Endothelial nitric oxide synthase gene/gender interactions and the renal hemodynamic response to angiotensin II

Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelial NO synthase (eNOS). One functional coding polymorphism of the eNOS gene (G894-->T) is associated with reduced enzyme activity, increased coronary heart disease, and the development of end-stage renal failure. Because gender and renin-angiotensin system activation also play key roles in the development of renal and cardiovascular disease and because NO plays a role in the response to angiotensin II (AngII), it was hypothesized that the eNOS gene G894-->T polymorphism would be a determinant of the systemic and renal vascular response to AngII. Fifty young, healthy, normotensive individuals who were on a controlled sodium and protein diet for 1 wk underwent assessment of BP and renal hemodynamic function at baseline and during AngII infusion (4 ng/kg per min for 45 min). Participants were genotyped for the eNOS gene G894-->T polymorphism and then segregated into groups on the basis of gender and genotype (GG versus GT/TT). Baseline values for renal blood flow, effective renal plasma flow, and GFR were lower in men with the T allele compared with men who were homozygous for the G allele (P = 0.03), but the polymorphism was not associated with renal hemodynamic function in women. The BP responses to AngII were similar in men and women regardless of genotype. Both multivariate linear regression and analysis of covariance (ANCOVA) revealed a relationship between gender and genotype. Men with the GT/TT genotype exhibited a significantly greater decrease in GFR (P = 0.04) in response to AngII than did those with the GG genotype. This association was not observed in women. The eNOS gene G894-->T polymorphism is a determinant of both baseline renal hemodynamic function and the hemodynamic response to AngII in men but not in women.     

Endothelial nitric oxide synthase polymorphisms are associated with hypertension and cardiovascular disease in renal transplantation

Aim: Nitric oxide (NO), produced by the polymorphic endothelial nitric oxide synthase (NOS3), plays an important role in endothelial function. The aim was to determine the effect of NOS3 polymorphisms on hypertension and cardiovascular disease (CVD) in renal allograft recipients. Methods: Three polymorphisms of NOS3 were examined in 168 renal allograft recipients. A 27 base pair repeat sequence in intron 4 (NOS3 a/b), a single G→T substitution in exon 7 at nucleotide 894 and a T‐786C substitution in the promoter region were studied. Results: Significant differences in the frequencies of the 894T and ?786C alleles between allograft recipients and controls (n = 141) were demonstrated (894T: 40.5% vs 30.1%, P < 0.01; ?786C: 45.2% vs 34.4%, P < 0.01). There was a significant excess of both the 894T and ?786C alleles in hypertensive allograft recipients compared with normotensive allograft recipients and controls (894T: 41.7%, 35.7% and 30.1%, respectively, P < 0.025; ?786C: 47.4%, 37.1% and 34.4%, respectively, P < 0.01), and in allograft recipients with CVD compared with those without CVD and controls (894T: 47.2%, 38.6% and 30.1%, respectively, P < 0.025; ?786C: 54.2%, 42.8% and 34.4%, respectively, P < 0.01). Conclusion: The 894T and ?786C alleles of the NOS3 gene were significantly associated with both hypertension and CVD in renal allograft recipients.     

Analysis of endothelial nitric oxide synthase (eNOS) G894T polymorphism and semen parameters in a Chinese Han population

Previous studies have shown that endothelial nitric oxide synthase (eNOS) gene may be involved in abnormal semen parameters. However, the relationship between eNOS G894T polymorphism and semen parameters remains controversial. The purpose of this study was to investigate the association of eNOS G894T polymorphism and semen parameters. The genotype frequency of eNOS G894T was determined in 270 idiopathic asthenozoospermia patients and 248 ethnically matched healthy volunteers using iPLEX genotyping assays on a MassARRAY^® (Sequenom, San Diego, CA, USA) platform. The statistical analysis performed with Fisher's exact test showed no significant difference in frequencies of genotypes between both groups. The logistic regression showed that genotypes GT, TT and allele T were nonassociated with increased risk of asthenozoospermia in the patient group with ≤5% or >5% sperm with normal forms. The dependence on genotypes of semen parameters was further investigated in both patients and control group. There was no significant difference as compared to control group (P > 0.05). Our study indicated that eNOS gene G894T polymorphism may not have an adverse effect on semen parameters in a Chinese Han population.     

Association of endothelial nitric oxide synthase gene polymorphisms with end-stage renal disease: a systematic review and meta-analysis

Background and objective: Endothelial nitric oxide synthase (eNOS) is one of the potent regulators of intra renal hemodynamics. Polymorphisms of eNOS gene may be involved in the progression of renal disease, and may be the causative factors that contribute to the deterioration of renal functions. During the past decades, several studies investigated the association of eNOS polymorphisms with the risk of end-stage renal disease (ESRD), but the results remain unclear and the mechanisms are not defined. Our study was designed to examine the role of different eNOS genetic polymorphisms in the progression of ESRD. Materials and methods: Relevant studies were identified through PubMed, Embase, Medline and CNKI (China National Knowledge Infrastructure) database published between January 2000 and November 2013. The association between eNOS polymorphisms and ESRD susceptibility was assessed by pooled odds ratios (ORs) and 95% confidence intervals (95% CI) in fixed or random effects models. Results: Sixteen articles were identified for the analysis of association between eNOS gene polymorphisms and ESRD risk. A total of 2729 patients and 2190 controls for 4b/a, 851 patients and 1171 controls for G894T, and 513 patients and 487 controls for T786C were included in our analysis. Overall, 4a allele of 4b/a polymorphism produced a significant association in the global population (OR?=?1.47, 95% CI?=?1.05–2.06, p?=?0.03) in a random-effect model; T allele of G894T was also significantly associated with ESRD susceptibility in overall populations (OR?=?2.12, 95% CI?=?1.44–3.12, p?=?0.0001). Furthermore, 4a and T carriers were significantly associated with ESRD risk as well. No association was found between T786C polymorphism and ESRD. Conclusion: The evidence accumulated suggested that 4b/a and G894T polymorphisms in the eNOS gene were associated with ESRD susceptibility, indicating that 4a and T allele carriers might become significant genetic molecular markers for the onset of ESRD in overall populations. However, more studies should be performed in the further studies.     

Glu298Asp endothelial nitric oxide synthase polymorphism is a risk factor for erectile dysfunction in the Mexican Mestizo population

Penile erection depends on the balanced action between antagonist vasoactive molecules such as nitric oxide (NO) and angiotensin. Endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) polymorphisms have been associated with endothelial dysfunction, which is described as a cause of erectile dysfunction (ED). Endothelial NOS and ACE are both regulators of vascular and corporal smooth muscle tone, which are connected by interaction between the NO-cyclic guanosine monophosphate pathway and the renin-angiotensin system. We analyzed the frequencies of 894 G/T (Glu298Asp) eNOS and ACE I/D polymorphisms in Mexican patients with ED (n=53) and in an age-matched control group (n=62). The populations analyzed were in Hardy Weinberg equilibrium. We found significant differences in allelic (chi2=4.42; P=.03) and genotypic frequencies (chi2=3.96; P=.04) between patients and controls for the 894 G/T eNOS polymorphism. Presence of the 894T allele in carriers increased the risk of ED (odds ratio [TT + GT versus GG] = 2.37; 95% confidence interval, 1.08 to 5.21; P=.02). Multiple logistic regression analysis showed that the Glu298Asp polymorphism was an independent factor for ED, as was diabetes mellitus, hypertension, cardiac disease, and cigarette smoking. No association was found between ACE I/D polymorphism and ED in the population studied. Therefore, our results suggest that Glu298Asp eNOS polymorphism plays a role as a genetic susceptibility factor for ED.     

