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ID PMID Title PublicationDate abstract
20349239 Association of cytosine-adenine repeat polymorphism of the estrogen receptor-beta gene wit 2010 Jul The influence of the polymorphism of the estrogen receptor-beta gene, cytosine-adenine (CA) dinucleotide repeat in intron 6, in the occurrence of rheumatoid arthritis (RA) was investigated. Forty-seven RA patients and 36 control subjects with osteoarthritis (OA) were recruited. CA repeat polymorphism was examined using denaturing high-performance liquid chromatography (WAVE DNA Fragment Analysis System). The mean number of CA repeats was significantly higher in RA than in OA patients. Two groups were established: or=22 repeats (long L); and 3 kinds of genotypes (SS, SL, LL) were found. In RA patients, the L allele frequency was higher (OR = 2.03; P
21121872 Clinical safety of tocilizumab in rheumatoid arthritis. 2011 Jan IMPORTANCE OF THE FIELD: Tocilizumab is a new biologic disease-modifying antirheumatic drug directed against the activity of IL-6, a key pro-inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). This drug has proved highly effective in RA patients, including those who had previously not responded to anti-TNFs. As side effects are a major cause for discontinuing biologic therapy, the present article focuses on the tolerability profile of tocilizumab. AREAS COVERED IN THIS REVIEW: This review describes the adverse events (AEs) reported in RA patients treated with tocilizumab. Most data are derived from controlled clinical trials and their open-label extensions. WHAT THE READER WILL GAIN: The reader will gain a comprehensive review of treatment-emergent AEs associated with tocilizumab therapy. These AEs include infections, including opportunistic infections, infusion and hyper-sensitivity reactions, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia. TAKE HOME MESSAGE: Based on current data, tocilizumab appears to have an acceptable safety profile inasmuch as most AEs were manageable or controllable. However, results from large scale pharmacoepidemiological investigations and appropriate post-marketing surveillance are awaited to identify the full spectrum of AEs and define the true benefit:risk ratio of tocilizumab.
20306049 Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid art 2010 Jul Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovium and subsequent joint destruction. Recently, genetic polymorphisms within the toll-like receptor 4 (TLR4) genes have been reported to be associated with RA. To analyze the association between the genetic polymorphisms within TLR4 gene and the susceptibility to RA in Chinese people, two functional variants, Asp299Gly and Thr399Ile, in the TLR4 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing techniques from 213 RA patients and 247 ethnically matched controls. None polymorphisms of Asp299Gly and Thr399Ile were detected in all RA cases and controls, which indicates that there is no relevance between these two SNPs and RA in the Chinese Han population. Further studies with extended single nucleotide polymorphisms (SNP) should be performed.
20216129 Giant iliopsoas bursitis: a complication of chronic arthritis. 2010 Mar Iliopsoas bursitis is a poorly recognized cause of hip pain that requires early recognition to avoid potentially serious complications caused by compression of adjacent structures. It can occur in the setting of trauma in athletes or those who engage in heavy labor and is also associated with acute or chronic arthritis. We describe the cases of 2 patients, one of whom developed a femoral neuropathy, while the other had marked venous compression of the lower limb resulting from enlargement of the iliopsoas bursa. Magnetic resonance imaging offers the most accurate information on the extent of the problem. Recalcitrant cases may require bursectomy in addition to treatment of the underlying cause.
20960435 Breaking communication barriers for RA patients of South Asian origin: the use of a biling 2011 Mar BACKGROUND: People from the Indian subcontinent represent one of the largest ethnic groups in the UK. Patient education resources are required to address language barriers, poor literacy and (potentially discordant) cultural beliefs. We have investigated a novel strategy to meet this need. METHODS: Rheumatoid arthritis (RA) patients of South Asian origin who prefer to communicate in a South Asian language were invited to a face-to-face interaction with a trained patient volunteer to provide linguistically appropriate peer support and education, and given a bilingual educational audio CD. Qualitative methods were used to assess this approach; three focus groups were held and 15 patients participated in total. RESULTS: Four important themes were identified: (1) The need for information about RA; all patients agreed that this was vital to learn how to live with their chronic disease. (2) Currently available approaches to education; particular concerns related to a lack of time in clinic, language barriers, difficulties in communicating via interpreters and that most written information was available only in English. (3) Support provided by a trained patient volunteer; patients appreciated that they were listened to, and were motivated by the volunteers' positive attitude. (4) The usefulness of the audio CD; patients appreciated that information was presented in a language they could understand, via a convenient medium and which offered a helpful perspective on their illness. CONCLUSIONS: This approach is a successful way of delivering information and encouraged patients from a difficult-to-reach community to become more involved in their disease management.
