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ID PMID Title PublicationDate abstract
18710403 Alteration of N-glycosylation in the kidney in a mouse model of systemic lupus erythematos 2009 Mar Changes in the glycan structures of some glycoproteins have been observed in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. A deficiency of alpha-mannosidase II, which is associated with branching in N-glycans, has been found to induce SLE-like glomerular nephritis in a mouse model. These findings suggest that the alteration of the glycosylation has some link with the development of SLE. An analysis of glycan alteration in the disordered tissues in SLE may lead to the development of improved diagnostic methods and may help to clarify the carbohydrate-related pathogenic mechanism of inflammation in SLE. In this study, a comprehensive and differential analysis of N-glycans in kidneys from SLE-model mice and control mice was performed by using the quantitative glycan profiling method that we have developed previously. In this method, a mixture of deuterium-labelled N-glycans from the kidneys of SLE-model mice and non-labelled N-glycans from kidneys of control mice was analysed by liquid chromatography/mass spectrometry. It was revealed that the low-molecular-mass glycans with simple structures, including agalactobiantennary and paucimannose-type oligosaccharides, markedly increased in the SLE-model mouse. On the other hand, fucosylated and galactosylated complex type glycans with high branching were decreased in the SLE-model mouse. These results suggest that the changes occurring in the N-glycan synthesis pathway may cause the aberrant glycosylations on not only specific glycoproteins but also on most of the glycoproteins in the SLE-model mouse. The changes in glycosylation might be involved in autoimmune pathogenesis in the model mouse kidney.
21123969 Atypical lymphoplasmacytic and immunoblastic proliferation of autoimmune disease : clinico 2010 Atypical lymphoplasmacytic immunoblastic proliferation (ALPIB) is a rare lymphoproliferative disorder (LPD) associated with autoimmune disease (AID). To further clarify the clinicopathologic, immunohistological, and genotypic findings of ALPIB in lymph nodes associated with well-documented AIDs, 9 cases are presented. These 9 patients consisted of 4 patients with systemic lupus erythematosus, 3 patients with rheumatoid arthritis, and one case each with Sjögren's syndrome and dermatomyositis. All 9 patients were females aged from 25 to 71 years with a median age of 49 years. Four cases presented with lymphadenopathy as the initial manifestation. In 4 patients, immunosuppressive drugs were administered before the onset of lymph node lesion. However, none of the 9 patients received methotrexate therapy. The present 9 cases were characterized by : (i) prominent lymphoplasmacytic and B-immunoblastic infiltration ; (ii) absence of pronounced arborizing vascular proliferation ; (iii) absence of CD10(+) "clear cells" ; (iv) presence of hyperplastic germinal center in 7 cases ; (v) immunohistochemistry, flow cytometry, and polymerase chain reaction demonstrated a reactive nature of the T- and B-lymphocytes ; and (vi) on in situ hybridization, there were no Epstein-Barr virus -infected lymphoid cells in any of the 9 cases. Overall 5-year survival of our patients was 83%. The combination of clinical, immunophenotypic, and genotypic findings indicated that the present 9 cases can be regarded as having an essentially benign reactive process. Finally, we emphasized that ALPIB should be added to the differential diagnostic problems of atypical LPDs, particularly lymph node lesions of IgG4-related diseases.
21109561 Genomic features and insights into the biology of Mycoplasma fermentans. 2011 Mar We present the complete genomic sequence of Mycoplasma fermentans, an organism suggested to be associated with the pathogenesis of rheumatoid arthritis in humans. The genome is composed of 977,524 bp and has a mean G+C content of 26.95 mol%. There are 835 predicted protein-coding sequences and a mean coding density of 87.6 %. Functions have been assigned to 58.8 % of the predicted protein-coding sequences, while 18.4 % of the proteins are conserved hypothetical proteins and 22.8 % are hypothetical proteins. In addition, there are two complete rRNA operons and 36 tRNA coding sequences. The largest gene families are the ABC transporter family (42 members), and the functionally heterogeneous group of lipoproteins (28 members), which encode the characteristic prokaryotic cysteine 'lipobox'. Protein secretion occurs through a pathway consisting of SecA, SecD, SecE, SecG, SecY and YidC. Some highly conserved eubacterial proteins, such as GroEL and GroES, are notably absent. The genes encoding DnaK-DnaJ-GrpE and Tig, forming the putative complex of chaperones, are intact, providing the only known control over protein folding. Eighteen nucleases and 17 proteases and peptidases were detected as well as three genes for the thioredoxin-thioreductase system. Overall, this study presents insights into the physiology of M. fermentans, and provides several examples of the genetic basis of systems that might function as virulence factors in this organism.
