G894T Polymorphism Research Articles

Polymorphisms of Angiotensin Converting Enzyme and Nitric Oxide Synthase 3 Genes as Risk Factors of High-Altitude Pulmonary Edema: A Case-Control Study and Meta-Analysis

High-altitude pulmonary edema (HAPE) is a non-cardiogenic type of pulmonary edema developing altitudes > 2,500 m. Angiotensin converting enzyme (ACE) and nitric oxide synthase 3 (NOS3) play important roles in regulating pulmonary vascular tone. To assess associations between genetic variants in the ACE and NOS3 genes and HAPE risk, 27 HAPE patients and 108 matched controls were genotyped and analyzed. The indicated HAPE association of the NOS3 G894T (Glu298Asp) single nucleotide polymorphism (SNP), which may change NO production, was further evaluated by a meta-analysis of six studies involving 399 HAPE patients and 495 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined with fixed-effects models. Stratification analyses of ethnicity and geographic location were performed. Significant associations were observed for the dominant model in two ACE tag SNPs influencing serum ACE concentrations (rs8066114 polymorphism: GG+CG vs. CC; rs4461142 polymorphism: TT+CT vs. CC). Furthermore, Single-locus analysis indicated significantly different distributions of G allele frequency between the cases (29.63%) and controls (17.13%) for the ACE rs8066114 polymorphism. The case-control distributions of genotype frequencies and T allele frequency of NOS3 G894T (Glu298Asp) polymorphism were significantly higher in the cases than controls, and the NOS3 G894T (Glu298Asp) SNP showed elevated HAPE risk under the dominant model (TT+GT vs. GG). Meta-analysis showed overall association of NOS3 G894T SNP with HAPE risk under the allele contrast and dominant genetic models, which remained significant for Asians. In conclusion, ACE rs8066114 and rs4461142 and NOS3 rs1799983 (G894T) polymorphisms may be associated with increased HAPE risk in Asians.

Is There Any Association Between Adiponectin Gene Polymorphisms and Cardiovascular Disease?

In this issue of Angiology, Rizk et al assess the association of adiponectin gene polymorphisms and, in particular, rs2241766 (þT45G) and rs1501299 (þG276T), with adiponectin levels and with the risk of acute coronary syndrome (ACS) in an Arabian cohort of Qatar. Despite the study’s limitations, such as the small sample size, the small proportion of females, and its cross-sectional nature, the authors concluded that only the single-nucleotide polymorphism (SNP) T45G (and not SNP G276T) was associated with ACS. Among the various genotypes of T45G, the GG carriers were associated with a higher risk of developing an ACS and having lower adiponectin levels. Some parameters were also addressed, such as diabetes mellitus (DM), number of blood vessels affected, and the ejection fraction status in ACS, but no association with the genotype distributions of T45G or G276T polymorphisms was found, except for EF with T45G. This editorial considers some additional aspects of this topic.

The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile

The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile

Are the Oxidoreductases (Endothelial NO Synthase, Catalase, Glutathione Peroxidase, Superoxide Dismutases) Genes Polymorphisms Correlated with Long-Term Function of Kidney Allografts?

Introduction: Chronic graft rejection is a result of enhanced oxidative stress. It can therefore be hypothesized that genetic variability of antioxidant enzymes may play a role in the development of this complication. Endothelial NO synthase (eNOS) is seen as a protective enzyme. Catalase plays a significant role in the development of tolerance to oxidative stress in the adaptive response of cells and tissues. The glutathione peroxidase (GPX)/ glutathione system is a major defense in oxidative stress. The superoxide dismutases (SODs) appear to be the most important enzymes involved in the defense against ROS, particularly against superoxide anion radicals. The aim of the study was to examine the association of endothelial NO synthase, catalase, glutathione peroxidase, superoxide dismutases genes polymorphisms with long-term function of kidney allografts. Methods: The study enrolled 187 Caucasian first renal transplant recipients (59% males, aged 17-75 years, mean: 43.1 years, duration of allograft: 2-11 years, mean: 5.8 years). The histories of the patients were assessed taking into the account long-term function of kidney allograft. All studied polymorphisms were analyzed using the PCR-RFLP method. Results: There were no significant associations between ENOS VNTR and ENOS G894T polymorphisms and decreased graft function. There were no statistically significant associations between CAT, GPX, SOD1 and SOD2 genes polymorphisms and chronic allograft nephropathy. Conclusions: The results of our study suggest that polymorphisms in the oxidoreductases (endothelial NO synthase, catalase, glutathione peroxidase, superoxide dismutases) genes are not correlated with long-term function of kidney allografts.