20857157 Synovial fluid β-endorphin level in avascular necrosis, rheumatoid arthritis, and osteoar 2011 Apr The goal of this study is to determine and compare the β-endorphin levels in the synovial fluid of patients with different joint disorders (avascular necrosis, AVN; osteoarthritis, OA; and rheumatoid arthritis, RA of the hip or knee). Eighty-seven patients were involved in our study with an average age of 62 years. Thirty-three patients had AVN (18 hips, 15 knees). Twenty-three patients were diagnosed with OA (14 hips, 9 knees), and 31 patients suffered from RA (12 hips, 19 knees). We measured the β-endorphin levels of the synovial fluids -harvested from surgery-with radioimmunoassay. No significant difference was found in the β-endorphin levels of the synovial fluid from AVN comparing to OA and RA, however β-endorphin level was significantly higher in RA group than among patients with OA (p = 0.01). Synovial β-endorphin level was slightly lower in knee comparing to hip joint p = (0.06). When examining the different joints separately in compliance with diagnoses, we concluded that the synovial β-endorphin level from AVN was between the values of OA and RA without significant difference, whereas it was significantly higher in the knee of RA, than of OA groups (p = 0.05 knee, p = 0.2 hip). Our results confirmed those experiments which stated that there is a significant increase in synovial β-endorphin level in patients with inflammatory autoimmune diseases (e.g., RA), comparing to the level measured in degenerative conditions (e.g., OA).
20360181 Observational studies of infections in rheumatoid arthritis: a metaanalysis of tumor necro 2010 May OBJECTIVE: Published metaanalyses of tumor necrosis factor (TNF) antagonists and infection have focused on randomized controlled trials, which tend to have short duration, relatively small size, and stringent inclusion/exclusion criteria that may limit enrollment to patients at low risk of infection. We performed a systematic review and synthesis of observational studies of TNF antagonists and infection risk. METHODS: We conducted a systematic literature search of studies estimating overall risk of serious infection after anti-TNF exposure in rheumatoid arthritis (RA). We estimated a pooled relative risk (RR) for the relevant observational studies, using a random-effects model. RESULTS: Five cohort studies and 2 nested case-control studies were included in the metaanalysis. Anti-TNF therapy appeared to significantly increase risk of serious infection (pooled adjusted RR 1.37, 95% CI 1.18, 1.60). CONCLUSION: Our metaanalysis of observational data demonstrated an increased risk of serious infection in subjects with RA receiving anti-TNF therapy, versus those not receiving these agents.
19458163 Methotrexate in combination with sulfasalazine is more effective in rheumatoid arthritis p 2009 Jul OBJECTIVES: For pharmacological reasons, the effect of the combination of MTX and SSZ may be different in RA patients who are naïve to these drugs compared to patients with an insufficient response to one of them. Therefore, we compared the results of randomized controlled trials (RCTs) on the combination of MTX and SSZ in naïve patients and in patients with an insufficient response to SSZ. METHODS: A systematic literature search was performed to identify RCTs that compared the MTX-SSZ combination to either drug alone. The databases MEDLINE and the Cochrane Clinical Trials registry were searched from 1966 up to April 2007. The efficacy of the single therapeutic agents or their combination was assessed using the mean change in the disease activity score (DAS) and the ACR improvement criteria. RESULTS: Four RCTs were identified to compare the efficacy of the combination MTX-SSZ to the efficacy of either drug alone. Two parallel trials were performed with patients naïve to both drugs and two add-on trials were performed in SSZ failures. In the trials with naïve patients, the mean DAS changes for the combination MTX and SSZ pointed to a sub-additive efficacy. In the trials with patients who previously failed to SSZ, the mean DAS changes for the combination MTX and SSZ indicated additive efficacy. CONCLUSIONS: In RA, addition of MTX to SSZ is a therapeutic option in SSZ failures, whereas combination of MTX and SSZ in DMARD-naïve patients has no added value.