Cytokine gene polymorphism in kidney transplantation--impact of TGF-beta 1, TNF-alpha and IL-6 on graft outcome

Chronic allograft nephropathy (CAN) is one of the main causes of graft loss in renal transplantation. Polymorphisms with functional significance in the promoter and coding regions of cytokine genes have been suggested as a possible factor for graft rejection. The aim of this study was to investigate the impact of cytokine gene polymorphism of pro and anti-inflammatory cytokines on development of CAN in a group of renal transplant patients and donors. Eight single nucleotide polymorphisms (SNPs) including TNFA (-308), TGFB1 (cdns10, 25), IL-10 (-1082, -819, -592), IL-6 (-174) and IFNG (+874) were analyzed in 56 patients with stable graft function (SGF), 10 with CAN and 28 kidney donors by PCR-SSP method. CAN was significantly associated with the recipient TGFB1 cod10 T/T and combination of cods10, 25 T/T G/G genotypes (high producer), (p<0.05). Influence of patient's TNFA genotype correlated with high level of gene expression on the development of CAN was further demonstrated when the patients were stratified according to the HLA mismatches (HLA-DRB MMs). Additionally donor TNFA-308 G/A (high) and IL-6-174 CC (low) genotypes were increased in cases with CAN. No statistically significant differences in distribution of IL-10, IL-6 and IFNG genotypes between recipients with SGF and CAN were found. In conclusion our data suggest that the high producer genotype of profibrogenetic TGF-beta1, pro-inflammatory TNF-alpha and genetically determined low production of immunoregulatory IL-6 cytokine might be risk factors for CAN development.     

Influence of eNOS gene polymorphisms on carotid atherosclerosis.

INTRODUCTION: Nitric oxide (NO) is an endothelium-derived relaxing factor which plays a role in atherogenetic events. Polymorphisms in the endothelial NO synthase gene (eNOS) influences the functional activity of the enzyme and affect the susceptibility to atherogenesis. In this study we determined whether T-786C, G894T and 4a/4b eNOS genetic variants may increase the susceptibility to carotid atherosclerosis. METHODS: The study groups included 304 consecutive patients with severe carotid stenosis (>/=70%) and 544 control subjects. The eNOS polymorphisms were analysed by molecular biology techniques. RESULTS: The genotype distribution and allele frequency of eNOS 4a/4b, but not T-786C and G894T, polymorphism was significantly different between patients and controls. Using logistic regression with adjustment for other risk factors, the 4a allele and the combined genotype 4a4a+4a4b/894TT+GT and -786CC+TC/894TT+GT were associated with carotid stenosis (OR=1.5, p=0.02; OR=1.8, p=0.01; OR=1.5, p=0.04, respectively). In a subset of patients (30 of 304) with no traditional risk factors for atherosclerosis, a relatively high incidence of the 4a allele and 4a4a+4a4b/-786CC+TC combined genotype was noted. DISCUSSION: Our findings suggest that the 4a allele and the eNOS combined genotypes are independent predisposing factors to carotid atherosclerosis.     

Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects

What's known on the subject? and What does the study add? We know that nitric oxide (NO) plays a significant role in penile tumescence. NO is produced during enzymatic conversion of L‐arginine to L‐citrulline by three distinct isoforms of NO synthase (NOS), namely, inducible (iNOS), endothelial (eNOS) and neural (nNOS). The endothelial isoform of NOS (eNOS), encoded by the NOS3 gene, is the main source of NO. We determined all three eNOS gene polymorphisms in men with vasculogenic erectile dysfunction. There was a significant difference between the group of men with vasculogenic erectile dysfunction and normal healthy men when compared by genotype distribution.

OBJECTIVE

? To investigate the association of the T‐786C, G894T and variable number of tandem repeats (VNTRs) in intron 4 (a/b) polymorphisms of the eNOS gene in Iranian subjects with vasculogenic erectile dysfunction (ED).

PATIENTS AND METHODS

? A total of 322 consecutive patients with vasculogenic ED were recruited. Patients with concomitant risk factors for ED were excluded. ? Patients with ED were identified based on history‐taking, detailed physical examination, serum biochemistry, sex hormone measurements, application of the International Index of Erectile Function (IIEF) questionnaire, and penile duplex Doppler ultrasonography after intracavernosal injection of 20 µg prostaglandin E₁. The control group comprised 318 age‐matched healthy male volunteers. ? Genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism and the T‐786C, G894T and VNTR intron 4 polymorphisms of the eNOS gene were determined.

