Tandem Repeats In Intron Research Articles

Polymorphism in the Interleukin-1 Receptor Antagonist Gene Is Associated with Serum Interleukin-1 Receptor Antagonist Concentrations and Postoperative Opioid Consumption

The interleukin-1 receptor antagonist (IL-1Ra) is the principal determinant of IL-1β bioactivity within the IL-1 gene cluster, regulating IL-1α and IL-1β release. This study was designed to determine whether polymorphisms of the IL-1Ra gene (IL1RN) produce clinically measurable differences in serum IL-1Ra concentrations and opioid consumption in the postoperative period. Opioid consumption and pain scores were evaluated in 96 patients undergoing a nephrectomy. DNA was extracted from all patients, and the genotypes of IL1RN were determined by polymerase chain reaction amplification of the variable number of tandem repeats of 86 base pairs in intron 2 of IL1RN. The concentrations of serum IL-1Ra concentrations at baseline and at 24 h postoperatively in 58 subjects were measured. Differences in opioid consumption among the three genotype groups (IL1RN*1 homozygotes and *2 and *3 carriers) were statistically significant in the first and second 12-h postoperative periods (P = 0.010). The IL1RN*2 carrier group consumed 43% (95% CI, 38-48%) less opioids in the first 24 h after surgery than the IL1RN*1 homozygote group (P = 0.003). Differences in the serum IL-1Ra concentration among the three genotype groups were statistically significant at 24 h postoperatively (P = 0.003), with IL1RN*2 carriers having the highest serum IL-1Ra concentrations. The variable number of tandem repeats in intron 2 of IL1RN may contribute to interindividual variations in opioid consumption in the first 24 h after surgery. Patients homozygous for the IL1RN*1 allele have lower concentrations of IL-1Ra and require higher doses of opioids postoperatively than patients carrying at least one IL1RN*2 allele.

Endothelial Nitric Oxide Synthase Haplotypes Associated with Aura in Patients with Migraine

There is strong evidence implicating nitric oxide (NO) in the pathophysiology of migraine and aura. Therefore, genetic polymorphisms in the endothelial NO synthase (eNOS) gene have been studied as candidate markers for migraine susceptibility. We compared for the first time the distribution of eNOS haplotypes including the three clinically relevant eNOS polymorphisms (T(-786)C in the promoter, rs2070744; Glu298Asp in exon 7, rs1799983; and a 27 bp variable number of tandem repeats in intron 4) and two additional tagging single-nucleotide polymorphisms (rs3918226 and rs743506) in 178 women with migraine (134 without aura and 44 with aura) and 117 healthy controls (control group). Genotypes were determined by TaqMan allele discrimination assay, real-time polymerase chain reaction, and polymerase chain reaction followed by fragment separation by electrophoresis. The GA (rs743506) genotype was more common in the control group than in women with migraine (odds ratio = 0.47, 95% confidence interval [CI] = 0.29-0.78, p < 0.01). No significant differences were found in allele distributions for the five eNOS polymorphisms. However, the haplotypes including the variants "C C a Glu G" and the variants "C C b Glu G" were more common in women with migraine with aura than in women with migraine without aura (odds ratio = 30.71, 95% CI = 1.61-586.4 and odds ratio = 17.26, 95% CI = 1.94-153.4, respectively; both p < 0.0015625). These findings suggest that these two eNOS haplotypes affect the susceptibility to the presence of aura in patients with migraine.

Role of Functional Polymorphisms of P53 and P73 Genes with the Risk of Prostate Cancer in a Case-Control Study from Northern India

P53 gene variants BstUI RFLP at codon 72 in exon 4, 16-bp tandem repeat in intron 3 and Msp I RFLP in intron 6 and P73 gene variants of G4C14-to-A4T14 (GC/AT), exon 2 polymorphism, which respectively codes for four functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms. We undertook this study to evaluate the role of P53 and P73 SNPs in prostate cancer in a Northern Indian population. P53 and P73 genotypes were assessed in a hospital-based case-control study comprised of 177 prostate cancer cases and 265 healthy controls. After the extraction of genomic DNA from blood, genotyping was done using PCR-RFLP and PCR-CTPP methods, respectively. A significant association was found in P53 intron 6 G>A and P53 R72P G>C polymorphism with PCa risk. In P53 intron 6 G>A polymorphism the heterozygous genotype (GA) showed marginal risk with the disease (OR = 1.48, 95% CI = 0.999-2.220). Individuals with heterozygous genotype only (GC) of P53 R72P G>C polymorphism demonstrated PCa risk (OR = 1.5, 95% CI = 1-2.199). Haplotypes G-C-D and A-G-D (OR = 1.58, 95% CI = 1.125-2.241 and OR = 2.70, 95% CI = 1.767-4.143, respectively) were also found to be associated with an increased risk of PCa. Our study provided evidence that the P53 intron 6 G>A and R72P G>C polymorphisms were associated with a higher risk of prostate cancer in a Northern Indian population.

Endothelial nitric oxide synthase gene polymorphism in gastric cancer

Nitric oxide, a labile compound synthesized by nitric oxide synthase, is a major regulator not only of physiological vascular tonus but also of the abnormal vascularity associated with tumors. Endothelial production of nitric oxide regulates blood flow and angiogenesis and reduces tumor cell adhesion to the endothelium. A high concentration of nitric oxide and its metabolites causes DNA damage during nitration, nitrosation and deamination. Both positive and negative effects on carcinogenesis and tumor growth, apoptosis, and cytotoxic mechanisms may be explained by differential susceptibility of tumor cells to nitric oxide-mediated reactions. In this study, three major polymorphisms (786T>C, the 27 base pair variable number of tandem repeats in intron 4, and 894G>T) of the endothelial nitric oxide synthase gene were investigated in gastric cancer and normal tissues of 50 patients with gastric cancer and in the peripheral blood of 98 healthy subjects. We found no significant differences in intron 4a/b and 894G>T (Glu298Asp) allele and genotype frequencies between control and patient specimens. Nevertheless, the genotype and allele frequencies of 786T>C polymorphism were found to be significantly different between the healthy controls and tumor tissues. The results suggest that endothelial nitric oxide synthase 786T>C polymorphism may play a role in the development of gastric cancer.

Endothelial Nitric Oxide Synthase Polymorphisms and Erectile Dysfunction: A Meta-Analysis

Erectile dysfunction (ED) is a common disorder noted for affecting quality of life. Several studies have reported the influence of endothelial nitric oxide synthase (eNOS) polymorphisms on ED susceptibility. However, results of association studies with individually low statistical power are conflicting. Our study aimed to carry out a meta-analysis estimating the association between eNOS variants and the risk of ED. Studies regarding the association between eNOS polymorphisms and ED were searched in Medline and Embase databases. The relevant studies that met the inclusion criteria were eligible for the analysis. Five genetic models and a generalized odds ratio (OR(G) ) were used to estimate the association between eNOS G894T and variable number of 27-bp tandem repeats in intron 4 (4 VNTR) and the risk of ED. Nine articles were included in our meta-analysis. Overall, significant association between the 894T variant and an increased risk of ED was derived for all genetic contrasts except for the recessive model (allele contrast: OR = 1.64, 95% confidence interval [CI]: 1.03-2.60). The meta-analysis based on the OR(G) also produced significant results: OR(G) = 1.64, 95% CI: 1.03-2.61. Significant heterogeneity and publication bias were detected. The cumulative meta-analysis showed the OR increased from 2003 to 2009 and then declined in 2010. Instability in the relative change of OR was observed. Regarding 4 VNTR and its association with ED, the overall analysis showed a lack of significant association (OR = 0.96, 95% CI: 0.72-1.28). No evidence for heterogeneity among studies was observed. Subgroup analysis by ethnicity and recruitment strategy also yielded nonsignificant results. The result supports that G894T variant is associated with an increase in the risk of ED. No evidence for a significant association between 4VNTR and ED is observed. The results of the present meta-analysis should be interpreted with caution. Further confirmation in large and well-designed studies is needed.

The interleukin‐1 cluster gene region is associated with multiple sclerosis in an Italian Caucasian population

Polymorphisms of the interleukin-1 (IL-1) gene family have been proposed as potential variants for different diseases including multiple sclerosis (MS). With respect to MS, IL-1 beta (-511 C/T; rs16944), IL-1 beta (+3954 C/T; rs1143634), IL-1 alpha (-889 C/T; rs1800587), IL-1 alpha (+4845 G/T; rs17561), and the variable number of tandem repeats in intron 2 of the IL-1 receptor antagonist (IL-1RN) gene polymorphisms have been studied in different ethnic groups, leading to conflicting results. This study investigates the association between IL-1 genes and MS by means of 70 markers spanning the 1.1 Mb region where the IL-1 genes map and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case-control design including 410 subjects (160 patients and 250 controls). From allelic/genotypic tests, significant association was found for several polymorphisms including the IL-1 beta (-511 C/T) variant (P-adjusted = 4.5 x 10(-4)) and some polymorphisms around the IL-1RN gene. The 'block-step' pattern obtained from both the LD map and pairwise analysis identifies four LD regions. Region 1 showed a significant association with MS for the global test (P < 0.0001) and haplotypes containing the IL-1 beta (-511 C/T) variant still demonstrate highly significant association with disease (P-value range: 9.9 x 10(-5) to 0.02). Our findings support the existence of a causative variant for MS within this candidate region in a representative Italian Caucasian population and, in particular, the role of the IL-1 beta (-511 C/T) variant warrants further investigation.

Endothelial Nitric Oxide Synthase Haplotypes Associated with Hypertension Do Not Predispose to Cardiac Hypertrophy

Left ventricular hypertrophy (LVH) is a complication that may result from chronic hypertension. While nitric oxide (NO) deficiency has been associated with LVH, inconsistent results have been reported with regards to the association of endothelial NO synthase (eNOS) polymorphisms and LVH in hypertensive patients. This study aims to assess whether eNOS haplotypes are associated with LVH in hypertensive patients. This study included 101 healthy controls and 173 hypertensive patients submitted to echocardiography examination. Genotypes for three eNOS polymorphisms were determined: a single-nucleotide polymorphism in the promoter region (T-786C) and in exon 7 (Glu298Asp), and variable number of tandem repeats in intron 4. We found no significant association between eNOS genotypes and hypertension or with LVH (all p > 0.05). However, while we found two eNOS haplotypes associated with variable risk of hypertension (all p < 0.05), we found no significant associations between eNOS haplotypes and LVH (all p > 0.05), even after adjustment in multiple linear regression analysis. These findings suggest that eNOS haplotypes that have been associated with variable susceptibility to hypertension were not associated with LVH in hypertensive patients. Further studies are necessary to examine whether other genes downstream may interact with eNOS polymorphisms and predispose to LVH in hypertensive patients.

Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study

To assess whether genetic variation in the interleukin-1 (IL-1) gene cluster contributes to familial osteoarthritis (OA) by influencing innate ex vivo production of IL-1beta or IL-1 receptor antagonist (IL-1Ra). Innate ex vivo IL-1beta and IL-1Ra production upon lipopolysaccharide (LPS) stimulation of whole blood cells was measured in subjects from the Genetics, Osteoarthritis and Progression (GARP) Study, which includes sibling pairs in which at least one sibling has symptomatic OA at multiple sites. Radiographic OA (ROA) was assessed by Kellgren/Lawrence score. Subjects from the GARP Study and controls from the Rotterdam Study were genotyped for 7 single-nucleotide polymorphisms (SNPs) encompassing the IL-1 gene cluster on chromosome 2q13. Linkage disequilibrium analysis and genotype and haplotype association analysis were performed to assess the relationship between the IL-1 gene cluster SNPs, innate ex vivo cytokine production, and OA. Among subjects in the GARP Study, the haplotype variable-number tandem repeat in intron 2/T+8006C/T+11100C 2/2/1 of the IL1RN gene was significantly associated with reduced innate ex vivo bioavailability of IL-1beta upon LPS stimulation (P = 0.026) and with ROA at the highest number of joint locations. These results show that genetic variation at the IL-1 gene cluster is associated with lower IL-1beta bioavailability and with OA at a large number of joint locations. The data further indicate that, among subjects with OA affecting the highest number of joints, the innate immune system may be activated, thereby obscuring possible underlying mechanisms.

T-786C Polymorphism in Promoter of eNOS Gene as Genetic Risk Factor in Patients With Erectile Dysfunction in Turkish Population

To investigate the effect of 2 endothelial nitric oxide synthase gene polymorphisms, namely, variable number of 27-bp tandem repeats in intron 4 and T-786C in the promoter region, on the susceptibility to erectile dysfunction (ED) in Turkish population. A total of 72 patients with ED (mean age 54.3 +/- 9.2 years) diagnosed by Doppler ultrasonography and 71 healthy controls (mean age 55.4 +/- 8.2 years) were analyzed. Genotypes were determined through polymerase chain reaction with or without restriction endonuclease digestions. Genotype distribution for CC genotype of T-786C polymorphism in promoter was significantly different between patients with ED and controls, the genotype frequency being 31.9% and 12.7%, respectively (P = .019). The univariate odds ratio (OR) associated with CC alleles revealed 3 times increased risk for ED (OR = 3.2; 95% confidence interval [CI], 1.4-7.6; P = .006). The risk also holds when excluding patients with hypertension and diabetes mellitus (P = .012, OR = 3.1; 95% CI, 1.2-7.7) as well as obesity (P = .05, OR = 4; 95% CI, 1.05-15.3). Patients with CC genotype of promoter present earlier symptoms of ED (51.7%) compared with controls (10.7%) (P <.001). No significant correlation was observed with variable number of tandem repeats in intron 4 and with the type of vascular insufficiency. The CC genotype of T-786C polymorphism in the promoter of eNOS gene is associated with increased risk of ED in Turkish population. Earlier onset of ED with CC genotype suggests that CC allele is an independent risk factor for endothelial dysfunction in the absence of other risk factors (hypertension, diabetes mellitus, obesity). An impaired NO production because of CC alleles may account for pathophysiology of ED.

Endothelial Nitric Oxide Synthase Polymorphisms and Haplotypes in Amerindians

Interethnic disparities in the distribution of endothelial nitric oxide synthase (eNOS) polymorphisms may affect nitric oxide (NO)-mediated effects of and responses to drugs. While there are differences between black and white subjects there is no information regarding the distribution of eNOS gene alleles and haplotypes in Amerindians. We studied three clinically relevant eNOS polymorphisms (T(-786)C in the promoter, a variable number of tandem repeats in intron 4, and the Glu298Asp in exon 7) and eNOS haplotypes in 170 Amerindians from three tribes of the Brazilian Amazon. The results were compared with previous findings for black and white Brazilians. The Asp298, C(-786), and 4a alleles were much less common in Amerindians (5.0%, 3.2%, and 4.1%, respectively) than in blacks (15.1%, 19.5%, and 32.0%, respectively) or whites (32.8%, 41.9%, and 17.9%, respectively) (p < 0.001). The haplotype including the most common alleles for each polymorphism was much more common in Amerindians (89%) than in blacks (45%) or whites (41%). Our findings are consistent with a lower genetic diversity in Amerindians compared with blacks and whites. These striking differences may be of major relevance for case-control association studies focusing on eNOS gene polymorphisms and may explain, at least in part, differences in the responses to cardiovascular drugs.

ASSOCIATION STUDY OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (NOS3) GENE POLYMORPHISMS AND SCHIZOPHRENIA

To investigate the effect of 2 endothelial nitric oxide synthase gene polymorphisms, namely, variable number of 27-bp tandem repeats in intron 4 and T-786C in the promoter region, on the susceptibility to erectile dysfunction (ED) in Turkish population.A total of 72 patients with ED (mean age 54.3 ± 9.2 years) diagnosed by Doppler ultrasonography and 71 healthy controls (mean age 55.4 ± 8.2 years) were analyzed. Genotypes were determined through polymerase chain reaction with or without restriction endonuclease digestions.Genotype distribution for CC genotype of T-786C polymorphism in promoter was significantly different between patients with ED and controls, the genotype frequency being 31.9% and 12.7%, respectively (P = .019). The univariate odds ratio (OR) associated with CC alleles revealed 3 times increased risk for ED (OR = 3.2; 95% confidence interval [CI], 1.4-7.6; P = .006). The risk also holds when excluding patients with hypertension and diabetes mellitus (P = .012, OR = 3.1; 95% CI, 1.2-7.7) as well as obesity (P = .05, OR = 4; 95% CI, 1.05-15.3). Patients with CC genotype of promoter present earlier symptoms of ED (51.7%) compared with controls (10.7%) (P <.001). No significant correlation was observed with variable number of tandem repeats in intron 4 and with the type of vascular insufficiency.The CC genotype of T-786C polymorphism in the promoter of eNOS gene is associated with increased risk of ED in Turkish population. Earlier onset of ED with CC genotype suggests that CC allele is an independent risk factor for endothelial dysfunction in the absence of other risk factors (hypertension, diabetes mellitus, obesity). An impaired NO production because of CC alleles may account for pathophysiology of ED.

Association of p53 polymorphisms and colorectal cancer: Modulation of risk and progression

Objectives p53 Gene variants BstUI RFLP at codon 72 in exon 4, 16 bp tandem repeat in intron 3 and MspI RFLP in intron 6, which code for two functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms. Methods p53 genotype was assessed in 90 CRC patients, 321 age-matched controls and 322 centenarians. Results The p53 codon 72 arginine, the p53 16 bp deletion, and the MspI RFLP were significantly more frequent in CRC patients in comparison to the controls and to the centenarians (odd ratio 1.44 and 1.93). In the CRC group, the BstUI RFLP polymorphism was the more frequent combination (62.2%), and it was significantly associated with highly infiltrating ( p < 0.01), poorly differentiated ( p < 0.01), and metastatic ( p < 0.05) tumours. Our findings indicate that the p53 codon 72 polymorphisms are associated with a higher risk of CRC and are associated with more advanced and undifferentiated tumours.

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

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

Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy

Most hypertensive patients require two or more drugs to control arterial blood pressure effectively. Although endothelial nitric oxide synthase (eNOS) haplotypes have been associated with hypertension, it is unknown whether eNOS genotypes/haplotypes are associated with resistance to antihypertensive therapy. We studied the distribution of three eNOS genetic polymorphisms: single nucleotide polymorphisms in the promoter region (T(-786)C), and in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a). Genotypes were determined for 111 normotensive controls (NT), 116 hypertensive individuals who were well controlled (HT), and 100 hypertensive individuals who were resistant to conventional antihypertensive therapy (RHT). We also compared the distribution of eNOS haplotypes in the three groups of subjects. No differences were found in genotype or allele distribution among the three groups (all P > 0.05). Conversely, the 'C Glu b' haplotype was more commonly found in the NT than in the HT or RHT groups (21 versus 8 and 7%, respectively; both P < 0.00625). In addition, the 'C Asp b' haplotype was more commonly found in the HT or RHT groups than in the NT group (22 and 20%, respectively, versus 8%; both P < 0.00625). The distribution of eNOS haplotypes was not significantly different in the HT and RHT groups (P > 0.05). Whereas our findings suggest a protective effect for the 'C Glu b' haplotype against hypertension and that the 'C Asp b' haplotype increases the susceptibility to hypertension, our results suggest that eNOS haplotypes are not associated with resistance to antihypertensive therapy.

Negative association of endothelial nitric oxide gene polymorphism with hypertension in Turkish patients: effect of ecNOS polymorphism on left ventricular hypertrophy

BackgroundEndothelial nitric oxide synthase produces nitric oxide which is involved in many physiologic regulatory functions. Variable number of tandem repeats in intron 4 of endothelial nitric oxide synthase gene are reported to be associated with blood pressure regulation. Nitric oxide is involved in regulation of cardiomyocyte genes but it is not known If endothelial nitric oxide synthase 4 gene polymorphisms are related with left ventricular hypertrophy. We studied endothelial nitric oxide synthase 4a/b allele status in hypertensive and normotensive patients and echocardiographic parameters in a subgroup of hypertensive group.MethodsWe performed a case-control study involving 110 Turkish hypertensive patients and 87 controls. All subjects were genotyped for endothelial nitric oxide synthase 4a/b polymorphism. Echocardiographic measurements were obtained in 94 of the hypertensive patients.ResultsEndothelial nitric oxide synthase 4a/b genotype frequencies were 6.4%, 23.6%, 70% in hypertensives and 1.1%, 18.4%, 80.5% in controls for a/a, a/b, b/b, respectively. Left ventricular dimensions, mass and diastolic indices were not different across endothelial nitric oxide synthase 4 genotypes. Patients with 4a/a genotype had higher interventricular septal thickness than the other group; 14.83(1.6), 11.91(1.51), 12.21(1.56) for a/a, a/b, b/b, respectively and p = 0.0001.ConclusionEndothelial nitric oxide synthase 4a/b gene polymorphism is not associated with hypertension in Turkish patients. 4a/a genotype was associated with higher interventricular septal thickness in hypertensive patients.

Relation between cytokine promoter gene polymorphism and toxicity of 5-fluorouracil plus cisplatin chemotherapy

Variability in the efficacies and toxicities of anticancer agents is a major problem. We hypothesized that polymorphisms in cytokine gene promoters may underlie genetic susceptibility to chemotherapy-induced toxicities in the Japanese. DNA was extracted from 100 patients undergoing 5-fluorouracil plus cisplatin chemotherapy. We used a case-only design to evaluate the relation between toxicities and cytokine promoter gene polymorphisms. The following polymorphisms were genotyped: tumor necrosis factor (TNF)-alpha-1031T/C, interleukin (IL)-1beta-511C/T, IL-6-634C/G, IL-10-819T/C, IL-18-137G/C, macrophage migration inhibitory factor -173G/C, and 86-basepair variable numbers of tandem repeat in intron 2 of the IL-1 receptor antagonist. The frequency of the IL-6-634 GC and GG genotypes was significantly higher in patients with grades 1-4 leukopenia (P=0.003; Crude-odds ratios (Cr-OR) =4.0), neutropenia (P=0.0051; Cr-OR=3.6), or thrombocytopenia (P<0.0001; Cr-OR=6.1) than in patients without these toxicities. Similarly, the frequency of the IL-1beta-511 TC and TT genotypes and the frequency of the TNF-alpha-1031 TT genotype were significantly higher in patients with grades 1-4 thrombocytopenia (P=0.015; Cr-OR=2.9) and stomatitis (P=0.02; Cr-OR=3.1), respectively. Multivariate analysis of factors such as age, sex, disease type, purpose of the chemotherapy, use of radiotherapy, and cytokine promoter gene polymorphisms showed polymorphisms to be significant predictors of toxicity. Our results suggest that polymorphisms in cytokine gene promoters may be associated with susceptibilities to leukopenia, neutropenia, thrombocytopenia and stomatitis in patients treated with 5-fluorouracil plus cisplatin.

Relationship of ENOS and RAS Gene Polymorphisms to Initial Peritoneal Transport Status in Peritoneal Dialysis Patients

