Oxidative stress and inflammation play a pathogenetic role in idiopathic environmental intolerances (IEI), namely, multiple chemical sensitivity (MCS), fibromyalgia (FM), and chronic fatigue syndrome (CFS). Given the reported association of nitric oxide synthase (NOS) gene polymorphisms with inflammatory disorders, we aimed to investigate the distribution of NOS2A -2.5 kb (CCTTT) n as well as Ser608Leu and NOS3 -786T>C variants and their correlation with nitrite/nitrate levels, in a study cohort including 170 MCS, 108 suspected MCS (SMCS), 89 FM/CFS, and 196 healthy subjects. Patients and controls had similar distributions of NOS2A Ser608Leu and NOS3 -786T>C polymorphisms. Interestingly, the NOS3 -786TT genotype was associated with increased nitrite/nitrate levels only in IEI patients. We also found that the NOS2A -2.5 kb (CCTTT)11 allele represents a genetic determinant for FM/CFS, and the (CCTTT)16 allele discriminates MCS from SMCS patients. Instead, the (CCTTT)8 allele reduces by three-, six-, and tenfold, respectively, the risk for MCS, SMCS, and FM/CFS. Moreover, a short number of (CCTTT) repeats is associated with higher concentrations of nitrites/nitrates. Here, we first demonstrate that NOS3 -786T>C variant affects nitrite/nitrate levels in IEI patients and that screening for NOS2A -2.5 kb (CCTTT) n polymorphism may be useful for differential diagnosis of various IEI.

Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors) pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product) to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555) and rectal cancer (n = 754) cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035). Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR) were associated with colon cancer mortality (PARTP < 0.05); JAK2 (PARTP = 0.0086), PIK3CA (PARTP = 0.0098), and SMAD3 (PARTP = 0.0059) had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05). SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002). Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1) were significantly associated with rectal cancer (PARTP < 0.05). The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74) and was 10.99 (95% CI 5.30, 22.78) for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies.

Evidence suggests that vascular and inflammatory components may be important in the aetiology of dementia and genetic risk factors affecting these processes may therefore influence disease development. Recently, polymorphisms in the endothelial constitutive nitric oxide synthase 3 (NOS3) and also the inducible nitric oxide synthase gene (NOS2A) have been suggested to lead to increased risk of Alzheimer's disease (AD) or dementia with Lewy bodies. We have studied the relationship of both these NOS gene polymorphisms to development of AD and dementia with Lewy bodies and find no evidence for association with either condition. We conclude that NOS gene polymorphisms do not alter disease risk in the majority of late-onset dementia cases.

OBJECTIVE

Complex interactions between environmental and genetic determinants in both the host immune system and the vasculature may operate modifying the vascular risk in rheumatoid arthritis (RA). An increased incidence of cardiovascular (CV) events in RA patients carrying HLA-DRB1 shared epitope alleles, in particular HLA-DRB1*0404, has recently been found. In the present study we have assessed the potential contribution of inducible and endothelial nitric oxide synthase (NOS2A and NOS3) gene polymorphisms to CV events in a cohort of patients with rheumatoid arthritis (RA). Also, interactions between NOS2A or NOS3 gene polymorphisms and HLA-DRB1 alleles for the risk of developing CV events were assessed.

METHODS

One hundred and eighty-two consecutive patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the Rheumatology outpatient clinic of Hospital Xeral Calde, Lugo, Northwest Spain, between March and September 1996 were included. Patients were genotyped by PCR based techniques for a multiallelic (CCTTT)n repeat in the promoter region of the NOS2A gene and for a T/C polymorphism at position -786 in the promoter region and a polymorphism in exon 7 (298Glu/Asp or 5557G/T) of the NOS3 gene. They were prospectively followed and clinical records were examined until patient's death or September 1, 2005. At the end of the study 39 (21%) patients had experienced CV events.