RESULTS

? After multivariate regression analysis, significant differences were seen in the frequencies of genotypes and alleles of the two T‐786C and G894T polymorphisms when patients with ED and normal controls were compared. ? In a multiple logistic regression analysis, the odds ratio (OR) of increased ED was strongly associated with the ‐786C allele [adjusted OR = 3.12, 95% confidence interval (CI) = 2.28–4.25; P= 0.001] and the 894T allele (adjusted OR = 3.87, 95% CI = 2.53–4.87; P= 0.001). ? The data showed a higher prevalence of the T‐786C CC genotype (adjusted OR = 2.72, 95% CI = 1.88–3.65; P= 0.006), and the G894T GT (adjusted OR = 1.72, 95% CI 1.24–2.83; P= 0.037) and G894T TT genotypes (adjusted OR = 3.42, 95% CI 2.42–4.26; P= 0.001) in patients with ED than in the controls.

CONCLUSIONS

? The findings of the present study suggest that the eNOS T‐786C and G894T polymorphisms are strong predictors of the predisposition to ED in addition to traditional risk factors, signifying a genetic influence for this multifactorial disease. ? Further studies in different ethnic populations are needed to better elucidate the role of eNOS gene polymorphism in the pathogenesis of ED.     

The associations among eNOS G894T gene polymorphism, erectile dysfunction and related risk factors

OBJECTIVE: To investigate the possible correlations among eNOS G894T polymorphism, erectile dysfunction (ED) and related risk factors in a Taiwanese population. MATERIALS AND METHODS: In all, 151 patients with ED and 77 healthy controls were enrolled. All the men had a complete clinical history taken and laboratory data was collected. To assess erectile conditions the five-item version of the International Index of Erectile Function (IIEF-5) was used. The eNOS G894T polymorphisms were determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: In all, 228 men were enrolled with a mean (sd) age of 58.6 (9.7) years. In a univariate analysis, age, serum testosterone level, and the prevalence of diabetes mellitus (DM) and hypertension were significantly different between patients with ED and the healthy controls (P < 0.01). In the multiple logistic regression analysis, DM, age and hypogonadism were three independent risk factors for ED (P = 0.018, P = 0.046 and P = 0.016, respectively). The prevalence of ED in T allele carriers (GT/TT) was significantly greater than in G allele carriers (GG; 80.0% vs 63.3%, P = 0.04). Also the eNOS 894T allele carriers had significantly lower IIEF-5 scores than the eNOS 894G allele carriers, at 13.2 (5.3) vs 15.7 (6.1) (P = 0.01) and it was associated with increment of T allele number (11.0 (5.6) vs 13.6 (5.2) vs 15.7 (6.1); P = 0.03). CONCLUSION: Our results indicate that DM, age and hypoganadism are three significant independent risk factors for ED. Also, in the Taiwanese population, the eNOS 894T allele carriers are at greater risk of ED, both in prevalence and severity, and this might be a factor of genetic susceptibility.     

冠心病与内皮型一氧化氮合酶基因多态性的关系

目的 探讨内皮型一氧化氮合酶(eNOS)基因-786T/C,4a4b,894G/T等3个多态性位点与冠心病(CAD)发病相关.方法 对146例中国汉族人群CAD患者和113例正常对照进行遗传学分析,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和PCR技术分析2个SNP位点即-786T/C和894G/T,以及1个VNTR位点4a4b,检测各位点基因型和等位基因频率,采用HaploView 4.0及SPSS 13.0软件经x2检验比较两组间各位点基因型及等位基因频率的差异.结果 CAD组中eNOS基因-786T/C位点CC基因型频率为2.0%,4a4b位点4a/4a基因型频率为5.4%,对照组eNOS基因-786T/C位点CC基因型频率为0.0%,4a4b位点4a/4a基因型频率为0.9%,差异有统计学意义(P＜0.05).CAD组和对照组在eNOS基因的894G/T位点等位基因和基因型频率分布差异均无统计学意义(P＞0.05).结论 eNOS基因-786T/C和4a4b多态性与中国汉族人群CAD存在关联,C等位基因和4a等位基因可能是CAD发病的危险因素.eNOS基因894G/T位点与CAD发病无明显相关.

