Association between -T786C NOS3 polymorphism and resistant hypertension: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>It is estimated that 5% of the hypertensive patients are resistant to conventional antihypertensive therapy. Polymorphisms in the endothelial nitric oxide synthase (NOS3) gene have been associated with high blood pressure levels, but not with resistant hypertension. The aim of the present study was to investigate if the -786T>C and G894T (Glu298Asp) polymorphisms of the NOS3 gene were associated with resistant hypertension.</p> <p>Methods</p> <p>A prospective case-control observational study was performed. From a series of 950 consecutive patients followed up during 42 months, 48 patients with resistant hypertension were detected. 232 patients with controlled high blood pressure were also included.</p> <p>Results</p> <p>No differences were observed in the distribution of G894T (Glu298Asp) NOS3 genotypes between the resistant hypertension group and the controlled hypertension patients. However, genotype -786CC was more frequent in the group of patients with resistant hypertension (33.3%) than in the group of patients with controlled high blood pressure (17.7%) (p 0.03). Furthermore carriers of allele T (-786TC and -786TT) were more frequent in patients with controlled hypertension (82.3%) than those with resistant hypertension (66.7%) (Multivariate analysis; RR 2.09; 95% CI 1.03–4.24; p 0.004).</p> <p>Conclusion</p> <p>Our results indicate that genotype -786CC of the NOS3 gene increase the susceptibility to suffer resistant hypertension, which suggest that resistance to conventional therapy could be determined at the endothelial level.</p

A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

VAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes. The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme

The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy

Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1-53.0)/(22.6-32.9), Portugal (39.0-74.4)/(21.4-38.9), Netherlands (40.6-66.3)/(25.3-38.8) and UK (37.5-62.4)/(23.3-34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2-12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8-19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR. Copyright

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism

Surgery of vagal paragangliomas: Six patients and review of literature

[Background and aims]: Vagal paragangliomas (VPs) represent a rare pathology in which surgery is usually recommended, but where experience is crucial to reduce the number of post-operative complications. In this study, we present our experience and a review of the literature. [Methods]: Between 1991 and 2006 we have treated 42 patients with 50 paragangliomas of the head and neck (26 carotid, 18 jugular/tympanic and 6 vagal). Examination of the literature (Medline and non-indexed Spanish source) from the last 30 years has revealed 23 series that each reported more than three cases; reaching a total of 332 VPs. [Results]: VPs are infrequent among paragangliomas of the head and neck (6/50) presenting clinical peculiarities such as multiple tumours, and malignant evolution. Within this current series, surgery was possible in all cases. Post-operative dysfunction in cranial nerves was frequent (the cranial X nerve was systematically sacrificed). There were no bronco-aspirations or mortalities. The literature review reveals similar results. [Conclusion]: To obtain the best results, it is important that the candidates for surgery be selected by experts within multidisciplinary groups. © 2008 Elsevier Ltd. All rights reserved.This work was supported by the Consejería de Sanidad de la Junta de Castilla y Leon (Grant: 166/A/07).Peer Reviewe

Novel mutation pA64D in the Serpina7 gene as a cause of partial thyroxine-binding globulin deficiency associated with increases affinity in transthyretin by a known p.A109T mutation in the TTR gene #

Partial thyroxine-binding globulin deficiency (TBG-PD) is an endocrine defect with a prevalence of 1:4 000 in newborns. Due to the presence of a single TBG gene on the X chromosome, most familial TBG defects follow an X-linked inheritance pattern. Abnormal T4 binding to T4-binding prealbumin (TTR) is a rare cause of euthyroid hyperthyroxinemia, which is transmitted by autosomal dominant inheritance. The purpose of the present study was to identify and characterize new mutations in the Serpina7 and TTR genes in a complete family with typical TBG-PD. All patients underwent clinical and biochemical evaluation. Sequencing of DNA, population screening by (SSCP) analysis, and bioinformatics studies were performed. Molecular studies revealed a novel p.A64D mutation in the exon 1 of Serpina7 gene associated with the previously reported p.A109T mutation in the exon 4 of TTR gene. To our knowledge, this is the first report of a patient with a TBG-PD by a mutation in Serpina7 that was coincident with a mutation in TTR gene that increased affinity of TTR for T4. This work contributes to elucidate the molecular basis of the defects of thyroid hormone transport in serum and the improvement of the diagnosis avoiding unnecessary therapy.This study was supported by Grants from the Universidad de Buenos Aires (20020100100594/2011 to CMR), CONICET (PIP2012/112-201101-00091 to HMT), FONCyT-ANPCyt-MINCyT (PICT 2010/05-1130 to CMR, PICT 2012/05-1090 to HMT), and by FIS (PI10/00219 to RG-S).Peer Reviewe

