1, uncovering the participation of an additional factor in the regulation of PDR16 and CDR1 expression. Sequencing of the TAC1 alleles identified one homozygous mutation in strain 5674, an Asn to Asp substitution at position 972 in the C-terminus of Tac1p. Introduction of the Asp(972) allele in a tac1Delta/Delta mutant caused high levels of fluconazole resistance and TAC1, PDR16, CDR1 and CDR2 constitutive induction. These results demonstrate that: (i) Tac1p controls PDR16 expression; (ii) Asn(972) to Asp(972) is a gain-of-function mutation; and (iii) Tac1p is positively autoregulated, directly or indirectly.

Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias

Studies on the relationship between endothelial nitric oxide (NOS3) gene variants and hypertension have been conflicting. To explore this hypothesis further, we performed a meta-analysis and re-evaluated the relationship between the three most widely studied NOS3 polymorphisms and hypertension status and blood pressure levels. Data on 40,413 subjects from 53 studies were combined in five distinct meta-analyses, and heterogeneity and publication bias were explored. Heterogeneity was observed in all meta-analyses. By a random-effects model, carriers of the four 27-basepair repeat variable number of tandem repeats in intron 4 were associated with a 28% increase in the risk of hypertension compared with those homozygous for the 5 repeat: odds ratio (OR) 1.28, 95% confidence interval (CI) 1.11-1.47, P=0.001. In Asian individuals, Asp allele carriers displayed a similar association: OR 1.28, 95% CI 1.06-1.54, P=0.01, as well as a 2 mmHg increase in both systolic (P=0.04) and diastolic (P=0.009) blood pressure levels. Furthermore, meta-regression analysis indicated that the effect of the Glu298Asp genotype on the risk of hypertension might be dependent on total cholesterol status. No effect of the T-786C variant on hypertension was detected. There was evidence that such findings might be a result of selectively reporting/publishing positive reports. Our results suggest that current data on the relationship between NOS3 variants and hypertension are subject not only to important heterogeneity but also to publication bias. Future research should preferentially focus on gene-environment interactions as well as haplotype analyses.

Candidate genes and growth curves for adiposity in African- and European-American youth

Obesity is associated with multiple health problems and often originates in childhood. This study investigated the association of genes with the development of general and central obesity from childhood into adulthood. Individual growth curves for measures of general adiposity were examined in an 11-year (1987-1998) cohort study. Single-nucleotide polymorphisms (SNPs) in 11 candidate genes were genotyped. Five hundred and twenty-six subjects classified by race (49% African American (AA)), sex (47% male) and socio-economic status (SES). AA female carriers of the 27Glu allele in the ADRB2 gene had a larger waist circumference (P<0.05). Subjects of high SES with the ApoB 4145Lys allele had a larger mean waist circumference than those without this allele (P<0.05). Only in the presence of an adverse environment (low SES) did carriers of the NOS3 298Asp allele have a larger mean body mass index, waist circumference and sum of skinfolds (P<0.05). These results suggest that several polymorphisms are associated with the mean level of adiposity, with the effects depending on other factors such as race, sex and/or SES.

Genetic polymorphisms and haplotypes of eNOS in breast cancer

To the Editor Recent studies published in this journal have shown contradictions regarding the possible association between polymorphisms of endothelial nitric oxide synthase (eNOS) gene and susceptibility to breast cancer [1–3]. While one study showed increased risk for breast cancer in subjects with the Asp allele for the Glu298Asp eNOS polymorphism [3], two other studies showed no significant association [1, 2]. Moreover, Lee and colleagues showed that eNOS haplotypes involving two eNOS polymorphisms (Glu298Asp in exon 7 and T-786C in the promoter region) were not associated with increased susceptibility to breast cancer [1]. However, these authors have not examined the influence of another important eNOS polymorphism in intron 4 (a variable number of tandem repeats), and maybe have missed important information. One major reason for such contradictions is that significant interethnic differences exist in the distribution of eNOS genotypes or haplotypes [4, 5]. However, haplotype (or diplotype) analysis can provide much more relevant biological information than the analysis of single polymorphisms, one by one. Indeed, the analysis of haplotypes may provide improved biological information in genetic association studies than the analysis of single polymorphisms [6]. For example, while single eNOS polymorphisms were not associated with increased susceptibility to another complex disease (hypertension), eNOS haplotypes involving three relevant eNOS polymorphisms were significantly associated with the development of hypertension [7–9]. These haplotype findings would have been missed if specific eNOS genotypes alone had been considered [7–9]. Importantly, the same specific eNOS haplotypes were associated with susceptibility to hypertension in subjects with different ethnic backgrounds [7–9], even though significant interethnic differences exist in the distribution of eNOS genotypes or haplotypes [4, 5]. Therefore genetic markers were much more important that ethnicity. We believe that the best way to avoid contradictions is to carry out studies based on the analysis of eNOS haplotypes involving all relevant polymorphisms. This approach will probably reveal which eNOS haplotypes, if any, are really associated with increased susceptibility to breast cancer.

Effect of beta lactoglobulin polymorphism on milk production in Holstein dairy cattle of Iran

Beta-Lacto globulin (BLG) is a major protein in the milk of ruminants. Bovine BLG gene is located on the chromosome 11q28 and has two common genetic variants, ‘A’ and ‘B’ (Gene-Bank X14710). These variants are different in amino acids at positions 64 and 118, where allele ‘A’ has Asp and Val and allele ‘B’ has Gly and Ala, respectively. Difference at position 118 can be detected by PCR-RFLP (Medrano and Agiular-Cordova 1990). It is reported that allele ‘A’ is associated with milk production (Strzalkowska et al. 2002) and allele ‘B’ has a positive effect on fat percentage (Tsiaras et al. 2005). The aim of our study was to estimate the allelic frequency in polymorphic site of exon IV (allele ‘A’ or HaeIII (-)) of BLG gene in Holstein dairy cattle of Iran and also to find any association of total milk production (first lactation) with BLG genotypes.

Endothelial Nitric Oxide Synthase Glu298Asp Gene Polymorphism in Periodontal Diseases

Endothelial nitric oxide synthase (eNOS) is involved in key steps of immune response. The aim of the present study was to evaluate genotype distribution and genotype-phenotype association in periodontal disease regarding Glu298Asp polymorphism of the eNOS gene. A total of 272 subjects were included into the study. Genomic DNA was obtained from the peripheral blood of 51 chronic periodontitis (CP) patients, 48 generalized aggressive periodontitis (GAgP), and 173 reference controls. Polymerase chain reaction (PCR) amplification and subsequent BanII restriction fragment length polymorphism (RFLP) analysis were used to detect eNOS Glu298Asp polymorphism. Probing depth, clinical attachment loss, plaque accumulation, and bleeding on probing (BOP) were recorded. The data were analyzed by the chi2 test, logistic regression, and Mann-Whitney U test. The distributions of eNOS Glu298Asp genotypes and alleles were similar among study groups. Subjects with the Asp allele (Asp+) were statistically higher in the CP group compared to the control group (odds ratio [OR] = 1.957; 95% confidence interval [95% CI] = 1.038 to 3.689). In the GAgP group, BOP (%) was significantly higher in patients with the 298Asp allele (Asp+) compared to patients without the Asp allele (Asp-) (P = 0.015). The present study showed that eNOS Glu298Asp polymorphism is associated with BOP in GAgP patients. Moreover, the 298Asp allele of the eNOS gene might be related to CP in the Turkish population.

Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) and development of pre-eclampsia: a case-control study and a meta-analysis

BackgroundPre-eclampsia is thought to have an important genetic component. Recently, pre-eclampsia has been associated in some studies with carriage of a common eNOS gene Glu298Asp polymorphism, a variant that leads to the replacement of glutamic acid by aspartic acid at codon 298.MethodHealthy women with singleton pregnancies were recruited from 7 district general hospitals in London, UK. Women at high risk of pre-eclampsia were screened by uterine artery Doppler velocimetry at 22–24 weeks of gestation and maternal blood was obtained to genotype the eNOS Glu298Asp polymorphism. Odds ratios (OR) and 95%CI, using logistic regression methods, were obtained to evaluate the association between the Glu298Asp polymorphism and pre-eclampsia. A meta-analysis was then undertaken of all published studies up to November 2005 examining the association of eNOS Glu298Asp genotype and pre-eclampsia.Results89 women with pre-eclampsia and 349 controls were included in the new study. The Glu298Asp polymorphism in a recessive model was not significantly associated with pre-eclampsia (adjusted-OR: 0.83 [95%CI: 0.30–2.25]; p = 0.7). In the meta-analysis, under a recessive genetic model (1129 cases & 2384 controls) women homozygous for the Asp298 allele were not at significantly increased risk of pre-eclampsia (OR: 1.28 [95%CI: 0.76–2.16]; p = 0.34). A dominant model (1334 cases & 2894 controls) was associated with no increase of risk of pre-eclampsia for women carriers of the Asp298 allele (OR: 1.12 [95%CI: 0.84–1.49]; p = 0.42).ConclusionFrom the data currently available, the eNOS Glu298Asp polymorphism is not associated with a significant increased risk of pre-eclampsia. However, published studies have been underpowered, much larger studies are needed to confirm or refute a realistic genotypic risk of disease, but which might contribute to many cases of pre-eclampsia in the population.