Abstract：

Objective To investigate the relationship between the 3 polymorphisms ( -786T/C,4a4b,894G/T) in endothelial nitric oxide synthase (eNOS) gene and coronary artery disease (CAD).Methods 146 patients with CAD and 113 healthy unrelated individuals in a Chinese Han nation were involved.The genotype and allele frequency of each polymorphism of the eNOS gene in these patients and normal controls were examined by using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) or PCR methods.Genotypes and allele frequency were analyzed by HaploView 4.0 and SPSS13.0 software.Results The frequency of CC genotype of the -786T/C was 2.0%,and that of 4a/4a genotype of the 4a4b was 5.4% in CAD.The frequency of CC genotype of the - 786T/C was 0.0%,and that of 4a/4a genotype of the 4a4b was 0.9% in controls ( P＜0.05 ).There were significant differences in both allele and genotype frequency of -786T/C and 4a4b between CDA group and control group.Between patients with CAD and controls,there were no significant differences in the frequency of the genotypes and alleles of the 894G/T in eNOS gene.Conclusion The - 786T/C and 4a4b polymorphisms of eNOS gene may be associated with CAD.The individuals with C allele of - 786T/C and 4a allele of 4a4b are susceptible to CAD.There is no significant correlation between 894G/T polymorphism in eNOS gene and CAD.     

eNOS G894T polymorphism as a mild predisposing factor for abdominal aortic aneurysm

OBJECTIVE: Abdominal aortic aneurysm (AAA) represents a chronic degenerative condition associated with atherosclerosis. Actually, data from experimental and clinical studies suggest that nitric oxide (NO) is a modulator in maintaining endothelial function and antithrombotic intravascular environment. Reduced vascular NO generation in subjects carrying the rare variants of the eNOS gene might predispose to AAA. No information is available about the influence of the eNOS gene T-786C, G894T, and 4a/4b polymorphisms in the susceptibility to the disease. METHODS: In this study, we evaluated the role of these polymorphisms in the predisposition to AAA and their influence in hypertensive and normotensive patients. We studied 250 consecutive patients with AAA referred to the Unit of Vascular Surgery of the University of Florence compared with 250 truly healthy subjects with a negative history of vascular diseases. All subjects, patients, and controls, underwent duplex scanning examination, and to assess the presence of other atherosclerotic localizations, all patients underwent clinical and instrumental examinations. RESULTS: A significant difference in genotype distribution and allele frequency was observed for eNOS G894T but not for T-786C and 4a/4b polymorphisms. At the multivariate analysis after adjustment for traditional vascular risk factors and other atherosclerotic localizations, the eNOS 894T variant was significantly associated with AAA, according to dominant and recessive models (dominant model odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.21-3.93, P = .007; recessive model OR: 2.7, 95% CI: 1.42-5.20, P = .002). When patients with other atherosclerotic localizations were excluded from the analysis, the 894T variant still remained associated with the predisposition to AAA, according to the models considered (dominant model OR: 2.1, 95%CI: 1.23-3.92, P = .007; recessive model OR: 2.8, 95%CI: 1.45-5.24, P = .002). CONCLUSIONS: The present study showed that the eNOS G894T polymorphism is a mild modulator of the predisposition to AAA apart from traditional risk factors, suggesting a genetic influence on the molecular mechanisms responsible for this complex disease.     

Nitric Oxide Synthase Gene Polymorphisms in Children with Primary Nocturnal Enuresis: A Preliminary Study