20039419 Response of Th17 cells to a citrullinated arthritogenic aggrecan peptide in patients with 2010 Jan OBJECTIVE: Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disease. However, the autoantigens that play an important role in the development of RA remain unclear. The aim of this study was to investigate whether T cells specific for citrullinated epitopes from self proteins are present in patients with RA. METHODS: Peripheral blood mononuclear cells (PBMCs) from 28 RA patients and 18 healthy controls were stimulated with citrullinated or noncitrullinated aggrecan peptide Agg(84-103), and proliferative and cytokine responses were assessed using (3)H-thymidine incorporation assay, enzyme-linked immunosorbent assay, and intracellular cytokine analysis. RESULTS: A proliferative response to the citrullinated aggrecan peptide was detected in >60% of RA patients but not in healthy controls. Furthermore, citrullinated aggrecan peptide-stimulated PBMCs from RA patients produced high levels of the proinflammatory cytokine interleukin-17 (IL-17), accompanied by an induction of IL-17+CD4+ T cells. In contrast, PBMCs from RA patients and healthy controls exhibited no response to stimulation with the noncitrullinated aggrecan peptide. CONCLUSION: Proinflammatory T cell responses to stimulation with a citrullinated arthritogenic aggrecan peptide were detected in RA patients but not in healthy individuals, suggesting a role for these autoantigen-specific T cells in the pathogenesis of RA. Our results suggest that the lack of response to the noncitrullinated analog peptide not only implicates the citrulline residue in T cell recognition but also highlights the potential value of citrullinated aggrecan peptide-specific responses as biomarkers of RA. To our knowledge, this is the first study to demonstrate the presence of citrullinated antigen-specific T cells in human RA.
20461791 Importance of immobilization after intraarticular glucocorticoid treatment for elbow synov 2010 May OBJECTIVE: To investigate whether better treatment results might be achieved with postinjection rest following intraarticular glucocorticoid treatment for elbow synovitis. METHODS: Ninety patients with rheumatoid arthritis and elbow synovitis were treated with 20 mg of intraarticular triamcinolone hexacetonide and randomized to either a 48-hour immobilization in a triangular sling (n = 46) or to normal activity without restrictions (n = 44). The primary end point was relapse of synovitis. In addition, pain, function according to a self-assessment questionnaire (the Patient Rated Elbow Evaluation), and range of movement were followed for 6 months. RESULTS: Thirteen relapses occurred in the rest group and 8 in the active group (results not significant). The secondary measures showed no statistically significant differences between the groups. CONCLUSION: Immobilization procedures do not improve the outcome of intraarticular glucocorticoid therapy for elbow synovitis. In future guidelines for such treatment of the upper extremity, normal activity after the injection should be recommended.
20852002 Integrated population pharmacokinetics of etanercept in healthy subjects and in patients w 2011 Jun Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first-order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2-compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics.
19479869 Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheum 2009 Jun OBJECTIVE: To analyze the frequency, surface phenotype, and cytokine secretion of CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared with both healthy control subjects and patients with rheumatoid arthritis (RA). METHODS: Eight-color flow cytometry was used to analyze the surface phenotype and cytokine production of PBMCs from 20 patients with AS, 12 patients with RA, and 16 healthy control subjects, following stimulation ex vivo with phorbol myristate acetate and ionomycin for 5 hours. Secretion of interleukin-17 (IL-17) by PBMCs was measured by enzyme-linked immunosorbent assay, following stimulation with anti-CD3/CD28 for 4 days. RESULTS: The percentages of IL-17-positive CD4+ T cells and IL-22-positive CD4+ T cells were increased in the PBMCs of both patients with AS and patients with RA compared with healthy control subjects, whereas there were no differences in the percentages of interferon-gamma (IFNgamma)-positive or IL-10-positive CD4+ T cells. Likewise, concentrations of IL-17 in supernatants from patients with AS were significantly higher compared with those from healthy control subjects. In patients with RA, the concentrations of IL-17 were increased but not significantly. There was a correlation between the percentages of IL-17-positive CD4+ T cells detected in PBMCs and the amounts of IL-17 in culture supernatants (r=0.414, P=0.0034). All IL-17-producing cells were CD4+CD45RO+; most expressed both CCR6 and CCR4, but only 50% expressed the IL-23 receptor (IL-23R). Nevertheless, there was a positive relationship between the percentage of IL-23R-positive CD4+ T cells and the frequency of IL-17-positive CD4+ T cells or IL-22-positive CD4+ T cells (r=0.57, P<0.0001 and r=0.46, P=0.001, respectively). A significant proportion of cells that produced IL-17 also produced IL-22 and IFNgamma, but none produced IL-10. CONCLUSION: The frequencies of IL-17-positive and IL-22-positive CD4+ T cells were increased in PBMCs from patients with AS and patients with RA, resulting in secretion of higher quantities of IL-17 by PBMCs following stimulation. These data support the hypothesis that Th17 cells, particularly when present in excess of IL-10-producing cells, are involved in the pathogenesis of inflammatory arthritis.
19147611 Adalimumab safety and mortality rates from global clinical trials of six immune-mediated i 2009 Dec OBJECTIVES: Clinical trials of tumour necrosis factor antagonists have raised questions about the potential risk of certain serious adverse events (SAE). To assess the safety of adalimumab in rheumatoid arthritis (RA) over time and across five other immune-mediated inflammatory diseases and to compare adalimumab malignancy and mortality rates with data on the general population. METHODS: This analysis included 19,041 patients exposed to adalimumab in 36 global clinical trials in RA, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis and juvenile idiopathic arthritis (JIA) to 15 April 2007. Events per 100 patient-years were calculated using SAE reported after the first dose to 70 days after the last dose. Standardised incidence rates were calculated for malignancies using national and state-specific databases. Standardised mortality rates (SMR) were calculated for each disease using data from the World Health Organization. RESULTS: Cumulative rates of SAE of interest in RA have remained stable over time. Rates of SAE of interest for PsA, AS, CD, psoriasis and JIA were similar to or lower than rates for RA. Overall malignancy rates for adalimumab-treated patients were as expected for the general population. SMR across all six diseases indicated that no more deaths occurred with adalimumab than expected in the general population. CONCLUSIONS: Based on 10 years of clinical trial experience across six diseases, this safety report and the established efficacy of adalimumab in these diseases provide the foundation for a better understanding of its benefit-risk profile.
19565503 Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage infl 2009 Jul OBJECTIVE: Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1beta (MIP-1beta), in RA. METHODS: Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation. RESULTS: The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP-1 and MIP-1beta in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP-1 or MIP-1beta in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP-1 or MIP-1beta, and this effect could be blocked by an anti-OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50-83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF-kappaB and MAPK pathways, involving the activation of IKKbeta, p38, and JNK. CONCLUSION: These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP-1 and MIP-1beta.
19105681 Do carotid artery diameters manifest early evidence of atherosclerosis in women with rheum 2009 Jan OBJECTIVE: Given the high incidence of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA), we examined the associations between RA diagnosis and characteristics and evidence of carotid atherosclerosis. We take a unique approach by evaluating lumen and interadventitial diameters in addition to intima-media thickness and plaque. METHODS: Ninety-three women with RA were matched with 93 healthy women by age, race, and menopause status. In cross-sectional analyses, we compared common carotid artery measures between groups and examined their relationships with measures of RA severity and activity. RESULTS: Mean age was 53.3 years, and median RA duration was 14 years. Lumen diameter in patients was significantly greater than in healthy women (5.50 vs. 5.19 mm, p < 0.001), as was interadventitial diameter (6.92 vs. 6.61 mm, p < 0.001). Having RA also was independently associated with greater lumen (beta = 0.256, p < 0.01) and interadventitial (beta = 0.261, p < 0.01) diameters, after controlling for cardiovascular risk factors and intima-media thickness. Carotid intima-media thickness (0.70 vs. 0.71 mm) was similar, and the prevalence of carotid plaque in patients (21%) was higher but not statistically different from healthy women (15%). In patients with RA, we found positive associations between methotrexate dose and interadventitial diameter, between hypothyroidism and intima-media thickness, and between hypothyroidism and soluble endothelial adhesion molecule and plaque, independent of cardiovascular risk factors. CONCLUSIONS: Women with RA have increased carotid artery diameters compared with healthy women. This may reflect premature vascular aging and may be an early indicator of increased cardiovascular risk.
20338859 Association between residences in U.S. northern latitudes and rheumatoid arthritis: A spat 2010 Jul BACKGROUND: The etiology of rheumatoid arthritis (RA) remains largely unknown, although epidemiologic studies suggest genetic and environmental factors may play a role. Geographic variation in incident RA has been observed at the regional level. OBJECTIVE: Spatial analyses are a useful tool for confirming existing exposure hypotheses or generating new ones. To further explore the association between location and RA risk, we analyzed individual-level data from U.S. women in the Nurses' Health Study, a nationwide cohort study. METHODS: Participants included 461 incident RA cases and 9,220 controls with geocoded addresses; participants were followed from 1988 to 2002. We examined spatial variation using addresses at baseline in 1988 and at the time of case diagnosis or the censoring of controls. Generalized additive models (GAMs) were used to predict a continuous risk surface by smoothing on longitude and latitude while adjusting for known risk factors. Permutation tests were conducted to evaluate the overall importance of location and to identify, within the entire study area, those locations of statistically significant risk. RESULTS: A statistically significant area of increased RA risk was identified in the northeast United States (p-value = 0.034). Risk was generally higher at northern latitudes, and it increased slightly when we used the nurses' 1988 locations compared with those at the time of diagnosis or censoring. Crude and adjusted models produced similar results. CONCLUSIONS: Spatial analyses suggest women living in higher latitudes may be at greater risk for RA. Further, RA risk may be greater for locations that occur earlier in residential histories. These results illustrate the usefulness of GAM methods in generating hypotheses for future investigation and supporting existing hypotheses.
20373059 Golimumab and malignancies: true or false association? 2011 Jun Malignancy is one of the comorbidities linked to golimumab, a biological TNF-α blocker. In this systematic review and meta-analysis, we searched different databases and analyzed original publications to elucidate the remaining open question about the real association of malignancies with golimumab therapy. The most frequent cancer in patients treated with golimumab, in association or not with methotrexate, is the lung adenocarcinoma. However, lymphoma is not very commonly represented in these patients. We show that there is no major and evident risk of malignancies associated with golimumab in current scientific literature. An increased risk of malignancies may be associated with golimumab, but this warrants further clinical confirmation. Also, this risk mentioned in different studies must be taken with caution because of number of limits and biases.
20635879 Implication of human endogenous retroviruses in the development of autoimmune diseases. 2010 Aug Retroviruses can exist in an endogenous form, in which viral sequences are integrated into the human germ line and are vertically transmitted in a Mendelian fashion. Human endogenous retroviruses (HERVs), probably representing footprints of ancient germ-cell retroviral infections, occupy about 1% of the human genome. Some HERVs emerged in the genome over 25 million years ago, while others have appeared rather recently, at about the time of hominid and ape lineages divergence. Although some of these elements show mutations and deletions, some HERVs are transcriptionally active and produce functional proteins. Some medical conditions, such as cancer and autoimmune diseases, are linked to the transcription of some of the HERVs genes, to the expression of HERVs proteins (that may act as superantigens, for example), and/or to the development of antibodies against them that might cross-react with our own proteins. Their genetic sequences may also be, totally or partially, integrated into genes that regulate the immune response. These mechanisms could give rise to autoimmune diseases, such as lupus erythematosus, insulin-dependent diabetes mellitus, multiple sclerosis, Sjögren's syndrome, and rheumatoid arthritis, among others. This review is aimed at discussing evidence for a possible role of HERVs in the etiopathogenesis of different autoimmune diseases.
20589684 Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors 2010 Nov OBJECTIVE: Abdominal adiposity, especially visceral adiposity, is emerging as a recognized cardiometabolic risk factor. This study was undertaken to investigate how abdominal fat is distributed in rheumatoid arthritis (RA), and its RA-related determinants. METHODS: Men and women with RA were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric studies and quantification of visceral and subcutaneous fat areas (VFA and SFA) using abdominal computed tomography. RESULTS: A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45 cm2 higher (+51%) in male RA patients versus male controls (P = 0.005), but did not significantly differ by RA status in women. The adjusted mean SFA was 119 cm2 higher (+68%) in female RA patients versus female controls (P < 0.001), but did not significantly differ by RA status in men. Elevated VFA (≥75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose level, hypertension, or meeting the composite definition of the metabolic syndrome in the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp/van der Heijde scores were significantly associated with both VFA and SFA. CONCLUSION: The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.
19277065 Using biological networks to search for interacting loci in genome-wide association studie 2009 Oct Genome-wide association studies have identified a large number of single-nucleotide polymorphisms (SNPs) that individually predispose to diseases. However, many genetic risk factors remain unaccounted for. Proteins coded by genes interact in the cell, and it is most likely that certain variants mainly affect the phenotype in combination with other variants, termed epistasis. An exhaustive search for epistatic effects is computationally demanding, as several billions of SNP pairs exist for typical genotyping chips. In this study, the experimental knowledge on biological networks is used to narrow the search for two-locus epistasis. We provide evidence that this approach is computationally feasible and statistically powerful. By applying this method to the Wellcome Trust Case-Control Consortium data sets, we report four significant cases of epistasis between unlinked loci, in susceptibility to Crohn's disease, bipolar disorder, hypertension and rheumatoid arthritis.