Background: Peritoneal membrane permeability is of major importance for adequate dialysis and fluid balance in peritoneal dialysis (PD) therapy. The peritoneal capillary endothelium plays a key role in peritoneal transport. Nitric oxide derived from endothelial cells is related to the maintenance of vascular permeability. We investigated the relationship between the endothelial nitric oxide synthase (ENOS) gene polymorphism, the renin-angiotensin system (RAS) gene polymorphisms, and initial peritoneal transport type in PD patients. Methods: This study included 74 incident continuous ambulatory PD patients. The ENOS gene polymorphism was identified at the 4a/b variable number of tandem repeats in intron 4. Genetic polymorphisms of the renin-angiotensin system were performed for the angiotensin-converting enzyme I/D, angiotensinogen M235T, and angiotensin II type 1 receptor A1166C and type 2 receptor C3123A by polymerase chain reaction. Patients were divided into two groups according to the initial peritoneal equilibration test results performed within 3 months of PD therapy: group 1 consisted of high/high average transporters (n = 41), and group 2 consisted of low/low average transporters (n = 33). Results: Demographic, clinical, and laboratory data were similar between the two groups (p > 0.05). Group 1 had a significantly higher prevalence of the ENOS b/b genotype than group 2 (78% vs. 48.5%, p < 0.008). In contrast, group 2 had a significantly greater prevalence of the ENOS a/a+a/b genotype than group 1 (51.5% vs. 22%, p < 0.008). Genetic polymorphisms of the renin-angiotensin system were not associated with initial peritoneal transport type (p > 0.05). Conclusions: Modulation of the nitric oxide activity via the ENOS a/b polymorphism may have a considerable effect on the basal peritoneal permeability.

Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene have been associated with the development of diabetic retinopathy (DR) in patients with type 1 diabetes mellitus (T1DM), but not with T2DM. However, no previous study has analyzed combinations of genetic markers (haplotypes), which can be more informative. We studied three eNOS genetic polymorphisms: a single nucleotide polymorphism in the promoter region (T −786C), in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a) in 103 healthy controls, and in 170 patients with T2DM (without DR, N = 114; with DR, N = 56). We also examined the association of eNOS gene haplotypes with T2DM and with DR. No differences were found in the frequencies of genotypes and alleles of the three polymorphisms among the three groups of subjects. However, the “C-Glu-b” haplotype was more common in healthy controls (24%) than in T2DM patients (7%) ( P = 0.0001). Finally, no significant difference in the distribution of eNOS haplotypes frequencies was found when T2DM patients with or without DR were compared ( P = 0.7372). These findings suggest no association between DR and individual eNOS haplotypes in T2DM patients. The “C-Glu-b” haplotype, however, may have a protective effect against T2DM. Further studies should be conducted to address the molecular basis for such an effect.

Influence of fibrillin-1 genotype on aortic stiffness in men: a note of caution

Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28–81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 G\?\T polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype ( P = 0.005). Pulse pressure also was increased in the 2-3 genotype ( P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease.

The Association Between the Interleukin-1 Polymorphisms and Gastric Cancer Risk Depends on the Family History of Gastric Carcinoma in the Study Population

The association between interleukin-1 polymorphisms, H. pylori and increased gastric cancer risk remains controversial. To compare the prevalence of these polymorphisms in individuals with two mutually exclusive diseases connected with infection, gastric cancer, and duodenal ulcer. 121 gastric cancer and 119 duodenal ulcer patients. Genomic DNA was typed for polymorphisms at position -511, -31 in the interleukin-1beta gene (IL-1 beta) using primer extension and mass-spectrometry. Analysis of the variable number of tandem repeats in intron 2, in its receptor antagonist gene (IL-1RN) was performed by PCR and agarose gel electrophoresis. All subjects were successfully genotyped for the three gene loci. IL-1 beta-511 was found to be in reverse linkage disequilibrium with IL-1 beta-31. The differences between gastric cancer and duodenal ulcer patients concerned only heterozygous variant of IL-1beta and were related to family history of gastric cancer, tumor stage, histology, site. Thus, CT carriers were found to have a higher risk of sporadic [OR 2.21 (95% CI, 1.22-3.99)], early [OR 2.81 (95% CI, 1.14-6.93)], diffuse [OR 2.48, (95% CI 1.21-5.09)] or non-cardia gastric cancer [OR 1.88 (95% CI 1.06-3.33)]. Furthermore, CT genotype was significantly more prevalent in gastric cancer patients with negative than in those with a positive family history (p = 0.039). The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population. This phenomenon may be in part responsible for differences in results of interleukin-1 studies performed on populations with low and high gastric cancer prevalence.