RESULTS

No significant differences in allele or genotype frequencies for the NOS2A promoter CCTTT repeat microsatellite and NOS3 gene polymorphisms between RA patients with or without CV events were found. However, an increased frequency of CV events was observed in RA patients who carried the HLA-DRB1*0404 allele and were homozygous for the NOS3 (-786) TT genotype (OR: 9.06 [95% CI: 1.29-63.37]; p= 0.03) or for the presence of long NOS2A alleles (OR: 11.7 [95% CI: 1.53-88.4]); p= 0.02).

CONCLUSIONS

Our results show that NOS2A or NOS3 gene polymorphisms do not infer a direct risk for CV events in RA. However, some interactions between NOS gene polymorphisms and HLA-DRB1 alleles confer and increased risk of developing CV events in patients with RA.

Inducible nitric oxide synthase (NOS2A) may be involved in the oxidative stress pathology of Parkinson disease (PD). Two previous studies reported an association of a single nucleotide polymorphism (rs1060826) with PD. A replication study of 340 German patients and 680 controls showed no significant association between 12 genotyped polymorphisms and PD. NOS2A is therefore not a major susceptibility locus in our relatively young sample population.

OBJECTIVE

Nasal polyposis (NP) is a chronic inflammatory disease of the upper airways with a variable clinical course and unknown pathogenesis that often coexists with other conditions. Considering the possibility of genetic predisposition, we decided to analyze whether polymorphisms in LTC4S, CYSLTR1, PTGDR, and NOS2A were associated with NP.

METHODS

The study population comprised 486 Caucasian individuals. Polyposis and aspirin intolerance were diagnosed following the recommendations of the European Position Paper on Rhinosinusitis and Nasal Polyps. Genotypes were determined using polymerase chain reaction amplification and direct sequencing.

RESULTS

The -444A>> C LTC4S polymorphism was significantly associated with NP and atopy (P = .033) and with NP and atopic asthma, (P =.012). In addition, a significant association was found when the (CCTTT) repetition of the NOS2A gene was present more than 14 times in patients with NP and asthma (P = .034), in patients with polyposis and intolerance to nonsteroidal anti-inflammatory drugs (P = .009), and in patients with the aspirin triad (P = .005). The PTGDR diplotype CCCT/CCCC (-613CC, -549CC, -441CC and -197TC) was more frequent in patients with NP (P = .043), NP with asthma (P = .013), and the aspirin triad (P = .041).

CONCLUSIONS

NP was associated with specific polymorphisms only when it occurred with related phenotypes. Our results suggest that this genetic background plays a more relevant role in the development of the associated clinical features of nasal polyposis than in simple polyposis.

Essential hypertension is a common multifactorial trait that results in a significantly increased risk for heart attack and stroke. The condition has a genetic basis, although at present the number of genes is unknown. In order to identify such genes, we are utilising a linkage scanning approach using microsatellite markers and affected sibships. Here we provide evidence for the location of at least one hypertension susceptibility locus on chromosome 17. Analysis of 177 affected sibpairs gave evidence for significant excess allele sharing to D17S949 (SPLINK: P=0.0029; MAPMAKER SIBS: P=0.0033; ASPEX: P=0.0061; GENEHUNTER: P=0.0096; ANALYZE (SIBPAIR): P=0.0025) on 17q22-24, with significant allele sharing also indicated for an additional marker, D17S799 (SPLINK: P=0.025; MAPMAKER SIBS: P=0.025) located close to the centromere. Since these two genomic regions are well separated, our results indicate that there may be more than one chromosome 17 locus affecting human blood pressure. Moreover, further investigation of this chromosome, utilizing a polymorphism within the promoter of the iNOS candidate gene, NOS2A, revealed both increased allele sharing among sibpairs (SPLINK: P=0.02; ASPEX: P=0.00004) and positive association (P=0.034) of NOS2A to essential hypertension. Hence these results indicate that chromosome 17 and, more specifically, the NOS2A gene may play a role in human essential hypertension.

OBJECTIVE

To assess the contribution of 2 polymorphisms within the inducible nitric oxide (NOS2A) promoter region to susceptibility to giant cell arteritis (GCA).

METHODS

One hundred three patients with biopsy-proven GCA and 198 ethnically matched controls from the Lugo region (Northwest Spain) were studied. Patients and controls were genotyped using polymerase chain reaction techniques for a multiallelic (CCTTT)n and for the TAAA repeat polymorphism in the promoter region of the NOS2A gene.

RESULTS

No significant differences in allele or genotype frequencies for the (CCTTT)n repeat polymorphism in the NOS2A gene between patients with GCA and controls were observed. However, significant differences for the TAAA repeat polymorphism between patients and controls were found. The overall distribution of NOS2A TAAA genotypes in patients with biopsy-proven GCA was significantly different than controls (p = 0.026). Patients with GCA had an increased frequency of the NOS2A TAAA+ allele (16.5%) compared with controls (9.1%) (p = 0.007; OR 1.98; 95% CI 1.20-3.27). This was due to an increased frequency of both heterozygotes (27.2%) and homozygotes (2.9%) for NOS2A TAAA+ observed in patients compared to controls (15.2% and 1.5%, respectively) (p = 0.007; OR 2.15; 95% CI 1.23-3.78).

CONCLUSIONS

Our results suggest a potential implication for NOS2A TAAA gene polymorphism in GCA susceptibility.

Inducible nitric oxide synthase (iNOS) is an important molecule involved in the host defense against infectious agents. iNOS is encoded by the NOS2A gene and well-defined haplotypes exist with respect to this gene. We examined whether these haplotypes were associated with the outcome of hepatitis C virus (HCV) infection in 619 Caucasian patients from seven European liver centres. We observed five major haplotypes: (-277A)+(-1026G)+(-1659C): haplotype 1; (-277G)+(-1026T)+(-1659C): haplotype 2; (-277G)+(-1026G)+(-1659C): haplotype 3; (-277G)+(-1026T)+(-1659T): haplotype 4; and (-277A)+(-1026T)+(-1659C): haplotype 5. Distributions of these haplotypes are comparable with those of previous studies. Homozygotes for haplotype 2 or those with haplotypes 2/4 were more likely than those with the 1/1 (wild type) combination to have self-limiting infections (odds ratios (OR)=3.43; 95% confidence intervals (95% CI): 1.10-8.0; P=0.0206 and OR=5.15; 95% CI: 1.32-14.32; P=0.0018, respectively). Conversely, carriage of haplotype 1 was associated with the lack of self-limiting disease (OR=0.48; 95% CI: 0.27-0.83; P=0.009). The effect was mainly among males (OR=0.41; 95% CI: 0.182-0.942; P=0.031 for males, and OR=0.55; 95% CI: 0.24-1.37; P=0.136 for women). Carriage of haplotype 1 was not associated with initial response (P=0.268) or sustained response (P>0.171). Combinations of haplotypes 1/4 were more likely to respond to interferon monotherapy in comparison of initial responders to nonresponders (OR=2.25; 95% CI: 1.05-5.68; P=0.0275).

Tuberculosis (TB) is one of the most common infectious diseases in the world. Mycobacterium tuberculosis infection leads to pulmonary active disease in approximately 5-10% of exposed individuals. Both bacteria- and host-related characteristics influence latent infection and disease. Host genetic predisposition to develop TB may involve multiple genes and their polymorphisms. It was reported previously that interferon gamma (IFN-γ) and nitric oxide synthase 2 (NOS2) are expressed on alveolar macrophages from TB patients and are responsible for bacilli control; thus, we aimed this study at genotyping single nucleotide polymorphisms IFNG+874T/A SNP and NOS2A-954G/C SNP to estimate their role on TB susceptibility and determine whether these polymorphisms influence serum nitrite and NOx(-) production. This case-control study enrolled 172 TB patients and 179 healthy controls. Neither polymorphism was associated with susceptibility to TB. NOS2A-954G/C SNP was not associated with serum levels of nitrite and NOx(-). These results indicate that variants of IFNG+874T/A SNP and NOS2A-954G/C SNP do not influence TB susceptibility or the secretion of nitric oxide radicals in the study population.

BACKGROUND

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disorder of the central nervous system.

OBJECTIVE

To explore the genetic basis of three nitric oxide synthase (NOS) genes: NOS1, NOS2A and NOS3, with susceptibility to MS.

METHODS

A total of 122 MS patients and 118 healthy controls screened for NOS1 (rs2682826, rs41279104), NOS2A (CCTTT)n/(TAAA)n and NOS3 (rs1800783, rs1800779, rs2070744, 27bpVNTR) markers, using TaqMan®SNP Genotyping Assays and fragment analysis were enrolled in this study. QRT-PCR and ELISA were used to analyse the expression of NOS3 mRNA and Nitric Oxide (NO) levels.

RESULTS

Two NOS3 markers were associated with susceptibility to MS and early disease development. The NOS3 rs1800779 G-allele (p = 0.04) and GG-genotype (p = 0.02) showed association with susceptibility to MS. Short NOS2 (CCTTT)n (p = 0.03) and short/long repeat (p = 0.04) genotypes also showed associations with MS. These associations were intensified by sub-division of patients into Kuwaiti Arabs and Persians (p < 0.05). The NOS3-27 bp-VNTR a-allele was associated with early MS disease onset ≤26 years (p = 0.04). The NOS3-27 bp-VNTR a/b-genotype resulted in 23% lower NO production and the NOS3-rs1800779 AA-genotype resulted in lower NOS3 expression. Haplotypes obtained from NOS2A and NOS3 showed increased susceptibility to MS. NOS1 showed no significant association with MS.

CONCLUSIONS

This study provides evidence for the association between selected NOS2 and NOS3 markers and MS susceptibility.

Pathophysiological processes in coronary artery disease (CAD) are influenced by genetic factors. Since (i) inducible nitric oxide synthase (iNOS) has important cardiovascular effects, and (ii) the promoter of the iNOS gene (NOS2A) is genetically modulated by a 4 bp insertion/deletion (+/-) polymorphism located 0.7 kb upstream, we decided to examine the influence of this variant on clinical variables in 856 CAD patients of Anglo-Celtic/Northern European extraction. We found that 2% of CAD patients were homozygous for the + allele, and 19% were heterozygous. Males made up 74% of the patient group, and in these the + allele was associated with 38% higher plasma glucose levels (P=0.005), a 4.8% elevation in the waist/hip ratio (P=0.009) and a 48% greater frequency of unstable angina (P=0.014). The + allele, by influencing iNOS expression, could thus contribute to indices of insulin resistance and angina severity in male CAD patients.

BACKGROUND

Being overweight and obese increases oxidative stress in the body. To test the hypothesis that genetic variations in oxidative stress pathway genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL), we conducted a population-based case-control study in Connecticut women.

METHODS

Individuals who were overweight/obese (BMI ≥ 25) were compared with normal and underweight individuals (BMI < 25), and their risk of NHL stratified assuming a dominant allele model for each oxidative stress pathway single-nucleotide polymorphism.

RESULTS

Polymorphisms in AKR1A1, AKR1C1, AKR1C3, CYBA, GPX1, MPO, NCF2, NCF4, NOS1, NOS2A NOS3, OGG1, ATG9B, SOD1, SOD2, SOD3, RAC1, and RAC2 genes after false discovery rate adjustment did not modify the association between BMI and risk of NHL overall and histologic subtypes.

CONCLUSIONS

The results suggest that common genetic variations in oxidative stress genes do not modify the relationship between BMI and risk of NHL.