MTHFR C677T and eNOS G894T variants in preeclamptic women: Contribution to lipid peroxidation and oxidative stress

ObjectivesWe aimed to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T and endothelial nitric oxide synthase (eNOS) G894T polymorphisms with lipid peroxidation, total antioxidant capacity (TAC) and the risk of preeclampsia in preeclamptic women. Design and MethodsWe screened a sample of 198 unrelated women with mild and severe forms of preeclampsia and 101 unrelated women with normal pregnancy with the eNOS and MTHFR variants using PCR-RFLP method. Also, the serum malondialdehyde (MDA) and TAC levels were determined using HPLC and commercial kits, respectively. ResultsThe frequency of combined genotypes of MTHFR CT and TT (CT+TT) and T allele tended to be higher in severe preeclamptic women compared to controls. There was no significant difference for eNOS G894T genotype and allele frequencies between patients and controls. A significantly higher level of triglycerides was observed in the presence of combined genotypes of MTHFR CT and TT and also eNOS GT and TT (GT+TT) in preeclamptic women compared to controls with the same genotype. Also, the presence of MTHFR TT genotype in severe preeclamptic women was significantly associated with the increased serum MDA level compared to CC genotype. In severe preeclamptic women the presence of CT and combined genotypes of CT and TT was significantly associated with the decreased TAC level compared to CC genotype. Also, a higher MDA level was observed in mild preeclamptic women with eNOS TT genotype compared to those with GG genotype but the difference was not significant. ConclusionThe present study indicates that MTHFR C677T polymorphism through affecting on TG level, lipid peroxidation and oxidative stress might be involved in the pathogenesis of severe preeclampsia.

Association of G894T polymorphism in endothelial nitric oxide synthase gene with the risk of ischemic stroke: A meta-analysis

Findings of a previous meta-analysis demonstrated no association between G894T polymorphism in endothelial nitric oxide synthase (eNOS) gene and ischemic stroke. Results of other studies have also been inconsistent. Updated meta-analysis was performed to assess the association between the eNOS gene G894T (rs1799983) polymorphism and the risk of ischemic stroke. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from fixed and random effects models were calculated. Heterogeneity in the studies was evaluated using the I2. Meta-regression and the 'leave-one-out' sensitive analysis were used to examine the potential sources of between-study heterogeneity. Publication bias was estimated using the Egger's test. Data were available for 6,607 cases and 6,947 controls from 22 studies. Studies deviating from the Hardy-Weinberg equilibrium (HWE) in the controls and the key contributors to between-study heterogeneity were excluded. Significant associations between eNOS gene G894T polymorphism and the risk of ischemic stroke were observed in the dominant (OR 1.249; 95% CI, 1.145-1.361), the recessive (OR 1.255; 95% CI, 1.082-1.456) and the codominant models (OR 1.195; 95% CI, 1.115-1.281). Moreover, in the subgroup analysis based on the region (Asia and Europe), significant associations were observed between the dominant and codominant genetic models but not in the recessive model. The results of our meta-analysis suggested that eNOS gene G894T polymorphism was associated with the increased risk of ischemic stroke, and that the T allele may be an important risk factor for ischemic stroke. However, further studies are required to confirm this result.

G894T Polymorphism of eNOS Gene is a Predictor of Response to Combination of Inhaled Corticosteroids with Long-Lasting β 2 -Agonists in Asthmatic Children

Nitric oxide synthase enzymes have an important role in airway inflammation in asthmatic children. In the present study, the association between eNOS gene polymorphisms and response to inhaled corticosteroids (ICS) and long-lasting β(2)-agonists (LABAs) was investigated. A total of 81 asthmatic children treated with ICS plus LABAs and 96 healthy controls were genotyped for eNOS G894T and -786T/C polymorphisms and their haplotypes using the PCR-RFLP method. G894T and -786T/C polymorphisms were not associated with asthma susceptibility. Among asthmatic children, 894TT carriers had higher change in forced expiratory volume in 1 s (FEV(1)) in response to ICS plus LABAs compared with 894GG carriers (21.9 ± 3.8 vs 1.6 ± 1.9%; p < 0.001). In responders (FEV(1) change ≥7.5%), frequency of 894TT genotype was significantly higher than in nonresponders (26.2 vs 2.6%, p < 0.001). Results for the -786T/C polymorphism alone were less clear and in most cases nonsignificant. The G894T polymorphism was associated with response to ICS and may serve as a useful pharmacogenetic marker of response to ICS plus LABAs in asthmatic children.

Close association between polymorphisms of the nitric oxide synthetase 3 gene and neurological disorders other than stroke

Correspondence: Shailendra Kapoor 2300 E Cary Street, Richmond, VA 23223, USA Email shailendrakapoor@yahoo.com To the editor I read with great interest the article by Du et al in a recent issue of your journal. The article makes highly interesting reading. Interestingly, the past few years have seen the discovery of a number of close associations between polymorphisms of the nitric oxide synthetase 3 (NOS3) gene and neurological diseases other than stroke. For instance, increased expression of NOS3 results in altered mitochondrial function in neurons. As a consequence, the intracellular levels of reactive oxygen species are accentuated, as are the levels of p53 and Bax, resulting in the dementia and neurodegeneration seen in individuals with Alzheimer’s disease. The G894T polymorphism acts as a risk factor for sporadic frontotemporal lobar degeneration. In fact, in a recent study, Venturelli et al have reported an incidence rate of 40% for the G894T polymorphism in individuals afflicted with frontotemporal lobar degeneration. Similarly, the risk of post-stroke dementia is increased in stroke patients with the rs1799983 polymorphism of the NOS3 gene. For instance, the hazard ratio is 3.14 in stroke patients with the TT genotype in comparison with those having the GG genotype. Similarly, individuals with Pick’s disease and Lewy body disease demonstrate altered NOS3 expression and accelerated proliferation of NOS3-positive neurons. An increased incidence of Parkinson’s disease is also associated with the rs12829185 and rs3782218 polymorphisms of the NOS1 gene and the rs944725 polymorphism of the NOS2A gene. Further, Sohn et al have recently demonstrated increased proliferation of NOS3-expressing glial cells in amyotrophic lateral sclerosis, as well as in progressive supranuclear palsy. The above examples illustrate a clear association between NOS3 and many neurological diseases, ranging from Alzheimer’s disease to Pick’s disease. Modulation of NOS3 function may alter and beneficially attenuate the progression of these diseases. Hopefully, the coming years will see the development of these NOS3 modulators.

Study on the influence of adiponectin genetic variants and adiponectin levels among Indonesian women with polycystic ovary syndrome

