Endothelial Nitric Oxide Synthase (eNOS) Gene Polymorphism in Early Term Chronic Allograft Nephropathy

Chronic allograft nephropathy (CAN) is a complex phenomenon caused by underlying kidney disease with superimposed enviromental and genetic factors. CAN development begins with progressive renal microvascular injury. Endothelial cells play key roles in the regulation of vascular tone, permeability, and remodeling. A reduction in basal nitric oxide (NO) release as a result of genetic variation in endothelial NO synthase (eNOS) function may predispose to hypertension, thrombosis, vasospasm, and atherosclerosis, all contributing to the development of CAN. We analyzed the G894T mutation at exon 7 of the eNOS gene in relationship to CAN among 81 children with renal transplantations. The 20 patients who developed CAN underwent renal biopsies for histological confirmation. Proteinuria and hypertension were observed in CAN. We selected 173 healthy reference subjects. The G894T polymorphism of the eNOS gene was determined by PCR–restriction fragment-length polymorphism analysis. The group included 33 male and 48 female subjects who received 32 living-related grafts and 49 from deceased donors (DD) donors. Donor age (y) was 32.7 ± 13.7 and the HLA A,B,DR mismatch number of the cadaveric cases was 3.5 ± 0.79. The distribution of the genotypes were ENOS GG/GT/TT 48%, 33%, 19%, respectively. G-alleles frequency was 64.8%; T-allele frequency was 35.2%. ENOS G894T gene polymorphism did not seem to influence long-term renal allograft outcome. Recipient ENOS G894T gene polymorphism did not alter the risk of chronic allograft failure. Even if NO synthesis and bioactivity are influenced by this polymorphism, many vasoactive factors may have roles to suppress the advantageous effects of NO.     

Interactions between gender and the angiotensin type 1 receptor gene polymorphism

BACKGROUND: The cardiovascular effects of angiotensin II are mediated by the angiotensin II type 1 receptor (AGT1R); one polymorphism of the AGT1R gene, A1166-->C, has been associated with hypertension. The hemodynamic response to angiotensin II is blunted in women compared to men, but interactions between gender, blood pressure, and AGT1R gene polymorphisms are unclear. METHODS: A total of 81 young healthy normotensive individuals maintained regulated sodium and protein intake prior to study. They were divided into four groups based on gender and A1166-->C genotype (AA versus AC/CC); serial supine blood pressures were obtained. A subset of 52 individuals received graded infusions of angiotensin II. Inulin and paraaminohippurate clearance techniques were used to measure renal hemodynamic function at baseline and in response to the infusions. RESULTS: Men with the AC/CC genotype exhibited higher blood pressures than men with the AA genotype; however, this relationship was not found among women. Analysis of covariance revealed a significant interaction between gender and AGT1R genotype in the determination of blood pressure. Glomerular filtration rate (GFR) declined variably in the study subjects following infusion of angiotensin II, and a statistical model incorporating gender and genotype best predicted the fall in GFR. There was a trend for females of the AA genotype to have a greater fall in GFR in response to angiotensin II infusion, than any of the other groups. CONCLUSION: In young healthy subjects, there is an important interaction between gender, the AGT1R A1166-->C gene polymorphism, and blood pressure. In addition, the renal hemodynamic response to angiotensin II infusion is a function of both gender and the AGT1R genotype.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Apolipoprotein m (APOM) levels and APOM rs805297 G/T polymorphism are associated with increased risk of rheumatoid arthritis

ObjectiveTo examine whether the apolipoprotein M (APOM) rs805297 G/T polymorphism is associated with risk of rheumatoid arthritis (RA) in a Chinese population.MethodsWe studied APOM rs805297 G/T gene polymorphism in 520 RA patients, and 520 controls in a Chinese population. Genotyping was done by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The blood plasma concentration of APOM was measured by an enzyme-linked immunosorbent assay in 84 RA patients and 84 controls.ResultsWhen the APOM rs805297 G/T GG homozygote genotype was used as the reference group, the TT or GT/TT genotype was associated with an increased risk for RA (TT vs. GG, adjusted odds ratio 1.76, 95% CI 1.11–2.77, P = 0.016; GT + TT vs. GG, adjusted odds ratio 1.30, 95% CI 1.02–1.67, P = 0.037). The average concentration of APOM in plasma was significantly higher in RA patients compared to controls. Stratification analysis found a significantly increased risk for RA associated with the APOM rs805297 TT genotype among male patients, C-reactive protein (CRP)-positive patients, anticitrullinated protein/peptide antibodies (ACPA) – positive patients, rheumatoid factor (RF) – positive patients, patients with higher levels of the erythrocyte sedimentation rate (ESR), patients with higher DAS28 score and patients with higher functional class compared to the APOM rs805297 GG genotype.ConclusionThese findings suggest that the functional single-nucleotide polymorphism APOM rs805297 G/T variant allele was associated with RA risk.     

