Familial Mediterranean Fever and Hypercoagulability

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. As such, FMF is a prototype of autoinflammatory diseases where genetic changes lead to acute inflammatory episodes. Systemic inflammation – in general - may increase procoagulant factors, and decrease natural anticoagulants and fibrinolytic activity. Therefore, it is anticipated to see more thrombotic events among FMF patients compared with healthy subjects. However, reviewing the current available literature and based upon our personal experience, thrombotic events related purely to FMF are very rare. Possible explanation for this discrepancy is that along with the procoagulant activity during FMF acute attacks, anticoagulant and fibrinolytic changes are also taking place. Colchicine which is the treatment of choice in FMF may also play a role in reducing inflammation thereby decreasing hypercoagulability

Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin

Cells cope with replication-blocking lesions via translesion DNA synthesis (TLS). TLS is carried out by low-fidelity DNA polymerases that replicate across lesions, thereby preventing genome instability at the cost of increased point mutations. Here we perform a twostage siRNA-based functional screen for mammalian TLS genes and identify 17 validated TLS genes. One of the genes, NPM1, is frequently mutated in acute myeloid leukaemia (AML). We show that NPM1 (nucleophosmin) regulates TLS via interaction with the catalytic core of DNA polymerase-eta (pol eta), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of pol eta. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in similar to 30% of AML patients results in excessive degradation of pol eta. These results establish the role of NPM1 as a key TLS regulator, and suggest a mechanism for the better prognosis of AML patients carrying mutations in NPM1

Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin

Cells cope with replication-blocking lesions via translesion DNA synthesis (TLS). TLS is carried out by low-fidelity DNA polymerases that replicate across lesions, thereby preventing genome instability at the cost of increased point mutations. Here we perform a twostage siRNA-based functional screen for mammalian TLS genes and identify 17 validated TLS genes. One of the genes, NPM1, is frequently mutated in acute myeloid leukaemia (AML). We show that NPM1 (nucleophosmin) regulates TLS via interaction with the catalytic core of DNA polymerase-eta (pol eta), and that NPM1 deficiency causes a TLS defect due to proteasomal degradation of pol eta. Moreover, the prevalent NPM1c+ mutation that causes NPM1 mislocalization in similar to 30% of AML patients results in excessive degradation of pol eta. These results establish the role of NPM1 as a key TLS regulator, and suggest a mechanism for the better prognosis of AML patients carrying mutations in NPM1

Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study

Autoinflammatory diseases (AIDs) are a relatively new family of disorders, defined about 19 years ago. Some of them are hereditary and some are not. The names given to these diseases do not follow any systematic guidelines, and sometimes the same disorder carries several names. The aim of this study is to refine the definition of AIDs and to provide some conventions for their naming. We focused mainly on monogenetic AIDs. Delphi technique, which enables consensus among a group of experts through internet and mail communication and questionnaires, was employed. After achieving 100% consensus among six members of a steering committee, the questionnaire containing AID definitions and the agreed-upon conventions were sent to 26 physicians and researchers working in the field of AIDs in order to gain broader support for the committee's proposals. The committee proposed the following definition for AIDs: "Autoinflammatory diseases are clinical disorders caused by defect(s) or dysregulation of the innate immune system, characterized by recurrent or continuous inflammation (elevated acute phase reactants-APR) and the lack of a primary pathogenic role for the adaptive immune system (autoreactive T-cells or autoantibody production)." Several rules were defined for guiding the naming of these diseases among which are: abandoning eponyms and preferring the name of the gene over its encoded protein. The new definition for AIDs allows inclusion of clinical disorders mainly associated with defects in the innate immune system. The new conventions propose names with clinical meaning and in some cases even clues for treatment