Background: Insulin resistance and central adiposity are frequent disorders in PCOS women, which are marked by biological marker dysregulation related to this metabolic abnormalities. Association between adiponectin and insulin resistance has been investigated in many studies, while only a few studies were done in PCOS patients. This study is to determine the association of T45G polymorphisms in Indonesian population with PCOS biological markers and their influence to adiponectin serum. Methods: Fifty-two PCOS patients and 52 normal ovulatory women without hyperandrogenism as control subjects were included. Blood samples were collected between day 3 and 5 of a spontaneous menstrual cycle at 7 to 9 am, after overnight fasting. Serum levels of FSH, LH, testosterone, SHBG, glucose, insulin, lipid profile and adiponectin were measured. Insulin resistance was estimated by HOMA-IR, HOMA- β, and SHBG. T45G gene polymorphisms were determined by PCR after genomic DNA was obtained from peripheral blood of patients and control subjects. Results: There were significant difference between PCOS and control group in term of BMI, LH, testosterone, SHBG, and FAI, but not significant to T45G gene polymorphisms frequency distribution. Adiponectin levels were lower in PCOS patients than control. There was an association between insulin resistance with PCOS. Among PCOS patients, no association between adiponectin LH, testosterone, SHBG, and FAI with T45G gene polymorphisms. T45G gene polymorphisms were more frequent in PCOS with low adiponectin levels compared to those with high adiponectin levels, although not significant statistically. Conclusion: T45G gene polymorphisms has no direct association with PCOS biological markers, but its association with adiponectin needs further study. (Med J Indones. 2012;21:83-91) &nbsp;

Nitric oxide synthase 3 (NOS3) 4b/a, T-786C and G894T polymorphisms in association with diabetic retinopathy susceptibility: A meta-analysis

Aims: To assess the association between the NOS3 4b/a, T-786C and G894T polymorphisms and diabetic retinopathy (DR) susceptibility.Materials and Methods: Twenty-one studies covering 8,111 subjects were included. The fixed or random effect model used was based on heterogeneity.Results: A significant association of the intron 4a allele in the NOS3 4b/a polymorphism with reduced risk of DR was found in dominant (OR 0.778, 95% CI 0.654–0.926) and additive (OR 0.809, 95% CI 0.698–0.937) models. Subgroup analysis revealed that the intron 4a allele additive model (OR 0.807, 95% CI 0.697–0.935) was associated with DR risk in type 2 diabetic patients. We also found a marginally significant association of the C allele in the T-786C polymorphism with reduced risk of proliferative DR. In contrast, no statistically significant association was observed between the G894T polymorphism and DR risk, either in the overall or subgroup analyses.Conclusions: The intron 4a allele of the 4b/a polymorphism in the eNOS gene has protective effects against DR, especially in type 2 diabetic patients. The C allele of the T-786C polymorphism may be a protective factor for proliferative DR. However, the G894T polymorphism does not appear to influence the development of DR. This conclusion warrants confirmation by further studies.

The G894T polymorphism on endothelial nitric oxide synthase gene is associated with increased coronary heart disease among Asia population: Evidence from a Meta analysis

IntroductionGrowing studies have revealed the underlying association between eNOS 894G/T (rs1799983) polymorphism and coronary heart disease (CHD) among Asia population. Results from these studies remained conflicting. We conducted this meta-analysis to estimate the overall CHD risk of eNOS 894G/T polymorphism regarding Asia population. Materials and methodsUp to October 2011, databases including PubMed, Embase and CNKI (China National Knowledge Infrastructure) were searched to access the relevant genetic association studies. Summary odds ratios and corresponding 95% confidence intervals (CIs) for eNOS 894G/T polymorphism and CHD risk were estimated using fixed or random-effects models when appropriate. Results18 case–control studies with 2,994 cases and 3,130 controls were available for this study, including 13 studies of East-Asia descendents, 5 studies of Non East-Asian descendents. The mean T allele frequency was 0.111 in the East-Asia population and 0.147 in the Non East-Asia population, respectively. The summary OR for CHD associated with the T allele was 1.52 (95% confidence intervals (95%CI), 1.37-1.69) by random effects model. Similarly, significantly increased risks were observed in the East-Asia population (OR=1.54; 95%CI=1.35–1.76) and in the Non East-Asia population (OR=1.48; 95%CI=1.24–1.77), respectively. ConclusionsThis meta-analysis indicated that eNOS 894G/T polymorphism may play an important role in CHD development among Asia population.