21087097 Interleukin-32 gamma specific monoclonal antibody and developing IL-32 specific ELISA. 2010 Dec Cytokines are essential coordinators of defensive immune responses for resolving the invasion of pathogens such as bacteria, virus, and fungi. However, dysregulated cytokines are the main cause of various autoinflammatory immune disorders such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Interleukin-32 (IL-32) is a recently described cytokine and characterized as a proinflammatory cytokine. IL-32 stimulates monocytes and macrophages to induce important proinflammatory cytokines (IL-1β, IL-6, and TNFα) and chemokines (IL-8 and MIP-2) by activating the NF-κB and p38 mitogen-activated protein (MAP) kinase pathways. The biological activities of IL-32 are associated with epidemic pathogens, Mycobacterium tuberculosis, influenza A virus, and human immunodeficiency virus (HIV). IL-32 is transcribed as six alternative splice variants (α, β, γ, δ, ɛ, and ζ), with IL-32γ being the most active isoform. However, it is unclear which isoform is related to specific disease activities since there are no high quality antibodies available to measure circulating IL-32 in biological samples of patients. Therefore, we developed specific anti-human IL-32γ monoclonal antibodies from recombinant human IL-32γ, which was expressed in Escherichia coli. The IL-32γ specific monoclonal antibodies recognized IL-32 in cell culture supernatants and serum of IL-32γ transgenic mice. The newly developed IL-32γ monoclonal antibodies will be a useful tool to measure IL-32 level in serum samples of various inflammatory diseases. These monoclonal antibodies will be helpful in investigating the precise function of IL-32 in immune responses and in autoinflammatory diseases.
20957732 Hyaluronan up-regulates IL-10 expression in fibroblast-like synoviocytes from patients wit 2011 Apr Progression to osteoarthritis (OA) is a frequent sequela of severe articular fracture, particularly when weight-bearing joints are involved. Prevention from post-traumatic OA remains a challenge. Hyaluronan (HA) therapy is reported to represent a safe and effective treatment for patients with OA and rheumatoid arthritis. However, the capacity of HA to prevent the occurrence of osteoarthritic changes in fractured joints has not been demonstrated. The present study was undertaken to examine the effects of HA on expression of six OA-related proteins in fibroblast-like synoviocytes (FLS) from 10 patients with tibia plateau fracture. OA-related factors were quantified using a sandwich enzyme-linked immunosorbent assay. Regardless of induction of the FLS with interleukin (IL)-1β, HA was found to down-regulate expression of catabolic factors (IL-1β, matrix metalloproteinase-3, and tumor necrosis factor-α) and to up-regulate production of anti-catabolic factors (tissue inhibitors of metalloproteinase-1 and metalloproteinase-2). HA also enhanced expression of IL-10, an anti-inflammatory cytokine, in FLS. Our results indicated that HA can promote the expression of both antiinflammatory and structure-protective factors in FLS of patients with tibia plateau fracture.
20932291 Women's experiences of wearing therapeutic footwear in three European countries. 2010 Oct 8 BACKGROUND: Therapeutic footwear is recommended for those people with severe foot problems associated with rheumatoid arthritis (RA). However, it is known that many do not wear them. Although previous European studies have recommended service and footwear design improvements, it is not known if services have improved or if this footwear meets the personal needs of people with RA. As an earlier study found that this footwear has more impact on women than males, this study explores women's experiences of the process of being provided with it and wearing it. No previous work has compared women's experiences of this footwear in different countries, therefore this study aimed to explore the potential differences between the UK, the Netherlands and Spain. METHOD: Women with RA and experience of wearing therapeutic footwear were purposively recruited. Ten women with RA were interviewed in each of the three countries. An interpretive phenomenological approach (IPA) was adopted during data collection and analysis. Conversational style interviews were used to collect the data. RESULTS: Six themes were identified: feet being visibly different because of RA; the referring practitioners' approach to the patient; the dispensing practitioners' approach to the patient; the footwear being visible as different to others; footwear influencing social participation; and the women's wishes for improved footwear services. Despite their nationality, these women revealed that therapeutic footwear invokes emotions of sadness, shame and anger and that it is often the final and symbolic marker of the effects of RA on self perception and their changed lives. This results in severe restriction of important activities, particularly those involving social participation. However, where a patient focussed approach was used, particularly by the practitioners in Spain and the Netherlands, the acceptance of this footwear was much more evident and there was less wastage as a result of the footwear being prescribed and then not worn. In the UK, the women were more likely to passively accept the footwear with the only choice being to reject it once it had been provided. All the women were vocal about what would improve their experiences and this centred on the consultation with both the referring practitioner and the practitioner that provides the footwear. CONCLUSION: This unique study, carried out in three countries has revealed emotive and personal accounts of what it is like to have an item of clothing replaced with an 'intervention'. The participant's experience of their consultations with practitioners has revealed the tension between the practitioners' requirements and the women's 'social' needs. Practitioners need greater understanding of the social and emotional consequences of using therapeutic footwear as an intervention.
20885332 Agalsidase beta treatment is associated with improved quality of life in patients with Fab 2010 Nov PURPOSE: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. METHODS: The SF-36® Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/² weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. RESULTS: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. CONCLUSION: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men.
20727041 B-cell targeted therapies in human autoimmune diseases: an updated perspective. 2010 Sep The advent of therapies that specifically target the B-lymphocyte lineage in human disease has rejuvenated interest in the mechanistic biology by which B cells mediate autoimmunity. B cells have a multitude of effector functions including production of self-reactive antibodies, ability to present antigen to T lymphocytes in the context of costimulation, involvement in generation and maintenance of neo-organogenesis at sites of disease, and opposing function through production of both immunostimulatory and immunomodulatory cytokines. In this review, we first discuss the role of B cells in driving autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and Sjögren's syndrome, and discuss how studies in these diseases have revealed differentially important roles for the multiple B-cell effector functions. These data reveal the complex and interrelated roles of B cells working in concert with other components of the innate and adaptive immune system to drive pathogenesis. We then focus on data from mouse and human in which B cells in the setting of disease have been targeted with drugs directed against CD20, CD22, and the BAFF (B-cell activating factor belonging to the tumor necrosis factor family)/APRIL (a proliferation inducing ligand) pathways. Pre-clinical studies in animal models in addition to and clinical trials targeting B cells have added further to the understanding of the differential roles B cells play in disease both through demonstration of clinical efficacy in the context of B-cell depletion or modulation, and also by failure of B-cell targeting in some diseases and disease patient subgroups. Moving forward, it will be imperative to apply these lessons to new interventional trials to ensure better targeting of the B-cell lineage and concomitantly better selection of patients most likely to benefit from these therapies.
20491796 How tumour necrosis factor blockers interfere with tuberculosis immunity. 2010 Jul 1 Tumour necrosis factor (TNF) is a potent inflammatory cytokine that plays an important role in immunity to numerous bacterial infections, including Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans. Infliximab, adalimumab, certolizumab pegol and etanercept are anti-TNF agents used to treat a range of inflammatory/autoimmune diseases, such as rheumatoid arthritis. The use of some of these drugs has been linked to reactivation TB. In addition to blocking TNF-mediated immune responses, some anti-TNF drugs have been found to interfere with innate immune responses, such as phagolysosomal maturation and monocyte apoptosis, as well as cell-mediated responses, including interferon-gamma secretion by memory T cells, complement-mediated lysis of Mtb-reactive CD8+ T cells and increased regulatory T cell activity. This review summarizes some of the reported effects of TNF blockers on immune cell responses in the context of the observed clinical data on TB reactivation in patients on anti-TNF therapy.
20486727 Identification of NSAID users at risk for gastrointestinal complications: a systematic rev 2010 Jun 1 NSAIDs are among the most often used drugs worldwide. Numerous NSAID users are at risk for developing gastrointestinal complications. The purpose of this review was to identify and stratify risk factors for gastrointestinal complications in NSAID users documented in guidelines and consensus agreements, and to collect recommendations regarding over-the-counter (OTC) NSAID use. To facilitate this, a PubMed search from 1 January 1999 until 1 March 2009 was performed, resulting in the inclusion of nine English-language guidelines in our analysis. Risk factors were defined as 'definite' if mentioned in all guidelines; otherwise they were defined as 'controversial' risk factors. 'Definite' risk factors were a history of (complicated) peptic ulcer disease, older age (cut-off range 60-75 years), concomitant anticoagulant or corticosteroid use and multiple NSAID use, including low-dose aspirin (acetylsalicylic acid). 'Controversial' risk factors were high-dose NSAID use, concomitant clopidogrel or selective serotonin reuptake inhibitor use, a history of gastrointestinal symptoms, rheumatoid arthritis disability and cardiovascular disease. Infection with Helicobacter pylori was identified as an additive risk factor. Risk factors in OTC NSAID users were difficult to identify in the current literature. Risk factors were not all uniformly present in analysed guidelines and consensus agreements. We identified a history of (complicated) peptic ulcer disease, older age, concomitant anticoagulant or corticosteroid use and multiple NSAID use, including low-dose aspirin, as definite gastrointestinal risk factors in NSAID users.
20411962 Prediction of aggregation prone regions of therapeutic proteins. 2010 May 20 Therapeutic proteins such as antibodies are playing an increasingly prominent role in the treatment of numerous diseases including cancer and rheumatoid arthritis. However, these proteins tend to degrade due to aggregation during manufacture and storage. Aggregation decreases protein activity and raises concerns about an immunological response. We have recently developed a method based on full antibody atomistic simulations to predict antibody aggregation prone regions [Proc. Natl. Acac. Sci. 2009, 106, 11937]. This method is based on "spatial-aggregation-propensity (SAP)", a measure of the dynamic exposure of hydrophobic patches. In the present paper, we expand on this method to analyze the aggregation prone regions over a wide parameter range. We also explore the effect of different hydrophilic mutations on these predicted aggregation prone regions to engineer antibodies with enhanced stability. The mutation to lysine is more effective than serine but less effective than glutamic acid in enhancing antibody stability. Furthermore, we show that multiple simultaneous mutations on different SAP peaks can have a cumulative effect on enhancing protein stability. We also investigate the accuracy of various cheaper alternatives for SAP evaluation because the full antibody atomistic simulations are highly computationally expensive. These cheaper alternatives include antibody fragment (Fab, Fc) simulations, implicit solvent models, or direct computations from a static structure (i.e., a structure from X-ray or homology modeling). The SAP evaluation from the static structure is 200,000 times faster but less accurate compared to the SAP from explicit atom simulations. Nevertheless, the SAP from a static structure still predicts most of the major aggregation prone regions, making it a potential approach for use in high-throughput applications. Thus, the SAP technology described here could be employed either in high-throughput developability screening of therapeutic protein candidates or to improve their stability at later stages of manufacturing.
20392505 Unregulated IL-23/IL-17 immune response in autoimmune diseases. 2010 Jun INTRODUCTION: Type 1A diabetes (T1D) is an autoimmune disease resulting from the selective destruction of pancreatic beta cells by T cells most likely due to interaction of environmental and genetic factors. The CD4(+) T cells, largely implicated in this disease, comprise different subsets; based on the cytokines they produce. These subsets include Th1, Th2, regulatory T cells and another population of recently described T cells called Th17 cells. Increased expression of interleukin 17 (IL-17) has been detected in sera and in target tissues of patients with various autoimmune diseases. The differentiation of Th17 cells from naïve T cells appears to involve signals from TGF-beta, IL-6, IL-21, IL-1beta and IL-23. IL-23, a member of the IL-12 family, which activate the effector function of Th17 cells to promote inflammatory responses. In animal models, IL-23 is involved in the development of autoimmune diabetes. In humans, it seems to cause multi-organ inflammation, contributing to rheumatoid arthritis, inflammatory bowel disease and celiac disease manifestations. CONCLUSIONS: The discovery that certain autoimmune disorders might be largely mediated by an unregulated IL-23/IL-17 response has important implications for the development of novel therapies for these diseases.
20360628 Strong antioxidant activity of carane derivatives. 2010 Jan Oxidants play a significant role in causing oxidative stress, which underlies the pathogenesis of inflammation and rheumatoid arthritis. The processes associated with inflammatory responses are complex and often involve reactive oxygen species. There are many mediators that initiate and amplify the inflammatory response such as histamine, serotonin and metabolic products of arachidonic acid (thromboxane, prostaglandins and leukotrienes). In the present study, we examined the antioxidant activity of carane derivatives--KP-23 and its optical isomers--that possess strong local anesthetic and anti-inflammatory activity. The antioxidant effects (expressed as Trolox Equivalent Antioxidants Capacity, TEAC) were observed for one of the optical isomers of carane, a derivative of propranolol--KP-23R. The relative scavenging effect (%R) of ABTS+ by KP-23S, KP-23R and standards measured at 30 min was the following, listed in decreasing order: tetracaine > KP-23S > KP-23R > procaine > lignocaine > benzocaine (99, 85, 80, 38, 21 and 20%, respectively, at a concentration of 10 mM). The IC50 values also show strong antioxidant properties of the investigated KP compounds (ranging between 11-18 mM) and tetracaine (6.2 mM) compared to other local anesthetics (129-348 mM). Moreover, monoterpene derivatives were more effective as antioxidants than propranolol diastereoisomers (280-528 mM). We found that carane derivatives, in contrast to propranolol diastereoisomers, serve as potent antioxidants by scavenging radicals.
20238220 Pure red cell aplasia and primary antiphospholipid syndrome: a unique association. 2012 May Pure red cell aplasia (PRCA) is a disease with important relationships to autoimmune mechanisms. Although some autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have been associated with PRCA, until this point no studies have described the association between PRCA and primary antiphospholipid syndrome (APS). This is the first case report of PRCA associated with primary APS in a 39-year-old man with acute heart failure secondary to an anaemic condition that was diagnosed as pure red cell aplasia. The patient was later diagnosed with retinal artery and vein thromboses and bilateral deep venous thromboses of the femoral and popliteal veins. The most common causes of PRCA and other thrombophilias were ruled out in this investigation through complementary tests. This association with APS adds a new possibility to the study of PRCA pathophysiology.
20137726 [Outcomes of posterior C(1-2) fusion for atlantoaxial instability or dislocation using ped 2009 Nov 15 OBJECTIVE: To retrospectively analyze and evaluate the results of treatment for atlantoaxial instability or dislocation employing pedicle screws of atlas and axis. METHODS: Thirty-one patients (23 male and 8 female) with atlantoaxial instability or dislocation were stabilized using pedicle screws of atlas and axis between May 2005 to January 2008. The patients ranged in age from 17 to 67 years (mean 43.5 years). Patients consisted of chronic odontoid fracture in 17, Os odontoideum in 8, fresh odontoid fracture in 4, transverse ligament rupture in 1, rheumatoid arthritis in 1. Clinical features included neck pain in 31; restricted neck movement in 28, varying degrees of spastic quadriparesis in 19. All patients underwent posterior C(1) to C(2) pedicle screw fixation. Operative time, intraoperative blood loss, complications were recorded, neurological and radiographic studies were carried. RESULTS: Mean follow-up time was 13 months. Operative time averaged 2.5 h. Mean intraoperative blood loss was 300 ml. A patient had postoperative wound infection and was treated conservatively with antibiotics and local wound care. A patient developed pulmonary artery embolism and got well with anticoagulation. Satisfactory stability was achieved in all cases with no vascular and C(2) neuralgia. Average JOA score in 19 cases increased at final follow-up (P < 0.01). Solid fusion was achieved in 29 cases, fusion rate was 93.6%. CONCLUSIONS: Stabilization of atlantoaxial complex via pedicle screws of atlas and axis has advantages of intraoperative restoration, easier placement of screw, solid fixation. It is a safe and effective treatment modality for posterior C(1-2) fusion.
20098600 Inhibitory effect of N,N-didesmethylgrossularine-1 on inflammatory cytokine production in 2009 Nov 17 N,N-Didesmethylgrossularine-1 (DDMG-1), a compound with a rare alpha-carboline structure, was isolated from an Indonesian ascidian Polycarpa aurata as responsible for the observed inhibitory activity against TNF-alpha production in lipopolysaccharide-stimulated murine macrophage-like RAW264.7 cells. DDMG-1 inhibited the mRNA level of mTNF-alpha, IkappaB-alpha degradation, and binding of NF-kappaB to the target DNA site in LPS-stimulated RAW 264.7 cells. Moreover, DDMG-1 had an inhibitory effect on the production of IL-8, which is produced in CD14(+)-THP-1 cells stimulated by LPS. DDMG-1 is thus a promising drug candidate lead compound for the treatment of chronic inflammatory diseases, such as rheumatoid arthritis.
20080935 Opinions of Japanese rheumatology physicians regarding clinical practice guidelines. 2010 Apr OBJECTIVE: To examine the views of rheumatology physicians concerning clinical practice guidelines in Japan, and changes to them following the dissemination of new guidelines for rheumatoid arthritis (RA) in 2004. DESIGN: Two cross-sectional questionnaire surveys, the first conducted before publication of new evidence-based RA clinical practice guidelines and the second conducted after implementation. SETTING: Rheumatology-focused practices in Japan. PARTICIPANTS: A random sample of physicians registered with the Japan Rheumatism Foundation who satisfied the registration criteria with regard to experience with RA care. RESULTS: The percentage of guideline users increased from 48 to 60% following publication of the new RA guidelines in 2004 (P < 0.01). The majority agreed that clinical practice guidelines support decision-making in practice, although the proportion of supportive responses decreased slightly in the second survey, from 83 to 77% (P < 0.01) for decision-making, while concern about restricting physician autonomy increased from 18 to 22% (P = 0.01). While only 39% of physicians felt that clinical practice guidelines would contribute to malpractice litigation, the proportion of physicians who were concerned that clinical practice guidelines would be used to bring legal action against providers was larger than that who expected they would defend providers (58 vs 30%, P < 0.001). CONCLUSIONS: Clinical practice guidelines are well accepted among Japanese rheumatology physicians, albeit that the proportion decreased slightly after the introduction of new guidelines. One reason for this may be concern about the use of the guidelines in malpractice litigation. To facilitate implementation, trends in physician support for the guidelines should be closely monitored.
20049410 A functionally relevant IRF5 haplotype is associated with reduced risk to Wegener's granul 2010 Apr Wegener's granulomatosis (WG), characterized by systemic vasculitis and granulomatous inflammation, is a rare chronic rheumatic condition potentially sharing some etiopathological principles with other autoimmune disorders, e.g., rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Several large association studies have identified genetic risk factors for RA and SLE. Thereof, we have evaluated the relevance of the most promising ones in WG. 22 single nucleotide polymorphisms (SNPs) within or in the vicinity of CCL21, CD40, CDK6, IL21, IL2RB, IRF5, KIF5A, KLF12, MMEL1, PRKCQ, STAT4, TNFAIP3, and TRAF1/C5 have been genotyped in >600 German WG cases and >800 matched controls. While most polymorphisms did not show suspicious effects on WG susceptibility, SNPs representing TNFAIP3 (rs6922466, p = 0.032, odds ratio (OR) 0.83, 95% confidence interval (CI) 0.7--0.98) and CDK6 (rs42041, p = 0.0201, OR 1.21, 95% CI 1.03-1.43) revealed nominally significant differences in allele distribution. The strongest association was detected for a functionally relevant four SNP haplotype of IRF5, which comprised a protective effect (p = 0.0000897, p (corrected) = 0.0012, OR 0.73, 95% CI 0.62-0.85) similar to those previously seen in RA and SLE. Thus, we suggest that WG, SLE, and RA share some, but not many, genetic risk factors, which supports models of partly overlapping etiopathological mechanisms in these disorders.
19996608 Evaluation of approaches to identify associated SNPs that explain the linkage evidence in 2010 Linkage analysis is often followed by association mapping to localize disease variants. In this paper, we evaluate approaches to determine how much of the observed linkage evidence, namely the identity-by-descent (IBD) sharing at the linkage peak, is explained by associated SNPs. We study several methods: Homozygote Sharing Tests (HST), Genotype Identity-by-Descent Sharing Test (GIST), and a permutation approach. We also propose a new approach, HSTMLB, combining HST and the Maximum Likelihood Binomial (MLB) linkage statistic. These methods can identify SNPs partially explaining the linkage peak, but only HST and HSTMLB can identify SNPs that do not fully explain the linkage evidence and be applied to multiple-SNPs. We contrast these methods with the association tests implemented in the software LAMP. In our simulations, GIST is more powerful at finding SNPs that partially explain the linkage peak, while HST and HSTMLB are equally powerful at identifying SNPs that do not fully explain the linkage peak. When applied to the North American Rheumatoid Arthritis Consortium data, HST and HSTMLB identify marker pairs that may fully explain the linkage peak on chromosome 6. In conclusion, HST and HSTMLB provide simple and flexible tools to identify SNPs that explain the IBD sharing at the linkage peak.
19951893 Evolutionary divergence and functions of the ADAM and ADAMTS gene families. 2009 Oct The 'A-disintegrin and metalloproteinase' ( ADAM ) and 'A-disintegrin and metalloproteinase with thrombospondin motifs' ( ADAMTS ) genes make up two similar, yet distinct, gene families. The human and mouse genomes contain 21 and 24 putatively functional protein-coding ADAM genes, respectively, and 24 versus 32 putatively functional protein-coding ADAMTS genes, respectively. Analysis of evolutionary divergence shows that both families are unique. Each of the two families can be separated, if need be, into groups of more closely related members: six subfamilies for ADAM , four subfamilies for ADAMTS. The presence of both disintegrin and peptidase domains within the ADAM and ADAMTS proteins implies multiple biological roles within the cell. Membrane-anchored ADAM proteins are best known for their role in activating zymogens--including tumour necrosis factor-alpha, epidermal growth factor (EGF) and amyloid precursor protein (APP). ADAM proteins can also participate in cell adhesion via their interaction with integrins in neighbouring cells. ADAMTS are secreted proteins that participate in extracellular matrix maintenance by way of their cleavage of procollagen and proteoglycans. ADAMTS proteins also are involved in coagulation by cleaving von Willibrand factor precursor protein. ADAM and ADAMTS proteins participate in a wide range of cellular processes, including cell adhesion and migration, ectodomain shedding, proteolysis, development, ovulation and angiogenesis. Because these enzymes are believed to play an important role in a number of pathologies, including Alzheimer's disease, rheumatoid arthritis, atherosclerosis, asthma and cancer progression, the products of the ADAM and ADAMTS genes represent promising drug targets for the prevention and management of a number of human diseases.