Gender differences in the renal response to renin-angiotensin system blockade

Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n = 15; mean age 27 +/- 2) and women (n = 15; mean age 28 +/- 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.     

PRM1基因C321A、G197T单核苷酸多态性对体外受精结局的影响

目的 探讨鱼精蛋白1的C321A、G197T基因多态性与体外受精结局的关系。方法 选取我院生殖中心进行常规IVF的182例(182个周期),根据受精率分为3组:A组受精率30%,43个周期;B组受精率在30%~65%之间,24个周期;C组受精率65%,115个周期。提取授精后剩余精子的基因组DNA,采用聚合酶链限制性片段长度多态性(PCRRFLP)方法检测PRM1基因C321A和G197T基因型频率和分布,比较3组间基因型的分布差异及所有研究对象不同基因型间受精率的差异。结果 3组间比较,PRM1基因C321A多态性位点的各基因型频率无显著性差异(P0.05),C321A多态性位点与IVF受精率无相关性(P0.05)。在A组中,PRM1基因G197T多态性位点GG、GT、TT基因型分布频率分别为9.3%(4)、25.6%(11)、65.1%(28);B组分别为8.3%(2)、25.0%(6)、66.7%(16);C组分别为38.3%(44)、26.1%(30)、35.6%(41)。A组和B组的TT基因型频率显著高于C组(65.1%vs.35.6%,66.7%vs.35.6%),差异均有统计学意义(P0.05),TT基因型增加了IVF受精失败的风险。结论 PRM1基因C321A多态性与IVF受精率不相关;PRM1基因G197T多态性改变与IVF受精率相关。     

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.     

Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II

Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II. BACKGROUND: Most of the known actions of angiotensin II (Ang II) are mediated by the Ang II type 1 receptor (AGT1R). A noncoding polymorphism of the AGT1R gene has been described in which there is either an adenine (A) or cytosine (C) base at position 1166. The functional significance of this polymorphism is unknown, prompting us to examine the relationship between this polymorphism and the systemic and renal responses to AGT1R blockade and subpressor Ang II infusion. METHODS: Sixty-six healthy Caucasian men and women, genotyped for the AGT1R polymorphism by polymerase chain reaction, were chosen to form two homogeneous groups: AA and AC/CC. Renal hemodynamic function was assessed with inulin and para-aminohippurate clearance before and after AGT1R receptor blockade with losartan and Ang II infusion. RESULTS: The mean values at baseline for glomerular filtration rate (GFR), renal plasma flow (ERPF), and renal blood flow (RBF) were significantly lower in the AC/CC group compared with the AA group. Losartan increased the GFR and decreased the mean arterial pressure (MAP) in the AC/CC group, but did not influence these parameters in the AA group. The aldosterone responses to losartan were blunted in the AA subgroup. During Ang II infusion, AC/CC subjects maintained GFR despite equivalent declines in RBF, suggesting an enhanced efferent arteriolar constrictive response. CONCLUSIONS: Taken together, these results suggest that there is a relationship between the AGT1R A1166-->C polymorphism and the humoral and renal hemodynamic responses to AGT1R blockade and to Ang II infusion in the sodium-replete state, and that the C allele is associated with enhanced intrarenal and peripheral Ang II activity. Further studies are required to determine the genetic locus for this effect.     

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.     