The Association of eNOS G894T Polymorphism with Metabolic Syndrome and Erectile Dysfunction

Accumulated evidences have outlined the potential relation between insulin resistance and endothelial dysfunction. The impaired ability of endothelium to synthesize or release nitric oxide may provide a common pathophysiological mechanism in the development of metabolic syndrome (MtS) and erectile dysfunction (ED). The aim of this article was to investigate the genetic susceptibility of endothelial nitric oxide synthase (eNOS) G894T polymorphism underlying the development of both disorders. A total of 590 subjects with a mean (standard deviation) age of 55.3 years (4.1) were enrolled during a free health screening. Complete clinical data and questionnaires were taken for all subjects. Multivariate logistic regression analysis was used to determine the independent predictors of MtS and ED. The eNOS G894T polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism method. The definition of MtS was according to the modified criteria developed by the Bureau of Health Promotion in Taiwan. Patients with ED were defined as those having a five-item International Index of Erectile Function (IIEF-5) <21. Our results showed that the eNOS 894T allele carriers had significantly higher prevalence of MtS and ED (odds ratio [OR]=1.64, 95% confidence interval [CI]=1.05∼2.56, P=0.02 and OR=1.76, 95% CI=1.11∼2.80, P=0.01, respectively) after adjustment for each other and age. Also the T allele carriers had significantly lower IIEF-5 score and more MtS components than G allele carriers (P<0.01 and P<0.01, respectively), which were significantly associated with an increment of the T allele number (P<0.05). The eNOS 894T allele carriers are at greater risk for both MtS and ED, suggesting that eNOS G894T gene polymorphism might play an implication as a common genetic susceptibility factor to develop both disorders.

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.

Associations of adiponectin gene polymorphisms with polycystic ovary syndrome: a meta-analysis

Adiponectin gene polymorphisms have been implicated in polycystic ovary syndrome (PCOS) development. However, results from previous studies were inconsistent and inconclusive. To shed some light on the relationship of two adiponectin gene polymorphisms, T45G and G276T, with PCOS, we conducted the current meta-analysis. PubMed was used for searching all eligible studies up to September 30, 2011. Odds ratio (OR) with the corresponding 95% confidence interval (CI) was adopted to evaluate the strength of the associations. In total, ten case-control studies involving 2,821 participants were included in the meta-analysis. Results showed that the T45G polymorphism was not associated with PCOS for allelic contrast (OR = 1.10, 95%CI: 0.83-1.44, P = 0.514), with evidence of large heterogeneity (P(heterogeneity) = 0.002). Concerning G276T polymorphism, the results showed that the T allele was related to a reduced risk of PCOS compared with the G allele under allelic genetic model (OR = 0.81, 95%CI: 0.70-0.93, P = 0.003), and no significant heterogeneity (P(heterogeneity) = 0.268) was revealed. Similar results were observed under additive, dominant and recessive genetic models for both of these two polymorphisms. No publication bias was detected. Our results suggested that the T45G polymorphism of adiponectin gene was not significantly associated with PCOS, while the G276T polymorphism was related to a decreased risk of PCOS.

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

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). 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. 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). 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.

