Javier Oliver

A functional polymorphism of the NFKB1 promoter is not associated with ulcerative colitis in a Spanish population

Background: This study investigated the influence of the NFKB1−94ins/delATTG in the susceptibility/phenotype to ulcerative colitis. Methods: We analyzed the distribution of −94ins/delATTG NFKB1 in 258 patients and 264 healthy controls from southern Spain by a polymerase chain reaction‐fluorescent method. Results: The genotype and allele frequencies of −94ins/delATTG did not significantly differ between patients and controls. In fact, the frequency of the −94delATTG allele was almost identical in both groups (34.8% and 35.4%, respectively), and the del/del genotype was underrepresented in UC patients (11.2% versus 14%). In addition, no association of this polymorphism was found with any of the clinical parameters analyzed. Conclusion: These results suggest that the NFKB1 −94ins/delATTG gene variation, previously associated with UC susceptibility in North Americans, does not influence either susceptibility or phenotype of UC in the Spanish population.

Association of the macrophage migration inhibitory factor gene polymorphisms with inflammatory bowel disease

Macrophage migration inhibitory factor (MIF), an immunoregulatory cytokine that has pro-inflammatory, hormonal and enzymatic activities, has been found to be markedly increased in the serum of patients with inflammatory bowel disease (IBD).1,2 MIF-deficient mice failed to develop disease1 and blockage with anti-MIF antibody reduced disease activity.1,2 Finally, functional polymorphisms of the human MIF gene have been associated with increased susceptibility to inflammatory and autoimmune diseases.3 These findings prompted us to investigate the potential association of the functional MIF −173G/C and −794 (CATT)n gene variants with the susceptibility and clinical expression of IBD. We studied a case–control cohort (cohort 1) comprising 336 patients with Crohn’s disease and 287 patients with ulcerative colitis from south Spain and 361 controls from the same area. An additional cohort (cohort 2) was analysed, comprising 325 patients with Crohn’s disease, 347 patients with ulcerative colitis and 526 controls from Madrid. Table 1 shows the clinical characteristics …

MYO9B polymorphisms in patients with inflammatory bowel disease

An abnormal function of the intestinal barrier has been found not only in patients with inflammatory bowel disease (IBD) but even in their healthy relatives, suggesting that this condition may precede disease onset by years.1 A genetic alteration in the intestinal permeability has also been proposed to exist in patients with coeliac disease. In support of this proposal, polymorphisms in the MYO9B gene (the gene for myosin IXb involved in cytoskeleton remodelling) were found to be associated with increased susceptibility to coeliac disease.2 The MYO9B gene has recently been investigated in relation to IBD and produced discordant results. No association was observed in a Norwegian population,3 but shortly afterwards an international collaboration group performed a statistically powerful study on samples collected from the UK, Netherlands, Canada and Italy in which MYO9B was found to be associated with IBD, and with ulcerative colitis and Crohn’s disease considered separately in some populations.4 In that study, a stronger effect was seen …

Polymorphisms in the transforming growth factor‐β1 gene (TGF‐β1) and the risk of advanced alcoholic liver disease

Abstract: Background/aims: There are wide interindividual differences in the risk of developing alcoholic cirrhosis. Transforming growth factor β1 (TGF‐β1) is the main cytokine involved in liver fibrogenesis. The TGF‐β1 gene is polymorphic at several sites and these polymorphisms are probably related to differences in the rate of TGF‐β1 synthesis. Our aim has been to analyse the influence of the TGF‐β1 gene polymorphisms in the predisposition to advanced alcoholic liver disease (ALD) in ethanol abusers.