CONCLUSIONS

Studies of BMI and oxidative stress independently may elevate NHL risk, but this study suggests no interaction of the two risk factors. Future studies with larger study populations may reveal interactions.

Previous reports suggest the nitric-oxide synthase 2 (Nos2) promoter contains negative and positive cis-regulatory regions. This study identified such regions using rat C6 glial cells. Activity of the serially deleted rat Nos2 promoter fused to a luciferase reporter gene was found to vary with construct size independent of stimuli, decreasing markedly from 160 to 130 bp then increasing significantly from 110 to 94 bp. In contrast, time to peak activity was stimulus-dependent but size-independent; 4-8 h for a cytokine mixture or lipopolysaccharide + interferon-gamma, and 8-16 h for lipopolysaccharide + phorbol 12-myristate 13-acetate. Peak activity with heterologous promoters also varied; 4 h for 3.7 kb of the human Nos2A promoter, and 36 h for 1.8 kb of the murine promoter. Electrophoretic mobility shift assays and in vivo DNA footprinting data confirmed nuclear protein binding to promoter regions suspected of containing important regulatory sites based on reporter gene data. A binding site for NF-kappaB was not required for Nos2 promoter activity. These findings provide significant new information on the relative importance of different regions of the rat Nos2 promoter for transcriptional activation and nitric oxide production by glial cells and support the existence of cell- and species-specific mechanisms for transcriptional regulation of Nos2 activation.

BACKGROUND

The inflammatory process underlying nasal polyposis is induced and perpetuated by the enhanced activity of several agents including transcription factors. It has recently been demonstrated that one of them, named nuclear factor-kappa B (NF-κB), is implicated in the regulation of multiple pro-inflammatory genes.

OBJECTIVE

The aim of the study was to identify using microarray technology which NF-κB-dependent genes are activated in nasal polyp (NP) samples compared to the control mucosa.

METHODS

The transcriptional activity of genes was analyzed using an oligonucleotide microarray on 15 NPs and 8 cases of normal nasal mucosa.

RESULTS

Gene expression patterns obtained in NPs were significantly different from those in normal mucosa. NPs and control cases clustered separately, each of them with large homogeneity in gene expression. Among 582 human NF-κB-dependent genes 25 showed a significantly higher expression in NPs compared to the control. The largest increase focused on gene encoding TFF3 (a 5-fold higher expression) followed by NOS2A (5x), SERPINA1 (4x), UCP2 (4x), OXTR (4x) and IL8 (3x) (p<0.05). In healthy mucosa 19 genes presented increased transcription activity compared to NPs. The most significantly enhanced levels were shown LTF gene (20 fold) followed by KRT6B (7x), LYZ (7x), SD11B2 (5x) and MMP3 (4x) (p<0.05).

CONCLUSIONS

DNA microarray technology highlights the involvement of many unsuspected pathologic pathways which could be involved in NP growth. The identification of novel disease-related genes may help to understand the biology of NPs and elaborate new targeted therapy.

Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.

15-Deoxy-∆(12,14)-prostaglandin J(2) (15d-PGJ(2)), a peroxisome proliferator-activated receptor γ ligand, has been reported to have antiproliferative activity in certain types of cancer. The purpose of this study was to elucidate the effect of 15d-PGJ(2) on endometrial cancer cells, as well as the mechanism of action. Endometrial cancer-derived cells (HHUA, Ishikawa and HEC-59) were treated with various concentrations of 15d-PGJ(2), and its effects on cell growth, the cell cycle and apoptosis were investigated in vitro. Using cDNA microarrays, some potential targets of this drug were identified. All endometrial cancer cell lines were sensitive to the growth-inhibitory effect of 15d-PGJ(2). Cell cycle arrest at the G2/M phase of the cell cycle and induction of apoptosis were observed. Concerning the gene expression changes induced by 15d-PGJ(2) treatment, the upregulation of aldo-keto reductase family 1 member C3 (AKR1C3) and the downregulation of anterior gradient homolog 3 (AGR3) and nitric oxide synthase 2A (NOS2A) were confirmed using western blot analysis in all the cell lines examined. These results suggest that 15d-PGJ(2) may be a novel therapeutic option for the treatment of endometrial cancer.

Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1β levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

Circulating microRNAs are beneficial biomarkers because of their stability and dysregulation in diseases. Here we sought to determine the role of miR-939, a miRNA downregulated in patients with complex regional pain syndrome (CRPS). Hsa-miR-939 is predicted to target several proinflammatory genes, including IL-6, VEGFA, TNFα, NFκB2, and nitric oxide synthase 2 (NOS2A). Binding of miR-939 to the 3' untranslated region of these genes was confirmed by reporter assay. Overexpression of miR-939 in vitro resulted in reduction of IL-6, NOS2A and NFκB2 mRNAs, IL-6, VEGFA, and NOS2 proteins and NFκB activation. We observed a significant decrease in the NOS substrate l-arginine in plasma from CRPS patients, suggesting reduced miR-939 levels may contribute to an increase in endogenous NOS2A levels and NO, and thereby to pain and inflammation. Pathway analysis showed that miR-939 represents a critical regulatory node in a network of inflammatory mediators. Collectively, our data suggest that miR-939 may regulate multiple proinflammatory genes and that downregulation of miR-939 in CRPS patients may increase expression of these genes, resulting in amplification of the inflammatory pain signal transduction cascade. Circulating miRNAs may function as crucial signaling nodes, and small changes in miRNA levels may influence target gene expression and thus disease.

BACKGROUND

The study aimed to examine the association between genes encoding molecules in the ornithine decarboxylase (ODC)-polyamine pathway (ODC1, AMD1, NQO1, NOS2A, and OAZ2) and gastric cancer risk and whether the gene-phytoestrogen interaction modifies gastric cancer risk.

METHODS

Among 76 gastric cancer cases and their 1:4 matched controls within the Korean Multi-center Cancer Cohort, a total of 30 SNPs in five genes involved in the ODC pathway were primarily analyzed. The second-stage genotyping in 388 matched case-control sets was conducted to reevaluate the significant SNPs interacting with phytoestrogens during the primary analysis. The summary odds ratios (ORs) [95 % confidence intervals (CIs)] for gastric cancer were estimated. Interaction effects between the SNPs and plasma concentrations of phytoestrogens (genistein, daidzein, equol, and enterolactone) were evaluated.

RESULTS

In the pooled analysis, NQO1 rs1800566 showed significant genetic effects on gastric cancer without heterogeneity [OR 0.83 (95 % CI 0.70-0.995)] and a greater decreased risk at high genistein/daidzein levels [OR 0.36 (95 % CI 0.15-0.90) and OR 0.26 (95 % CI 0.10-0.64), respectively; p interaction < 0.05]. Risk alleles of AMD1 rs1279599, AMD1 rs7768897, and OAZ2 rs7403751 had a significant gene-phytoestrogen (genistein and daidzein) interaction effect to modify the development of gastric cancer. They had an increased gastric cancer risk at low isoflavone levels, but a decreased risk at high isoflavone levels (p interaction < 0.01).

CONCLUSIONS

Our findings suggest that common variants in the genes involved in the ODC pathway may contribute to the risk of gastric cancer possibly by modulating ODC polyamine biosynthesis or by interaction between isoflavones and NQO1, OAZ2, and AMD1.