Aims. Recent studies demonstrated some differences in urinary electrolytes of enuretic children. Intrarenal nitric oxide (NO) serves as a major regulator of renal sodium and water excretion like an endogenous diuretic. This study aimed to investigate endothelial (eNOS), and neuronal (nNOS) NO synthase gene polymorphisms in children with primary nocturnal enuresis (PNE). Materials and Methods. The eNOS gene polymorphism was investigated in 171 Turkish children (57 PNE cases and 114 healthy, non-enuretic controls), and nNOS gene polymorphism was determined in 158 Turkish children (83 PNE cases and 75 healthy, non-enuretic controls). The glu298asp (G/T) polymorphism of the eNOS and C276T (C/T) polymorphism of nNOS genes were genotyped using PCR. Results. The distribution of GG, TG, and TT genotypes for eNOS gene was 48%, 33%, and 19% in PNE, compared with 61%, 26%, and 13% in the controls (p > 0.05). The distribution of CC, TC, TT and genotypes for nNOS gene was 31%, 29%, and 40% in PNE compared with 10%, 43%, and 47% in the controls. CC genotype was found higher in enuretic children (p?=?0.002). The eNOS and nNOS gene polymorphisms were not associated with positive family history, frequency of enuresis, and clinical response to desmopressin. Conclusions. This study is the first to search the NOS gene polymorphisms in children with PNE. It was determined that eNOS gene polymorphism may not be associated with PNE, while nNOS gene polymorphism, a predominantly CC genotype, may be associated with PNE in Turkish children. Further studies with larger samples together with the detection of enuresis gene may help determine the exact role of nNOS gene polymorphism in enuresis.     

Improved renal function after kidney transplantation is associated with heme oxygenase-1 polymorphism

Heme oxygenase-1 (HO-1) has a microsatellite polymorphism based on the number of guanosine-thymidine nucleotide repeats (GT) repeats that regulates expression levels and could have an impact on organ survival post-injury. We correlated HO-1 polymorphism with renal graft function. The HO-1 gene was sequenced (N = 181), and the allelic repeats were divided into subclasses: short repeats (S) (<27 repeats) and long repeats (L) (>/=27 repeats). A total of 47.5% of the donors carried the S allele. The allograft function was statistically improved six months, two and three yr after transplantation in patients receiving kidneys from donors with an S allele. For the recipients carrying the S allele (50.3%), the allograft function was also better throughout the follow-up, but reached statistical significance only three yr after transplantation (p = 0.04). Considering only those patients who had chronic allograft nephropathy (CAN; 74 of 181), allograft function was also better in donors and in recipients carrying the S allele, two and three yr after transplantation (p = 0.03). Recipients of kidney transplantation from donors carrying the S allele presented better function even in the presence of CAN.     

Concomitant presence of endothelial nitric oxide 894T and angiotensin II-converting enzyme D alleles are associated with diabetic nephropathy in a Kurdish population from Western Iran

Aim: The present study investigated the influence of insertion (I)/deletion (D) polymorphism of the angiotensin II‐converting enzyme (ACE) gene in combination with endothelial nitric oxide (eNOS) G894T polymorphism on the predisposition to diabetic nephropathy (DN). Methods: Using polymerase chain reaction (PCR) and PCR‐restriction fragment length polymorphism (PCR‐RFLP) method, the ACE and eNOS polymorphisms were genotyped in 72 microalbuminuric, 68 macroalbuminuric and 72 normoalbuinuric type 2 diabetes mellitus (T2DM) patients from Western Iran. Results: The presence of eNOS T or ACE D allele was not associated with increased risk of macroalbuminuria (odds ratio (OR) = 1.36, P = 0.27 and OR = 1.6, P = 0.062, respectively). However, in the presence of both alleles there was a trend towards increased risk of macroalbuminuria (fivefold, P = 0.05). Conclusion: Our study indicates that the concomitant presence of both ACE D and eNOS T alleles tends to be associated with an elevation risk of macroalbuminuria compared with the presence of each polymorphism alone. This risk could be attributed to the increasing activity of ACE and angiotensin II level in the presence of D allele and decreasing NO production in the presence of T allele accelerating diabetic nephropathy.     

Effects of the T-786C,G894T,and Intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene on the risk of prostate cancer

Several studies have shown that nitric oxide (NO) and nitric oxide synthase (NOS) system plays an important role in carcinogenesis. Endothelial nitric oxide synthase (eNOS) gene polymorphisms significantly affects serum NO concentrations. Studies addressing the relationship between eNOS gene polymorphisms and prostate cancer (CaP) are very scarce. We examined the association between the 3 eNOS gene polymorphisms (T-786C, G894T, and 4a/b) with risk and clinical features of CaP. One hundred seventy patients with CaP (mean age 63.6 ± 12.4 years) and 340 age-matched healthy controls (mean age 64.9 ± 12.9 years) were recruited in this case-control study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. For T-786C polymorphism, we found that CC genotype was associated to CaP risk [odds ratio (OR) = 3.62, 95% confidence interval (CI): 1.89–7.74, P = 0.002), high grade tumor (OR = 2.46, 95% CI:1.78–4.72; P = 0.006), and advanced disease (OR = 4.67, 95% CI: 2.64?8.61; P = 0.002). Neither the CaP risk nor clinical features of CaP were associated with the G894T polymorphism. It was found that, compared with 4a/b bb genotype, the 4a/b “a” variant genotypes were associated with an increased risk of CaP in an allele dose dependent manner (OR = 2.12, 95% CI: 1.68–3.44; P = 0.031 for 4a/b ab genotype, and OR = 4.32, 95% CI: 2.21–6.08; P = 0.001 for 4a/b aa genotype). In addition, genotypes with the “a” allele of the eNOS 4a/b polymorphism predispose the patients to high grade (OR = 4.76, 95% CI: 2.74–8.62; P = 0.001) and advanced CaP (OR = 5.28, 95% CI: 3.64–8.72; P = 0.001). Furthermore, the T-Asp-b and C-Asp-b haplotypes were associated with a significantly decreased risk of CaP (OR = 0.44, 95% CI: 0.33–0.77; P = 0.004, and OR = 0.39, 95% CI: 0.26–0.61; P = 0.001, respectively). We found significant differences in genotype distribution and allelic frequencies between CaP patients and controls for the T-786C, and 4a/b eNOS polymorphisms.     

Association of the genetic polymorphisms of the renin-angiotensin system and endothelial nitric oxide synthase with chronic renal transplant dysfunction

BACKGROUND: Chronic allograft dysfunction (CAD) is a complex phenomenon caused by underlying kidney disease and superimposed environmental and genetic factors. We investigated the association of polymorphisms in the genes for angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II receptor type 1 (ATR1) and type 2 (ATR2), and endothelial nitric oxide synthase (ENOS) with the initiation of CAD. METHODS: Genotyping was performed in 125 patients who underwent renal transplantation during a 5-year period for the ACE I/D, AGT M235T, ATR1 A1166C, ATR2 C3123A, and ENOS intron 4a/b gene polymorphisms. The following information was collected for each case: date of transplantation, age and sex of donor and recipient, donor type, cold ischemia time, number of human leukocyte antigen mismatches, number of acute rejection episodes, and laboratory findings at discharge from hospital and annual rechecks. Blood pressure was measured at yearly intervals throughout follow-up. RESULTS: The proportions of the genotypes were ACE II/ID/DD 12%, 33.6%, 54.4%; AGT MM/MT/TT 33%, 65.2%, 1.9%; ATR1 AA/AC/CC 68.6%, 30.7%, 0.7%; ATR2 CC/CA/AA 57.9%, 27.5%, 14.4%; and ENOS aa/ab/bb 6.4%, 22%, 71.6%, respectively. Statistical analysis of the major risk factors for the initiation of CAD showed that ACE DD genotype, cadaveric donor type, and level of proteinuria at 1 year posttransplantation were associated with poorer renal function. The graft function was not affected by AGT, ATR1, ATR2, and ENOS gene polymorphisms. CONCLUSIONS: These findings suggest that the DD variant of the ACE gene polymorphism is associated with increased risk of developing CAD.     

Endothelial Nitric Oxide Synthase Gene [G894T] polymorphism as a possible risk factor in aneurysmal subarachnoid haemorrhage

Summary Background. The exact aetiology, growth and rupture of intracranial aneurysms is unclear. In this study we investigated a possible association between intracranial aneurysm rupture and polymorphism of the endothelial nitric oxide synthase gene G894T. Methods. Endothelial nitric oxide synthase gene polymorphism of 53 patients with ruptured intracranial aneurysms and 60 control subjects were analysed by the polymerase chain reaction-restriction fragment length polymorphism technique. The genotype distribution and allele frequencies of endothelial nitric oxide synthase gene polymorphism in patients with ruptured intracranial aneurysm and healthy subjects were compared. Findings. The homozygous (TT) genotype frequency was significantly higher in patients with ruptured intracranial aneurysms. It was also found that the presence of eNOS 894TT genotype was significantly associated with the risk of intracranial aneurysm rupture (p < 0.05). Conclusion. Polymorphism in exon 7 of the endothelial nitric oxide synthase gene G894T seems to be a possible risk factor for intracranial aneurysm rupture. Correspondence: ünal ?züm, MD, PhD, Department of Neurosurgery. Cumhuriyet University School of Medicine, 58140 Sivas, Turkey.     

Interleukin-2 gene polymorphism is associated with renal but not cardiac transplant outcome

It was recently shown that IL-2 gene single nucleotide polymorphism (SNP) at position -330 (G-->T) is related to in vitro cytokine production levels, with the T/T and T/G genotypes being associated with low production and the G/G genotype associated with high production. The objective of this study was to investigate a possible influence of this polymorphism on renal and cardiac allograft outcomes. IL-2 SNP G-T (-330) was determined by PCR-RFLP in 67 recipients of heart allografts and in 63 recipients of renal grafts from HLA-haplo-identical, related donors. A higher frequency of the T/T genotype was observed in renal transplant patients who experienced at least one acute rejection episode during the first 3 months after transplantation than in those without rejection during this period (80% vs 49%, respectively, P <.05). Accordingly, the same genotype tended to be more frequent in renal recipients with a 6-month serum creatinine level above 1.5 mg/dL (median value for the whole group of kidney recipients) than in patients with lower creatinine levels (79% vs 45%, P <.08). Regarding cardiac transplant recipients, no associations were observed concerning acute rejection or graft survival. The finding of the association of T/T but not T/G genotype with acute kidney rejection was unexpected considering that both genotypes were shown to be associated with equal (low) IL-2 in vitro production. Further studies are necessary not only to dissect the nature of IL-2 T/T genotype association with kidney rejection, but also to explain why this genotype does not apparently influence cardiac allograft outcome.     

The association between eNOS intron 4 VNTR polymorphism and delayed graft function of kidney allografts

Dutkiewicz G, Domanski L, Binczak‐Kuleta A, Pawlik A, Safranow K, Ciechanowicz A, Dziedziejko V, Ciechanowski K. The association between eNOS intron 4 VNTR polymorphism and delayed graft function of kidney allografts.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01187.x
© 2009 John Wiley & Sons A/S. Abstract: Nitric oxide (NO) is a multifunctional agent which serves as a key signaling molecule in physiological processes such as host defense, neuronal communication, and the regulation of vascular tone. Different polymorphic variations have been identified in the human NOS3 (eNOS) gene.The aim of the present study was to examine the association between polymorphisms of the NOS3 gene (G894T substitution within exon 7 and intron 4 VNTR polymorphism) and the development of delayed graft function as well as acute and chronic rejection.One hundred eighty‐seven recipients of first renal transplants were included in the study. There were no significant associations between these polymorphisms and acute and chronic kidney allograft rejection. The intron 4 polymorphism was associated with delayed graft function after transplantation. The results of this study suggest that patients with the a allele of the eNOS intron 4 VNTR polymorphism may be predisposed to delayed graft function.     

Pretransplant and early posttransplant predictors of chronic allograft nephropathy in cadaveric kidney allograft—a single-center analysis of 1112 cases

This retrospective series reviews risk factors for chronic allograft nephropathy (CAN) based on the 10-year experience of a single institution. One thousand one hundred and twelve primary cadaveric renal transplant recipients whose graft survived for more than 6 months were followed for a mean of 4.6 years. The data were analyzed using the multivariate Cox proportional hazards model. CAN was defined as an irreversible rise of serum creatinine (SCr) by 30% in the absence of other causes and occurred in 42% of the patients. The risk of CAN was significantly increased in patients who experienced late rejections. Recipients of organs from donors that were older than 50 years and from such who died secondary to cerebrovascular accident were at increased risk of incurring CAN. Early markers of progression to CAN found at 6 months after transplantation included SCr levels of greater than 1.8 mg/ml, proteinuria, hypoalbuminemia, and hypertension. In conclusion, immune and non-immune factors affect progression to CAN in renal allograft recipients.