Endothelial Nitric Oxide Synthase Gene Variants and Coronary Heart Disease

Nitric oxide synthase (NOS) was first recognized and reported in 1989. After that, considerable research was published (using the term ‘‘nitric oxide synthase,’’ a search of PubMed from its inception through March 2011 produced 54 335 articles). The significance of NO gained even more importance following the Nobel Prize award in 1998 to R. Furchgott, L. Ignarro, and F. Murad. In humans and generally in mammals, these synthases catalyze NO production from L-arginine and co-substrates, molecular oxygen, and 5 electrons provided by nicotinamide adenine dinucleotide phosphate (NADPH). There are 3 NOS isoforms that are products of different genes, with different localization, regulation, catalytic properties, and inhibitor sensitivity. NOS-1 is located mainly in neuronal tissue, NOS-2 is inducible in a wide range of cells and tissues, whereas NOS-3 is found in vascular endothelial cells (also called eNOS). However, NOS-3 is not only expressed by vascular endothelial cells (where it mediates relaxation, migration, and inhibition of vascular smooth muscle cells growth, inhibition of platelet and leukocyte adhesion to vascular endothelium, and limitation of the oxidation of low-density lipoprotein particles), but it is also present within cardiac myocytes, where the enzyme associates with the scaffolding/regulatory protein caveolin 3 in T tubules of plasmalemmal caveolae. It follows that many investigators have studied the cardiac effects of various NOS inhibitors, NO-donating drugs, and NO itself. Indeed we have witnessed an explosion of information regarding NO, leading to a better understanding of its physiological and pathophysiological roles. Another, important issue concerning NO was the encoding of the NOS-3 gene, which has been extensively screened for polymorphisms. Much attention has focused on putatively functional variants (-786T>C [rs2070744], intron 4 27-basepair repeat, and Glu298Asp [rs1799983]). In this issue of Angiology, Rahimi and Nourosi-Rad reported the role of NOS-3 G894T polymorphism on predisposition to coronary heart disease (CHD). They found significantly higher frequency of the NOS-3 894T allele in patients with CHD, independently of the presence of diabetes mellitus, compared with controls. They also observed 2.15 times increased CHD risk in the presence of the T allele of NOS-3 gene. Studies examining the functionality of NOS-3 G894T polymorphism found that individuals with the -786C variant have lower NOS-3 messenger RNA (mRNA) and serum nitrite/nitrate levels. Also, homozygotes for the -786C allele have a decreased maximal forearm blood flow response to acetylcholine, a pharmacologic model to evaluate NO production in vivo. In case–control studies among Japanese participants, those carrying the C-786 and T894 alleles of the NOS-3 gene had a significantly higher risk of vasospastic angina, supporting a functional role of these polymorphisms on coronary endothelial function. In addition, mice in which the NOS-3 gene has been deleted are hypertensive, and those with deletions in both the apolipoprotein E and NOS-3 genes have increased susceptibility to atherosclerosis. Endothelial NO availability is influenced by intensity of synthesis. Thus, the gene encoding the NOS-3 is an attractive candidate gene for cardiovascular risk. A recently published meta-analysis supported an influence of this variant on CHD risk. Nevertheless, there are some conflicting studies that were discussed by Rahimi and Nourosi-Rad. One can argue that the small number of individuals in this study is a major limitation. However, research evaluating the genetic associations with atherosclerosis is a promising tool for primary and secondary prevention. The NOS-3 G894T polymorphism may become a useful genetic marker to identify individuals prone to the development of atherosclerotic diseases. CHD is a multifactorial disorder with genotype, environmental, and ethnic interactions, which have an important role in its development. Larger populations of patients and controls

Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery

PurposeTo evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms (XRCC1, TP53, MSH2, MSH3, XPD), oxidative stress response (GSTP1, GSTA1, eNOS, SOD2) and fibroblast proliferation (TGFβ1) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy. Material and methodsSkin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery. Genotyping was conducted by PCR-RFLP analysis and real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. ResultsIn the multivariate analysis, nominally significant associations, before multiple testing corrections, were found between XRCC1 T-77C (T carriers vs. CC, OR: 2.240, 95% CI: 1.015–4.941, P=0.046), eNOS G894T polymorphisms (TT vs. G carriers, OR: 2.473, 95% CI: 1.220–5.012, P=0.012), breast diameter (OR: 1.138, 95% CI: 1.001–1.293, P=0.048), boost dose-fractionation (3Gy vs. no boost, OR: 4.902, 95% CI: 1.458–16.483, P=0.010) and ⩾grade 2 acute radiation skin toxicity in breast cancer patients. ConclusionsAs our exploratory study suggests that XRCC1 T-77C and eNOS G874T may confer an increased risk of acute skin reactions to radiotherapy in breast cancer patients, further confirmatory studies are warranted to determine the clinical significance.

Endothelial Nitric Oxide Synthase Gene Polymorphism and Periodontal Disease

The endothelial isoform of nitric oxide synthase (eNOS) is responsible for the physiological production of NO in endothelial cells and platelets. There is evidence that the G894T polymorphism of the eNOS gene is associated with this enzyme's basal activity and NO production, which could contribute to the pathogenesis of periodontal diseases (PD). Therefore, this study was designed to investigate the role of G894T polymorphism in the eNOS gene as a predisposing factor to periodontal disease. In this study we investigated the association of this polymorphism with PD in an admixture population (N = 119) separated into three groups: Healthy control, Moderate and Severe PD, without statistical differences among them for risk factors for PD, such as age, gender and smoking status. We observed that the GG genotype was associated with the progression of PD as indicated by an increase in frequency of approximately 18% in the Moderate and 26% in the Severe groups compared to the Healthy control group (p = 0.0302). This finding indicates that patients carrying the GG genotype have a greater chance of developing PD compared with those carrying the T allele, and it reinforces the notion that genetic factors contribute to the development and aggravation of PD.

Adiponectin gene polymorphisms (T45G and G276T), adiponectin levels and risk for metabolic diseases in an Arab population

In this study we examined the association of adiponectin gene variants with circulating adiponectin, and known metabolic diseases in 298 healthy controls and 297 Saudi subjects with type 2 diabetes mellitus (T2DM). Anthropometric and biochemical parameters were measured by standard procedures. Genotyping of T45G and G276T single nucleotide polymorphisms of adiponectin gene was carried out by PCR-RFLP analysis. No significant differences in the genotype distribution of T45G and G276T polymorphism were found between control and diabetic subjects. Neither SNP conferred an association with T2DM, obesity, hypertension or dyslipidemia. Despite a marked decrease in patients as opposed to controls, adiponectin levels were not different according to genotypes of T45G and G276T polymorphisms in control and patients. Thus, neither adiponectin SNPs independently conferred increased T2DM risk nor in other metabolic conditions considered such as obesity, hypertension or dyslipidemia. These findings support the existence of population based differences in the association of adiponectin gene variants with metabolic phenotypes and emphasize the importance of studying multiple polymorphisms, sufficient enough to identify the adiponectin gene as a genetic marker for several non-chronic communicable diseases.

Associations between eNOS polymorphisms and susceptibility to systemic lupus erythematosus: a meta-analysis

To determine whether endothelial nitric oxide synthase (eNOS) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE). A meta-analysis was conducted on the associations between the 4b/a, G894T, and C786T polymorphisms of eNOS and SLE and lupus nephritis (LN) (when available) using (1) the allele contrast, (2) the recessive, (3) the dominant, and (4) the additive models. A total of eight studies, which included 1,297 cases and 1,214 controls, were included in the meta-analysis. Meta-analysis showed no association between SLE and the 4b/a polymorphism in any study subjects. Stratification by presence of LN indicated a significant association between the a allele and the aa+ab genotype of the 4b/a polymorphism and LN in SLE patients [odds ratio (OR)=2.125, 95% confidence interval (CI)=1.289-3.054, p=0.003; OR=2.655, 95% CI=1.509-4.671, p=0.001]. No association was found between SLE and the G894T polymorphism using the allelic, recessive, or dominant, or additive models. Meta-analysis of the T786C polymorphism showed a tendency to an association between the TT genotype and SLE (OR=1.220, 95% CI=1.000-1.489, p=0.050), and meta-analysis of the TT versus CC genotype of the C786T polymorphism in group in Hardy-Weinberg equilibrium revealed a significant association between the TT genotype and SLE (OR=1.643, 95% CI=1.021-2.644, p=0.041). This meta-analysis of published studies shows that the 4b/a polymorphism may be associated with the development of LN, and the C786T polymorphism may be associated with SLE susceptibility.