Type 2 diabetes mellitus (T2DM) remains one of the major health problems in Europe. Retinopathy is one of the major causes of morbidity in T2DM, strongly influencing the evolution and prognosis of these patients. In the last 2 decades, several studies have been conducted to identify the possible genetic susceptibility factors involved in the pathogenesis of the disease. However, there is little data related to the involvement of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) gene polymorphisms in the T2DM Caucasian population. The objective of this study was to identify a possible connection between NOS2A -954G/C (rs2297518) and VEGF +936C/T (rs3025039) polymorphisms and the risk of developing T2DM and nonproliferative diabetic retinopathy in a Caucasian population group. We investigated 200 patients diagnosed with T2DM and 208 controls. Genotypes were determined by multiplex polymerase chain reaction-restriction fragment length polymorphism. Statistical and comparative analyses (Fisher's exact test) for dominant and recessive models of NOS2A -954G/C and VEGF +936C/T polymorphisms revealed an increased risk of T2DM (χ (2)=8.14, phi =0.141, P=0.004, odds ratio [OR] =2.795, 95% confidence interval [CI] =1.347-5.801; χ (2)=18.814, phi =0.215, P<0.001, OR =2.59, 95% CI =1.675-4.006, respectively). Also, comparative analysis for the recessive model (using Pearson's chi-square test [χ (2)] and the phi coefficient [phi]) reveals that the variant CC genotype of NOS2A gene is more frequently associated with T2DM without retinopathy (χ (2)=3.835, phi =-0.138, P=0.05, OR =0.447, 95% CI =0.197-1.015). In conclusion, the results of the study place VEGF +936C/T polymorphisms among the genetic risk factor for T2DM, whereas NOS2A -954G/C polymorphisms act like a protective individual factor for nonproliferative retinopathy.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Variation in the major histocompatibility complex on chromosome 6p21, specifically the HLA-DRB1*15 haplotype, is the strongest genetic factor for MS, yet it is estimated to account for only a portion of risk for the disease. Previous evidence has implicated the nitric oxide synthase gene (NOS2A) encoding inducible NOS on chromosome 17q11 as a potential MS susceptibility gene. To determine whether variation in the NOS2A gene contributes to MS risk, we investigated a total of 50 polymorphisms within or flanking the locus for evidence of association using a comprehensive analytical strategy. A total of 6265 members from 1858 well-characterized MS families were utilized. No evidence for overtransmission of any individual single-nucleotide polymorphism allele or haplotype to the MS-affected individuals was observed. Furthermore, different transmission rates were not observed in either DRB1*15-positive or DRB1*15-negative family subgroups, or when extreme clinical outcomes characterizing disease progression were examined. The very largest study of NOS2A variation in MS, to date, excludes even a modest role for this locus in susceptibility.

Nitric oxide (NO) is a nonspecific inflammatory mediator that has been involved in the pathogenesis of multiple sclerosis (MS). The influence of the promoter polymorphism of inducible NO synthase gene ( NOS2A) on susceptibility and outcome was studied in 140 MS Spanish patients and 147 healthy controls matched for sex, age, and ethnicity. No association was found between MS susceptibility, course or outcome of the disease, and NOS2A polymorphisms.

OBJECTIVE

Nasal polyposis (NP) is a multifactorial disease manifesting in chronic inflammation of upper respiratory tract of unknown etiology. We studied mRNA gene expression profiles in NP compared with normal mucosa as well as pointed at genes characteristic of different expression in examined tissues.

METHODS

Fifty-three patients with NP (36 eosinophilic and 17 neutrophilic NP) were included into the study. Transcriptional activity of genes was analyzed using oligonucleotide microarray in 17 NP and 8 cases of normal nasal mucosa. A study of mRNA expression of selected genes was performed using QRT-PCR.

RESULTS

We identified 556 genes, which were differentially expressed between the studied and the control group. Among them 217 showed significantly higher expression, whereas 339 lower expression in NP than in controls. The microarray and QRT-PCR results were compatible for 7 of 8 evaluated genes. In NP strongly significant higher transcriptional activity of MMP10, NOS2A, ALOX15 and IL-8 genes was observed. In the control group, significantly higher expression of DMBT1, ALOX12 and LTF genes was detected.

CONCLUSIONS

The analysis of gene expression in inflammatory changed nasal polyp tissues may become a supplementary method in diagnostics and treatment. Molecular alterations may indicate changes during the clinical course of the disease.