Association of an Asn40Asp (A118G) polymorphism in the μ-opioid receptor gene with substance dependence: A meta-analysis

Introduction The μ-opioid receptor has been implicated in the pathogenesis of dependence on opioids, alcohol, nicotine, and cocaine. Studies examining the association of the μ-opioid receptor gene (genetic locus OPRM1) with substance dependence (SD) have focused on the Asn40Asp (A118G) single nucleotide polymorphism (SNP). Method We used meta-analysis to examine the literature on the association of Asn40Asp with SD. Twenty-two articles describing 28 distinct samples and over 8000 subjects were included. A variety of factors (i.e., ethnicity, type of SD, rigor with which controls were screened, severity of SD among cases) were examined as potential moderators of the association. Results Four studies showed a significantly higher frequency of the Asp40 allele among SD cases, while three studies showed a significantly higher frequency of the Asp40 allele among controls. There was no significant association between Asn40Asp and SD (OR = 1.01, 95%CI = 0.86–1.19), nor was there substantial evidence of a moderator effect. Conclusion The Asn40Asp SNP in OPRM1 does not appear to affect risk for SD. Additional research is needed to determine whether these findings reflect no role for OPRM1 in determining risk for SD or whether another polymorphism in the gene influences receptor function and risk for SD.

Associations of Uric Acid with Polymorphisms in the δ-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: δ-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 μg/g bone mineral, 32.0± 15.0 g/dL, and 0.77± 0.86 μg/mg creatinine, respectively, in 798 current and former lead workers. Participants with the eNOS Asp allele had lower mean serum uric acid compared with those with the Glu/Glu genotype. Among older workers (age ≥ 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 VDR B 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.

Polymorphisms in glutathione S -transferase omega-1 and AD, vascular dementia, and stroke

Glutathione S-transferase omega-1 (GSTO1) protects from oxidative stress, a risk factor for Alzheimer disease (AD), vascular dementia (VaD), and stroke. Polymorphisms in GSTO1 might influence the function of the protein and thus the risk of AD, VaD, and stroke. The GSTO1 gene was screened for variations. The effect of the detected polymorphisms on the risk of AD, VaD, and stroke was evaluated. CSF levels of cholesterol and plasma homocysteine levels were compared according to the GSTO1 genotype. Two missense polymorphisms in exon 4 of GSTO1 (Ala140Asp and Glu155DeltaGlu) were detected and tested for their association with AD, VaD, and stroke. The Asp/Asp and Ala/Asp genotypes increased the risk of stroke (p = 0.003, OR = 2.1), and the Asp/Asp genotype increased the risk of VaD (p = 0.02, OR = 2.2). GSTO1 polymorphisms did not influence the risk of AD, but the Asp allele influenced the age at onset (p = 0.05). In nondemented probands CSF levels of cholesterol were increased in carriers of the Asp/Asp genotype (p = 0.004); however, in patients with manifest dementia the authors found decreased CSF levels of cholesterol in carriers of the Asp/Asp genotype (p = 0.028). Serum homocysteine levels in stroke patients were higher in carriers of at least one Asp allele (p = 0.011). The GSTO1 Asp allele may be a genetic risk factor for cerebrovascular diseases, and might influence the course of Alzheimer disease, even though effects vary in different studies.

Effects of NOS3 Glu298Asp polymorphism on hemodynamic reactivity to stress: influences of ethnicity and obesity.