CD209 in inflammatory bowel disease: a case-control study in the Spanish population

BackgroundThe etiology of Ulcerative Colitis (UC) and Crohns Disease (CD), considered together as Inflammatory Bowel Diseases (IBD), involves environmental and genetic factors. Although some genes are already known, the genetics underlying these diseases is complex and new candidates are continuously emerging. The CD209 gene is located in a region linked previously to IBD and a CD209 functional polymorphism (rs4804803) has been associated to other inflammatory conditions. Our aim was to study the potential involvement of this CD209 variant in IBD susceptibility.MethodsWe performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the CD209 single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using χ2 tests.ResultsNo association between CD209 and UC or CD was observed initially. However, stratification of UC patients by HLA-DR3 status, a strong protective allele, showed that carriage of the CD209_G allele could increase susceptibility in the subgroup of HLA-DR3-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04–3.02, vs. controls).ConclusionA functional variant in the CD209 gene, rs4804803, does not seem to be influencing Crohns disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in HLA-DR3-positive individuals but further studies are necessary.

Anakinra in mutation-negative CINCA syndrome.

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare congenital inflammatory disorder with variable clinical manifestations but devastating in a great majority of the cases. The syndrome is characterized by a generalized, wandering palpable rash eruption of neonatal onset, chronic arthropathy characterized by abnormal proliferation of cartilage and an abnormal ossification, and a progressive neurological impairment as the result of a chronic meningitis caused by polymorphonuclear cell infiltration [1, 2]. Nevertheless, many other manifestations are described, including fever, generalized lymphadenopathy, hepatosplenomegaly, developmental retardation, hydrocephalus, cerebral atrophy, ocular involvement in the form of uveitis and papilitis, and perceptive deafness. Recently, the syndrome has been associated with mutations in the CIAS1 gene [3]. These mutations will imply a higher level of interleukin-1 (IL-1) and a good response with the recombinant human IL-1 receptor antagonist anakinra [4, 5]. Nevertheless, CINCA syndrome has not always been associated with CIAS1 mutations, but in these cases, patients can also respond well to the treatment with anakinra [6], as in the case of the patient we present. Case report

Strong Protective Effect of DR3 Against Ulcerative Colitis in the Spanish Population

OBJECTIVES:Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon. Major histocompatibility complex (MHC) on the short arm of human chromosome 6 has been thoroughly studied as a susceptibility locus. However, one of the strongest MHC associations found, that of HLA-DR3 with UC protection, has not been observed in all populations. Our aim in the present study was to evaluate this negative association in a large cohort of Spanish UC patients and controls, and to try to elucidate which, if any, of the diverse DR3 haplotypes (identified by TNFa and b microsatellites, located in the MHC class III region) is most tightly associated (negatively) with the disease.METHODS:A total of 537 UC patients and 748 healthy controls from Spain were included in the present study. Low-resolution DR genotyping was performed by PCR and hybridization with allele-specific oligonucleotide probes. TNFa and b microsatellites were studied in a subset of samples (279 UC patients and 503 healthy controls) by PCR followed by capillary electrophoresis. DR-TNFa-TNFb haplotypes were estimated by the expectation-maximization algorithm and comparisons were performed by a χ2 test.RESULTS:After a stepwise procedure, the only DR alleles significantly associated with the disease were DR3 (very strongly, protection) and DR4 (weakly, protection). The strong protective effect of DR3 was evenly distributed among the haplotypes DR3-TNFa1b5, DR3-TNFa2b3, and DR3-TNFother.CONCLUSIONS:Our results confirm the strong protective effect of DR3 in our population, and suggest that the relevant protective gene is located centromeric to TNFa and TNFb markers in the MHC region.

Enhancing tumor-targeting monoclonal antibodies therapy by PARP inhibitors

ABSTRACT Monoclonal antibodies (mAbs) have become a successful therapeutic approach in cancer. However, some patients do not achieve long-term clinical benefit and most mAbs only exert modest effects as monotherapies. Therefore, combinations with chemotherapy are currently being investigated. Emerging studies have shown a synergistic therapeutic effect of PARP inhibitors and mAbs in cancer. PARP enzymes catalytically cleave β-NAD+ and transfer the ADP-ribose moiety to acceptor proteins, modifying their function. In here, we update recent data about the therapeutic effect of the combination of PARP inhibitors with mAbs in cancer treatment and discuss the molecular mechanisms involved in this synergy.

Factores genéticos comunes en autoinmunidad

Autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) among others, are characterized by a complex etiology in which the combination of several genetic and environmental factors leads to an altered immune response. Several lines of evidence, such as the presence of chromosomal regions associated with several AIDs and the existence of similar gene expression patterns in autoimmune disorders, suggest that different AIDs share common genetic factors. The identification of common genetic factors associated with autoimmunity is of great relevance, since it will allow a better understanding of disease pathogenesis and could help for the development of molecular diagnosis tools and new therapeutic targets. In the past few years, a great progress has been made in the knowledge of the common genetic factors associated with autoimmunity. The PTPN22 gene, an important regulator of T cell response, has been identified as a relevant genetic marker for AIDs. This gene is implicated in the susceptibility to autoimmune disorders such as, RA, SLE, and type 1 diabetes (T1D). In the case of RA the association with the PTPN22 gene is the most replicated after association with HLA genes. In addition, genes implicated in the altered balance between cytokines, such as MIF and IRF5, have been identified as genetic factors predisposing to AIDs.Las enfermedades autoinmunitarias, entre las que se incluyen la artritis reumatoide (RA) o el lupus eritematoso sistemico (LES), se caracterizan por tener una etiologia compleja, en la que varios factores geneticos de susceptibilidad y factores ambientales interaccionan y resultan en una respuesta inmunitaria alterada. Hay diversos indicios de que existen elementos geneticos comunes de predisposicion a las enfermedades autoinmunitarias, como la existencia de regiones cromosomicas asociadas a numerosas enfermedades autoinmunitarias y que haya patrones de expresion genica similares en varias de ellas. La identificacion de factores geneticos comunes asociados con autoinmunidad es de gran relevancia, ya que contribuiria a comprender mejor la patogenia de estas enfermedades, desarrollar nuevas estrategias de diagnostico a escala molecular e identificar posibles nuevas dianas terapeuticas. En los ultimos anos se ha producido un gran avance en el conocimiento de los marcadores geneticos comunes asociados a las enfermedades autoinmunitarias. El gen PTPN22, importante regulador de la respuesta de los linfocitos T, se ha perfilado como un importante marcador genetico de autoinmunidad. Este gen esta implicado en la susceptibilidad a diversas enfermedades autoinmunitarias como el LES, la diabetes mellitus tipo 1 (DM1) y la RA, en la que la asociacion con el gen PTPN22 se ha convertido en la mas solida y repetida despues de la asociacion con los genes HLA. Tambien se han identificado como nuevos marcadores geneticos de susceptibilidad a las enfermedades autoinmunitarias genes implicados en la alteracion del equilibrio de citocinas como los genes MIF e IRF5.

Influencia de las mutaciones de los receptores activados por proteinasa F2R/PAR1 y F2RL1/PAR2 en la enfermedad inflamatoria intestinal

Fundamento y objetivo: La enfermedad inflamatoria intestinal (EII) es una enfermedad poligenica compleja. Tanto la expresion de PAR1 y PAR2 como su presencia en biopsias de pacientes con EII apuntan a un posible papel de estos genes en la susceptibilidad genetica a presentar EII. Este es el primer estudio de asociacion genetica que se realiza con estos genes en la EII. Pacientes y metodo: Se analizaron mediante sondas TaqMan dos polimorfismos en el gen F2R/PAR1 y otro mas en el gen F2RL1/PAR2 en 778 controles sanos y 943 afectados de EII (pacientes con enfermedad de Crohn y colitis ulcerosa de Madrid y Granada). Resultados: No se encontraron diferencias significativas en la distribucion de alelos entre pacientes y controles. Conclusiones: No hay evidencia de asociacion de los polimorfismos analizados en F2R/PAR1 y F2RL1/PAR2 con modificaciones del riesgo de presentar EII.