Glucocorticoid sensitivity in Behcet's disease

WOS: 000209773300007PubMed ID: 23781311Objective: Glucocorticoid (GC) sensitivity is highly variable among individuals and has been associated with susceptibility to develop (auto-) inflammatory disorders. The purpose of the study was to assess GC sensitivity in Behcet's disease (BD) by studying the distribution of four GC receptor (GR) gene polymorphisms and by measuring in vitro cellular GC sensitivity. Methods: Healthy controls and patients with BD in three independent cohorts were genotyped for four functional GR gene polymorphisms. To gain insight into functional differences in in vitro GC sensitivity, 19 patients with BD were studied using two bioassays and a whole-cell dexamethasone-binding assay. Finally, mRNA expression levels of GR splice variants (GR-alpha and GR-beta) were measured. Results: Healthy controls and BD patients in the three separate cohorts had similar distributions of the four GR polymorphisms. The Bcll and 9 beta minor alleles frequency differed significantly between Caucasians and Mideast and Turkish individuals. At the functional level, a decreased in vitro cellular GC sensitivity was observed. GR number in peripheral blood mononuclear cells was higher in BD compared with controls. The ratio of GR-alpha/GR-beta mRNA expression levels was significantly lower in BD. Conclusions: Polymorphisms in the GR gene are not associated with susceptibility to BD. However, in vitro cellular GC sensitivity is decreased in BD, possibly mediated by a relative higher expression of the dominant negative GR-b splice variant. This decreased in vitro GC sensitivity might play an as yet unidentified role in the pathophysiology of BD.The Dutch Arthritis AssociationThis work was supported by a grant from The Dutch Arthritis Association

Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet Disease

Introduction: The etiology of Behçet's disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genomewide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts. Methods: We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published. Results: We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended metaanalysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3. Discussion: We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our

Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey

<p>Abstract</p> <p>Objective</p> <p>To analyze the prevalence of diagnosed and suspected autoinflammatory diseases in Eastern and Central European (ECE) countries, with a particular interest on the diagnostic facilities in these countries.</p> <p>Methods</p> <p>Two different strategies were used to collect data on patients with periodic fever syndromes from ECE countries- the Eurofever survey and collection of data with the structured questionnaire.</p> <p>Results</p> <p>Data from 35 centers in 14 ECE countries were collected. All together there were 11 patients reported with genetically confirmed familial Mediterranean fever (FMF), 14 with mevalonate-kinase deficiency (MKD), 11 with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and 4 with chronic infantile neurological cutaneous and articular syndrome (CINCA). Significantly higher numbers were reported for suspected cases which were not genetically tested. All together there were 49 suspected FMF patients reported, 24 MKD, 16 TRAPS, 7 CINCA and 2 suspected Muckle-Wells syndrome (MWS) patients.</p> <p>Conclusions</p> <p>The number of genetically confirmed patients with periodic fever syndromes in ECE countries is very low. In order to identify more patients in the future, it is important to organize educational programs for increasing the knowledge on these diseases and to establish a network for genetic testing of periodic fever syndromes in ECE countries.</p

Identification of Disease-Promoting HLA Class I and Protective Class II Modifiers in Japanese Patients with Familial Mediterranean Fever

Objectives: The genotype-phenotype correlation of MEFV remains unclear for the familial Mediterranean fever (FMF) patients, especially without canonical MEFV mutations in exon 10. The risk of FMF appeared to be under the influence of other factors in this case. The contribution of HLA polymorphisms to the risk of FMF was examined as strong candidates of modifier genes. Methods: Genotypes of HLA-B and -DRB1 loci were determined for 258 mutually unrelated Japanese FMF patients, who satisfied modified Tel-Hashomer criteria, and 299 healthy controls. The effects of carrier status were evaluated for the risk of FMF by odds ratio (OR). The HLA effects were also assessed for clinical forms of FMF, subsets of FMF with certain MEFV genotypes and responsiveness to colchicine treatment. Results: The carriers of B?39:01 were increased in the patients (OR = 3.25, p = 0.0012), whereas those of DRB1?15:02 were decreased (OR = 0.45, p = 0.00050), satisfying Bonferroni\u27s correction for multiple statistical tests (n = 28, p<0.00179). The protective effect of DRB1?15:02 was completely disappeared in the co-existence of B?40:01. The HLA effects were generally augmented in the patients without a canonical MEFV variant allele M694I, in accordance with the notion that the lower penetrance of the mutations is owing to the larger contribution of modifier genes in the pathogenesis, with a few exceptions. Further, 42.9% of 14 colchicine-resistant patients and 13.5% of 156 colchicine-responders possessed B?35:01 allele, giving OR of 4.82 (p = 0.0041). Conclusions: The differential effects of HLA class I and class II polymorphisms were identified for Japanese FMF even in those with high-penetrance MEFV mutations