Impact of renin angiotensin system modulation on the hyperfiltration state in type 1 diabetes

The initial stages of diabetic nephropathy are characterized by glomerular hyperfiltration and hypertension, processes that have been linked to initiation and progression of renal disease. Renin angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the presence of hyperfiltration. Baseline renal hemodynamic function was characterized in 22 patients. Eleven patients exhibited glomerular hyperfiltration (GFR>or=135 ml/min), and in the remaining 11 patients, the GFR was <130 ml/min. Renal hemodynamic function was assessed in response to a graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of angiotensin-converting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but not in the normofiltration group. After ACE inhibition, GFR fell but did not normalize in the hyperfiltration group; the normofiltration group showed no change. These data show significant differences in renal hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in hyperfiltering patients suggests that vasodilation may complement RAS activation in causing the hyperfiltration state. The interaction between glomerular vasoconstrictors and vasodilators requires examination in future studies.     

Impact of Donor-Dependent Genetic Factors on Long-Term Renal Graft Function

Our aim was to study the association of donor genetic features with long-term graft function as well as the impact of donor age, gender compatibility, cold ischemia time (CIT), and delayed graft function (DGF). We observed the outcomes of 125 kidney recipients for a minimum of 12 months (mean, 30.9 ± 13.0 months). Grafts were obtained from 89 donors who underwent profiling for AHSG 1/2, MMP9 -1562C/T, IL6 -174G/C, IL1β 3954C/T, MTHFR 677C/T, MTHFR 1298A/C, NOS3 -786C/T, and PAI1 4G/5G single-nucleotide polymorphisms (SNPs) using sequence-specific probe (SSP) polymerase chain reaction (PCR) and MPO -463G/A and CRP -390C/T/A with restriction fragment length polymorphism (RFLP) analysis. NOS3 IVa/b VNTR polymorphism was genotyped by gel electrophoresis of the respective PCR-generated DNA fragment. The presence of the aa eNOS genotype was connected with worse graft function. The aa genotype was also linked to acute rejection episodes. The lowest values of glomerular filtration rate (GFR) were displayed by recipients of grafts from donors with homozygotic PAI1 gene 5G polymorphism, linking paradoxically with lower PAI-1 synthesis suggesting that the intensity of proteolysis led to increased alloantigen specificity stimulating alloresponses. Graft function depended significantly on donor age with an influence of gender matching. GFR showed a significant dependence on DGF. Genetic features of the donor influenced long-term graft function. Variant eNOS gene polymorphism, which produced decreased eNOS activity, was linked to worse remote graft function. A similar negative impact was observed in the case of donor PAI1 polymorphism, with the functional consequence of lower gene product synthesis.     

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.     

The Collagen Ia1 SP1 Polymorphism is Associated With Differences in Ultrasound Transmission Velocity in the Calcaneus in Postmenopausal Women

Bone mineral density (BMD) and fracture risk are under genetic control. An association of a G to T polymorphism in the Sp1 binding site of the collagen Ia1 (COLIa1) gene with the risk for fractures has been previously reported. This association is only partly explained by differences in BMD. Thus, we analyzed the relationship between the COLIa1 Sp1 polymorphism and ultrasound (US) transmission velocity (speed of sound; SOS) in bone. In a population-based sample of 740 women (aged 55-80 years) we determined COLIa1 genotype and US parameters in the calcaneus. SOS in the "GG" genotype group was 1522 +/- 31 m/sec, in the "GT" group, 1519 +/- 30 m/sec, and in the "TT" group 1508 +/- 30 m/sec (P = 0.01). While the difference between the GG and TT genotype groups corresponds to 0.5 SD or 1%, we observed an allele-dose-effect of 4.3 m/sec decrease in SOS per each copy of the "T" allele (P = 0.01). The differences remained significant after adjustment for BMD measured at the femoral neck. When we analysed 45 incident nonvertebral fractures in this group of women, we found the risk for fracture by COLIA1 Sp1 genotype to be partly explained by SOS differences as well as by BMD differences. Linear regression analysis showed a progressive negative slope of the regression line of SOS over age from "GG" over "GT" to "TT" genotype. These data indicate that the collagen Ia1 Sp1 polymorphism is associated with the modulus of elasticity of bone as determined in vivo by acoustical measurement. The relationship is independent of BMD and increases with age, contributing to an explanation of the increased fracture risk observed for this polymorphism.