Studies on the associations between the nitric oxide synthase gene (NOS3) Glu298Asp polymorphism and hypertension status or blood pressure (BP) levels have had inconsistent results. Potential moderating influences of ethnicity, sex, and obesity on the effects of the NOS3 polymorphism have not been examined. We evaluated the influence of these factors on associations between the NOS3 polymorphism, nitric oxide metabolites (NOx), and hemodynamics at rest and during stress. Subjects were 235 African American (AA) and 262 European American (EA) young adults (18.5+/-2.6 years). Hemodynamic measurements and blood samples for NOx assays were taken before and after a competitive video game challenge. Glu298Asp polymorphism was detected by polymerase chain reaction-restriction enzyme digestion assay. A regression model was built using genotypes, ethnicity, sex, and obesity (body mass index >85th percentile) and their interactions controlling for age; 20.1% of AAs and 49.8% of EAs were carriers of the Asp allele. AAs, regardless of obesity status, exhibited high diastolic blood pressure (DBP) reactivity unless they were nonobese and noncarriers of the Asp allele. EAs exhibited lower DBP reactivity unless they were obese Asp allele carriers. AA nonobese carriers exhibited the greatest total peripheral resistance reactivity. Obese Asp allele carriers exhibited the greatest increases in cardiac output and the greatest decrease in NOx to the stressor. Results indicate the importance of examining impact of BP control-related genetic polymorphisms within the context of moderating factors such as adiposity and ethnicity.

Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study.

Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and -786T-->C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or -786T-->C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the "Asp298-786C-4b" haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the "Glu298-786T-4b" haplotype. The eNOS Glu298Asp polymorphism and the Asp298-786C-4b haplotype are risk factors for preeclampsia.

Genetic risk of atherosclerotic renal artery disease: the candidate gene approach in a renal angiography cohort.

It is largely unknown to what extent genetic abnormalities contribute to the development of atherosclerotic renal artery disease. Among the potential candidate genes, those of the renin-angiotensin system and the endothelial nitric oxide synthase (eNOS) rank high because of their importance in the atherosclerotic process. We investigated the association of polymorphisms in these genes (the angiotensinogen Met235Thr, the angiotensin-converting enzyme insertion/deletion, the angiotensin II type-1 receptor A1166C, and the eNOS Glu298Asp) with the presence or absence of atherosclerotic renovascular disease in 456 consecutive hypertensive patients referred for renal angiography on the suspicion of renovascular hypertension. Nondiseased normotensive (n=200) and hypertensive (n=154) patients from a family practice served as external controls. Renal artery disease was present in 30% of our angiography group. The Asp allele of the eNOS Glu298Asp polymorphism was associated with atherosclerotic renal artery stenosis with an odds ratio of 1.44 (95% confidence interval 1.00 to 2.09) versus hypertensives with angiographically proven patent arteries, of 1.89 (1.24 to 2.87) versus hypertensive family practice controls, and of 2.09 (1.29 to 3.38) versus normotensive family practice controls. However, this allele also differed significantly between patients with patent renal arteries and normotensive and hypertensive controls. No differences were found with respect to the other genetic polymorphisms. We hypothesize that the Asp allele of the Glu298Asp polymorphism may predispose to the development of atherosclerotic lesions but that renal artery involvement depends on other factors, also.

Endothelial nitric oxide synthase gene polymorphisms in giant cell arteritis.

To examine potential associations of the Glu/Asp(298) polymorphism in exon 7 and the 4a/b polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of giant cell arteritis (GCA), particularly in patients with versus those without ischemic complications. Ninety-one consecutive patients with biopsy-proven GCA, who were residents of Reggio Emilia, Italy, and 133 population-based controls from the same geographic area were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for eNOS polymorphisms in exon 7 and intron 4. The patients were separated into 2 subgroups according to the presence or absence of ischemic complications (visual loss and/or jaw claudication and/or aortic arch syndrome). The distribution of the Glu/Asp(298) genotype differed significantly between GCA patients and controls (corrected P [P(corr)] = 0.003). Carriers of the Asp(298) allele (Asp/Asp or Glu/Asp) were significantly more frequent among the GCA patients than among the controls (P(corr) = 0.0002, odds ratio 3.3, 95% confidence interval 1.7-6.3). The distribution of the 4a/b genotype was similar in GCA patients and controls. No significant associations were found when GCA patients with and without ischemic complications were compared. Our findings show that the Glu/Asp(298) polymorphism of the eNOS gene is associated with GCA susceptibility.

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.