Bases genéticas del dolor

Perception of pain is a complex process which implies multiple biochemical pathways together with unknown processes of cortical integration. The existence of individual differences in the response to painful stimuli suggests that genetic factors can be involved in its modulation. Two different experimental approaches have been developed to study the implication of genotype in the response to pain: linkage studies and the association studies. Up to now linkage studies have allowed the association of TRKA gene mutations with the syndrome of congenital insensitivity to pain with anhidrosis (CIPA) and CACNL1A4 gene mutations with the familial hemiplegic migraine (FHM). Few association studies have been performed until now, and have been focused on the study of patients with migraine. Here we review the studies carried out up to now in different laboratories and suggest new perspectives for the future.La percepción de la sensación dolorosa es un proceso complejo en el que intervienen mútiples procesos bioquímicos bien conocidos junto con otros de integración cortical desconocidos hasta el momento. La existencia de diferencias individuales en la respuesta al estímulo doloroso es una observación bien conocida que sugiere qué factores genéticos pueden estar implicados en la modulación de la respuesta a estímulos dolorosos. Existen dos aproximaciones experimentales para estudiar la implicación del genotipo en la respuesta al estímulo doloroso, los estudios de ligamiento y los estudios de asociación. Hasta el momento los estudios de ligamiento han permitido asociar mutaciones en el gen TRKA con el síndrome de insensibilidad congénita al dolor con anhidrosis (CIPA) y el gen CACNL1A4 y la migraña hemipléjica familiar (FHM). Los estudios de asociación son escasos y se han centrado principalmente en el estudio de pacientes con migraña. En este trabajo revisamos los estudios llevados a cabo hasta el momento en diferentes laboratorios y planteamos nuevas perspectivas de futuro

Prognostic value of telomere length in acute coronary syndrome

Telomere and telomerase are involved in cellular and organismal ageing and have been related to human diseases. Coronary artery disease is one of the most common age-related health problems in developed countries. Nevertheless, the specific role of cellular ageing in this process is still unclear. In this study, we analyze the possible prognostic value of telomere length and telomerase polymorphisms in a population of 150 middle aged males (mean age 62 ± 7) admitted for acute coronary syndrome who were followed up for more than 600 days. Peripheral blood samples were obtained and relative and comparative qPCR was used to measure telomere length and real time PCR to study the polymorphisms. Two prognostic combined events were defined. Long telomere length was revealed as an independent predictor (protector) of combined event presentation during long term follow up in our patients.Peer Reviewe

Effect of telomere length on prognosis in men with acute coronary syndrome

Telomere length is related to cellular aging and cardiovascular disease. Nevertheless, the specific role of cellular aging in this process is still unclear. The aim of this report was to analyze the prognostic value of telomere length in men admitted for acute coronary syndrome. Telomere length was measured by quantitative polymerase chain reaction in peripheral blood leukocytes of 203 men classified into 2 groups: those aged 50 to 75 years and those >75 years. Clinical follow-up had been done for >600 days, and a prognostic combined event was defined. In men aged 50 to 75 years, we found a statistically significant worse prognosis in patients with short telomeres (log-rank: 5.22, p 75 years (log-rank: 0.01, p = 0.91). Cox analysis confirmed short telomeres in men aged 50 to 75 years as an independent prognostic risk factor. In conclusion, telomere length is a good predictor of cardiovascular prognosis in men admitted for acute coronary syndrome, but this relation depends on the chronological age of the population studied.This work was supported by the FIS Grant PI 100219 to Dr. Gonzalez-Sarmiento.Peer Reviewe