Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population

Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population

Could Warsaw be differently rebuilt – alternative history of the city

Zarysowując alternatywną koncepcję powojennej odbudowy Warszawy uznano za celowe przypomnieć, że w latach powojennych dyskutowano nad kształtem przyszłej Warszawy, a nawet nad jej stołecznym statusem. Z jednej strony występowali architekci pragmatycy, którzy nieźle funkcjonowali na prywatnym rynku zleceń projektowych i widzieli szansę odbudowy zniszczonych domów przez ich dotychczasowych właścicieli. Do tej grupy można zaliczyć także miłośników historycznego miasta pragnących odbudować zniszczone zabytki. Z drugiej strony silną grupę tworzyli radykałowie głoszący konieczność totalnych zmian w zabudowaniu miasta kapitalistycznego. Ci o socjalistycznych poglądach, domagali się natychmiastowego przejęcia terenów miejskich przez gminę, ponieważ ich zdaniem bez komunalizacji nie będzie możliwa przebudowa Warszawy. W artykule zestawiono dwie wstępne koncepcje odbudowy Warszawy z początku 1945 roku dla odzwierciedlenia rysujących się w owym czasie różnic w postawach, także społecznych w środowisku urbanistów i architektów. Omówiono podłoże ideologiczne, typowe nie tylko dla Polski, przyświecające koncepcjom przebudowy miast po zniszczeniach wojennych. Przedstawiono sytuację zniszczonej Warszawy i prowadzone działania Biura Odbudowy Stolicy (BOS). Przypomniano rozważania Lecha Niemojewskiego o odbudowie Warszawy oraz opinię Tadeusza Tołwińskiego o szkicowym planie Warszawy wykonanym przez BOS. Zarysowano prawdopodobne cechy przestrzenne jakie mogłaby uzyskać Warszawa gdyby jej odbudową sterowała inna grupa planistów. W podsumowaniu wymieniono – co w Warszawie bezpowrotnie utracono, co osiągnięto i czego nie udało się osiągnąć.While outlining an alternative concept of post-war reconstruction of Warsaw, it is expedient to recall that the future shape of Warsaw and even its capital status were discussed in the post-war years. On the one hand, there were architects pragmatists who functioned well in the architectural projects market and saw a chance to rebuild the destroyed houses by their current owners. This group included admirers of the historic city who wanted to rebuild damaged monuments. On the other hand, an influential group of radicals promoted the momentus changes of the capitalist city. Those with socialist views demanded immediate taking of urban land by the municipality, because they believed that without communalisation reconstruction of Warsaw was not possible. The article discusses two preliminary concepts for the reconstruction of Warsaw from early 1945 to reflect the differences in attitudes amongst urban planners and architects. It also discusses the ideological basis, not only typical for Poland, that guided the concepts of urban reconstruction after the World War II. The situation of destroyed Warsaw and ongoing activities of Bureau of Capital Reconstruction (BOS) were also portrayed. The opinion of Tadeusz Tołwiński about the sketch map of Warsaw made in BOS was recalled and the likely spatial characteristics were outlined for reconstruction of Warsaw to show potentially what it would look like if it was reconstructed by another group of planners. The final part summarises: what Warsaw irretrievably lost, what has been achieved and what could not be realized

Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype : results from the IBDchip European project

Objective Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. Design This retrospective study included 1528 patients with CD with more than 10years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. Results Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02x10(-06), OR=1.90), stenosing (p=3.16x10(-06), OR=1.82) and penetrating (p=1.26x10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28xe-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86x10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3years after diagnosis led to a reduction in bowel stenoses (p=1.48x10(-06), OR=0.35) and surgical rate (p=1.71x10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12x10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01x10(-02), HR=1.29) among patients with low and high score. Conclusions This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course

Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease

Objective: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up.Design: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis.Results: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-?B regulator CYLD. This resulted in I?B-? degradation and NF-?B activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly.Conclusions: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors