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ID PMID Title PublicationDate abstract
20935309 Assessing chloroquine toxicity in RA patients using retinal nerve fibre layer thickness, m 2010 Dec AIMS: To assess chloroquine (CQ) toxicity by visual field testing, multifocal electroretinography (mfERG) and measurement of retinal nerve fibre layer (RNFL) thickness in patients with rheumatoid arthritis (RA) under treatment with CQ but with normal ocular fundus manifestation. METHODS: 60 RA patients taking CQ, 30 RA patients not receiving CQ treatment and 100 normal subjects were enrolled in this study. Examinations included visual field testing (Humphrey 10-2 testing strategy), mfERG and scanning laser polarimetry (GDxVCC) to measure RNFL. Data from one eye of a patient were used for analysis. RESULTS: The mfERG ring 2 data among the three groups differed, and a correlation between cumulative dose of CQ and mfERG N1 response of ring 2 was detected. Two patients in the CQ group had central or paracentral scotoma, but all others were normal. No difference in mean deviation and pattern standard deviation values of visual field were found among the three groups, and there was no correlation between the cumulative dose of CQ and these values. There was a significant negative correlation between the cumulative dose of CQ and RNFL loss and a positive correlation between the cumulative dose of CQ and the nerve fibre indicator. CONCLUSION: Visual field, scanning laser polarimetry and mfERG are useful tools for early detection of CQ retinopathy. Thinning RNFL and reduced ring 2 response of mfERG may be useful signs for early CQ retinopathy.
20388564 Characterisation of complex chromosome 18p rearrangements in two syndromic patients with i 2010 Jul There have been reports that a number of patients with a chromosome 18pter deletion have developed autoimmune disorders, including juvenile diabetes, rheumatoid arthritis, thyroiditis and Graves' disease, and/or show little or no reduction in serum IgA levels. We describe two female patients bearing complex rearrangements involving chromosome 18p. Array-CGH and BAC FISH molecular cytogenetic analyses enabled the precise identification of the affected 18p region. One patient has a 2 Mb terminal deletion associated with a 9.2 Mb inverted duplication of the adjacent region; the other has a more extended 10.1 Mb terminal deletion associated with a 4.1 Mb quadruplication of the adjacent region and a 2.6 Mb duplication of the pericentromeric region. Both patients have dysmorphic features typical of 18p deletion syndrome, such as growth retardation, epicanthal folds, a long philtrum and toe defects, and are also affected by immunological disorders. One has a form of immunological deficiency that takes the form of recurrent pulmonary infections and low IgA levels; the other has an autoimmune form of juvenile rheumatoid arthritis. Relating the refined molecular cytogenetic characterisation of these 18p chromosomal rearrangements to the patients' specific clinical characteristics can improve our understanding of the role of the 18p region in immune responses.
20357249 CXC chemokine ligand 2 induced by receptor activator of NF-kappa B ligand enhances osteocl 2010 May 1 CXCL2 has been known to regulate immune functions mainly by chemo-attracting neutrophils. In this study, we show that CXCL2 can be induced by receptor activator of NF-kappaB ligand, the osteoclast (OC) differentiation factor, through JNK and NF-kappaB signaling pathways in OC precursor cells. CXCL2 in turn enhanced the proliferation of OC precursor cells of bone marrow-derived macrophages (BMMs) through the activation of ERK. Knockdown of CXCL2 inhibited both the proliferation of and the ERK activation in BMMs. During osteoclastogenesis CXCL2 stimulated the adhesion and the migration of BMMs. Moreover, the formation of OCs from BMMs was significantly increased on treatment with CXCL2. Conversely, the CXCL2 antagonist repertaxin and a CXCL2 neutralizing Ab potently reduced receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Furthermore, CXCL2 evoked fulminant bone erosion in the in vivo mouse experiments. Finally, prominent upregulation of CXCL2 was detected in synovial fluids and sera from rheumatoid arthritis patients, suggesting a potential involvement of CXCL2-mediated osteoclastogenesis in rheumatoid arthritis-associated bone destruction. Thus, CXCL2 is a novel therapeutic target for inflammatory bone destructive diseases.
20054486 Hexane-Soluble Fraction of the Common Fig, Ficus carica, Inhibits Osteoclast Differentiati 2009 Dec Osteoclasts, derived from multipotent myeloid progenitor cells, play homeostatic roles in skeletal modeling and remodeling, but may also destroy bone in pathological conditions such as osteoporosis and rheumatoid arthritis. Osteoclast development depends critically on a differentiation factor, the receptor activator of NF-kappaB ligand (RANKL). In this study, we found that the hexane soluble fraction of the common fig Ficus carica (HF6-FC) is a potent inhibitor of osteoclastogenesis in RANKL-stimulated RAW264.7 cells and in bone marrow-derived macrophages (BMMs). HF6-FC exerts its inhibitory effects by suppression of p38 and NF-kappaB but activation of ERK. In addition, HF6-FC significantly decreased the expression of NFATc1 and c-Fos, the master regulator of osteoclast differentiation. The data indicate that components of HF6-FC may have therapeutic effects on bone-destructive processes such as osteoporosis, rheumatoid arthritis, and periodontal bone resorption.
20018002 Genome-wide gene-based association study. 2009 Dec 15 Genome-wide association studies, which analyzes hundreds of thousands of single-nucleotide polymorphisms to identify disease susceptibility genes, are challenging because the work involves intensive computation and complex modeling. We propose a two-stage genome-wide association scanning procedure, consisting of a single-locus association scan for the first stage and a gene-based association scan for the second stage. Marginal effects of single-nucleotide polymorphisms are examined by using the exact Armitage trend test or logistic regression, and gene effects are examined by using a p-value combination method. Compared with some existing single-locus and multilocus methods, the proposed method has the following merits: 1) convenient for definition of biologically meaningful regions, 2) powerful for detection of minor-effect genes, 3) helpful for alleviation of a multiple-testing problem, and 4) convenient for result interpretation. The method was applied to study Genetic Analysis Workshop 16 Problem 1 rheumatoid arthritis data, and strong association signals were found. The results show that the human major histocompatibility complex region is the most important genomic region associated with rheumatoid arthritis. Moreover, previously reported genes including PTPN22, C5, and IL2RB were confirmed; novel genes including HLA-DRA, BTNL2, C6orf10, NOTCH4, TAP2, and TNXB were identified by our analysis.
20018074 Identifying rheumatoid arthritis susceptibility genes using high-dimensional methods. 2009 Dec 15 Although several genes (including a strong effect in the human leukocyte antigen (HLA) region) and some environmental factors have been implicated to cause susceptibility to rheumatoid arthritis (RA), the etiology of the disease is not completely understood. The ability to screen the entire genome for association to complex diseases has great potential for identifying gene effects. However, the efficiency of gene detection in this situation may be improved by methods specifically designed for high-dimensional data. The aim of this study was to compare how three different statistical approaches, multifactor dimensionality reduction (MDR), random forests (RF), and an omnibus approach, worked in identifying gene effects (including gene-gene interaction) associated with RA. We developed a test set of genes based on previous linkage and association findings and tested all three methods. In the presence of the HLA shared-epitope factor, other genes showed weaker effects. All three methods detected SNPs in PTPN22 and TRAF1-C5 as being important. But we did not detect any new genes in this study. We conclude that the three high-dimensional methods are useful as an initial screening for gene associations to identify promising genes for further modeling and additional replication studies.
20018057 Detecting single-nucleotide polymorphism by single-nucleotide polymorphism interactions in 2009 Dec 15 The objective of this study was to detect interactions between relevant single-nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA). Data from Problem 1 of the Genetic Analysis Workshop 16 were used. These data consisted of 868 cases and 1,194 controls genotyped with the 500 k Illumina chip. First, machine learning methods were applied for preselecting SNPs. One hundred SNPs outside the HLA region and 1,500 SNPs in the HLA region were preselected using information-gain theory. The software weka was used to reduce colinearity and redundancy in the HLA region, resulting in a subset of 6 SNPs out of 1,500. In a second step, a parametric approach to account for interactions between SNPs in the HLA region, as well as HLA-nonHLA interactions was conducted using a Bayesian threshold least absolute shrinkage and selection operator (LASSO) model incorporating 2,560 covariates. This approach detected some main and interaction effects for SNPs in genes that have previously been associated with RA (e.g., rs2395175, rs660895, rs10484560, and rs2476601). Further, some other SNPs detected in this study may be considered in candidate gene studies.
20017994 Pathway-based analysis of a genome-wide case-control association study of rheumatoid arthr 2009 Dec 15 Evaluation of the association between single-nucleotide polymorphisms (SNPs) and disease outcomes is widely used to identify genetic risk factors for complex diseases. Although this analysis paradigm has made significant progress in many genetic studies, many challenges remain, such as the requirement of a large sample size to achieve adequate power. Here we use rheumatoid arthritis (RA) as an example and explore a new analysis strategy: pathway-based analysis to search for related genes and SNPs contributing to the disease.We first propose the application of measure of explained variation to quantify the predictive ability of a given SNP. We then use gene set enrichment analysis to evaluate enrichment of specific pathways, where pathways, are considered enriched if they consist of genes that are associated with the phenotype of interest above and beyond is expected by chance. The results are also compared with score tests for association analysis by adjusting for population stratification.Our study identified some significantly enriched pathways, such as "cell adhesion molecules," which are known to play a key role in RA. Our results showed that pathway-based analysis may identify other biologically interesting loci (e.g., rs1018361) related to RA: the gene (CTLA4) closest to this marker has previously been shown to be associated with RA and the gene is in the significant pathways we identified, even though the marker has not reached genome-wide significance in univariate single-marker analysis.
19505194 BMS-582949: crystalline form of a p38alpha inhibitor? WO2008079857. 2009 Aug The p38 kinases have long been recognized as potentially valuable targets in the development of novel anti-inflammatory therapies. An application claiming a single crystalline form of N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-5-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide and its therapeutic use for the treatment of inflammatory diseases including rheumatoid arthritis, psoriasis and atherosclerosis points to the claimed compound being a development compound. The available evidence suggests that the compound could be BMS-582949, a compound in Phase II studies for the treatment of rheumatoid arthritis, psoriasis and atherosclerosis.
19593141 Targeting interleukin-6 in pediatric rheumatic diseases. 2009 Sep PURPOSE OF REVIEW: To describe the most recent data regarding the role of interleukin-6 (IL-6) in immune and inflammatory responses, the mode of action and safety information on tocilizumab, the only available IL-6 inhibitor, and discuss recent results on the therapeutic inhibition of IL-6 in pediatric rheumatic diseases. RECENT FINDINGS: New data on the effects of IL-6 on T and B cells have been published. Clinical trials with tocilizumab in adults, particularly with rheumatoid arthritis, provide new data on mechanism of action and a reasonably wide safety database. A withdrawal design trial showed marked efficacy in systemic juvenile idiopathic arthritis (s-JIA). Open label studies or anecdotal reports suggest possible efficacy also in other JIA subtypes, as well as other rheumatic diseases. SUMMARY: Targeting IL-6 activities is an effective approach in the treatment of chronic inflammatory diseases. The long-term benefit and safety of tocilizumab have to be defined in long-term extension studies. The risk/benefit ratio appears to be particularly favorable in s-JIA. With the increasing number of biologics becoming available, future efforts should be directed to the definition of biomarkers that will identify responders to each novel biologic, allowing a personalized approach.
20018006 Case-control genome-wide association study of rheumatoid arthritis from Genetic Analysis W 2009 Dec 15 Currently, genome-wide association studies (GWAS) are conducted by collecting a massive number of SNPs (i.e., large p) for a relatively small number of individuals (i.e., small n) and associations are made between clinical phenotypes and genetic variation one single-nucleotide polymorphism (SNP) at a time. Univariate association approaches like this ignore the linkage disequilibrium between SNPs in regions of low recombination. This results in a low reliability of candidate gene identification. Here we propose to improve the case-control GWAS approach by implementing linear discriminant analysis (LDA) through a penalized orthogonal-components regression (POCRE), a newly developed variable selection method for large p small n data. The proposed POCRE-LDA method was applied to the Genetic Analysis Workshop 16 case-control data for rheumatoid arthritis (RA). In addition to the two regions on chromosomes 6 and 9 previously associated with RA by GWAS, we identified SNPs on chromosomes 10 and 18 as potential candidates for further investigation.
19926120 Receptor Activator for Nuclear Factor kappa B Ligand (RANKL) as an osteoimmune key regulat 2011 Feb The strength and integrity of the human skeleton depends on a delicate equilibrium between bone resorption and bone formation. Bone resorption is an elementary cellular activity in the modelling of the skeleton during growth and development. Later in life a most important physiological process in the skeleton is bone remodelling, which is locally initiated by resorption. During remodelling bone resorption is coupled to new bone formation that ensures renewal of bone with only minor local and temporary bone loss. Cells responsible for bone resorption and subsequent bone formation are the osteoclasts and osteoblasts, respectively. The osteoclast is derived from the pluripotent hematopoietic stem cell, which gives rise to a myeloid stem cell that can further differentiate into megakaryocytes, granulocytes, monocytes/macrophages and osteoclasts. The respective bone resorbing and forming actions of osteoclasts and osteoblasts are finely coupled, so that bone mass remains remarkably stable in a healthy adult. Imbalance between osteoclast and osteoblast activities can arise from a wide variety of hormonal changes or perturbations of inflammatory and growth factors resulting in postmenopausal osteoporosis, Paget's disease, lytic bone metastases, or rheumatoid arthritis, leading to increased bone resorption and crippling bone damage. In view of the critical role of osteoclasts in diverse pathology, there has been immense effort aimed at understanding the biology of this unique cell. The present review is focused on the current knowledge of the mechanisms that regulate the functional links between bone turnover and the immune system helping us to understand the main factors that lead to bone loss observed in osteoporosis, cancer and in rheumatoid arthritis. The aim of this review paper is to consider the key molecular interactions involved in the formation of osteoclast cells in normal and pathological conditions.
21136988 MS characterization of apheresis samples from rheumatoid arthritis patients for the improv 2009 Jul Identification of proteins from apheresis samples was performed by both SDS-PAGE and 2-D gel separation of eluted proteins from staphylococcal protein A-based immunoadsorption columns (Prosorba(®) ) followed by MS peptide mass fingerprinting and MS/MS peptide sequencing on a MALDI QIT TOF mass spectrometer. MS/MS peptide sequencing was performed in conjunction with a micro reversed phase HPLC configured with an online MALDI plate-spotting device. Apheresis treatment had been performed in three patients with longstanding therapy refractory rheumatoid arthritis. 2-D gels displayed ca. 500 spots representing proteins that were eluted from the Prosorba(®) columns. From 54 gels, a total of 1256 protein spots had been picked and yielded in the identification of 56 non-redundant proteins without counting isoforms. Proteins from the eluates belong to five major groups comprising (i) immunoglobulins (IgG, IgA, IgM heavy and light chains; about 40% of the spots), (ii) proteins involved in coagulation, (iii) HDL/LDL-associated proteins, (iv) proteins from the complement system, and (v) acute phase proteins. MS analysis showed that the full-length C3 complement protein had been cleaved upon complement activation, presumably on the column, such that the anaphylatoxin C3a was produced and released during therapy. Our results are consistent with clinical observations on both patient responses to therapy and reported adverse events. For the first time, direct molecular information has become available to support mechanistic reasoning for the principle of function of staphylococcal protein A-based immunoadsorption therapy and for the explanation of adverse events. According to our results, removal and/or modulation of immune complexes together with complement activation can be regarded as the major events that are taking place during Prosorba(®) therapy. In order to avoid complement activation and induction of an inflammatory cascade, we suggest the prevention of C3a anaphylatoxin-related reactions during immunoadsorption therapy.
20948566 Prediction of disease severity in patients with early rheumatoid arthritis by gene express 2009 Apr 27 In order to test the ability of peripheral blood gene expression profiles to predict future disease severity in patients with early rheumatoid arthritis (RA), a group of 17 patients (1 ± 0.2 years disease duration) was evaluated at baseline for gene expression profiles. Disease status was evaluated after a mean of 5 years using an index combining pain, global and recoded MHAQ scores. Unsupervised and supervised algorithms identified "predictor genes" whose combined expression levels correlated with follow-up disease severity scores. Unsupervised clustering algorithms separated patients into two branches. The only significant difference between these two groups was the disease severity score; demographic variables and medication usage were not different. Supervised T-Test analysis identified 19 "predictor genes" of future disease severity. Results were validated in an independent cohort of subjects of established RA with using Support Vector Machines and K-Nearest-Neighbor Classification. Our study demonstrates that peripheral blood gene expression profiles may be a useful tool to predict future disease severity in patients with early and established RA.
22870450 Treatment strategies for osteoarthritis patients with pain and hypertension. 2010 Aug Out of 100 patients with osteoarthritis (OA), almost 40 have a concomitant diagnosis of hypertension. Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors may trigger a rise in blood pressure (BP), which is more marked in patients with established hypertension. NSAIDs and COX-2 inhibitors attenuate the antihypertensive effect of several antihypertensive agents. Frequent BP controls are needed in treated hypertensive patients who are concomitantly receiving NSAIDs or COX-2 inhibitors because even a small increase in BP may be associated with an important rise in the risk of major cardiovascular complications. In meta-analyses, an increase in systolic BP of 5mmHg was associated with a 25% higher risk of cardiovascular events. These data have been confirmed in randomized studies with rofecoxib and celecoxib, where a modest increase in BP was associated with a significantly higher risk of cardiovascular disease. There is emerging evidence that the COX-inhibiting nitric oxide donator (CINOD) class is promising in the treatment of patients with OA. Naproxcinod, the first CINOD investigated in clinical trials, is composed of the traditional NSAID naproxen covalently bound to the nitric oxide (NO)-donating moiety butanediol mono-nitrate (BDMN). The molecule has the potential to provide a sustained release of NO. In clinical studies, naproxcinod prevented the BP rise in normotensive and hypertensive patients observed with naproxen. The BP benefit of naproxcinod over naproxen was greater in patients concomitantly receiving angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. These investigational data suggest that naproxcinod is a valuable alternative to NSAIDs and COX-2 inhibitors for treatment of OA patients.
19801257 [Severe tularaemia mimicking glandular tuberculosis during adalimumab therapy]. 2009 Oct BACKGROUND: Tularaemia is an anthropozoonosis, transmitted by small mammals (hares) and arthropods (ticks, horseflies). The causative agent is Francisella tularensis, a facultatively intracellular Gram-negative bacillus. We report a case of tularaemia in its ulceroglandular form occurring during methotrexate and adalimumab treatment (Humira) for rheumatoid arthritis. PATIENTS AND METHODS: A 58-year-old man with a history of primary tuberculosis receiving adalimumab in combination with methotrexate for rheumatoid arthritis for almost 1 year consulted for a febrile inflammatory plaque on the left leg with a small central necrotic area. An enlarged left inguinal lymph node was present. Doxycycline has previously been prescribed for a tick bite. The lymphadenopathy gradually became enlarged resulting in skin fistulisation. After surgical excision, histopathology revealed epithelioid granulomas accompanied by giant cells and central necrosis. Mycobacterial cultures were negative. Positive tularaemia serology at significant titres suggested a diagnosis of tularaemia, with probable transmission via a tick bite. The diagnosis was confirmed by F. tularensis DNA amplification using PCR on a lymph node biopsy. Doxycycline was continued for a further 6 weeks. One year later, no relapse had occurred. DISCUSSION: A febrile adenopathy presenting the histological features of necrotic granulomas in a patient receiving anti-TNF alpha treatment initially suggested reactivation of tuberculosis. However, the history of tick bite and failure to isolate mycobacteria from different tissue specimens prompted screening for a tick-borne disease, finally leading to a diagnosis of tularaemia. We discuss the possible relationship between immunosuppression and the clinical course of this rare infection.
20446489 Edentulism and comorbid factors. 2010 Apr INTRODUCTION: Complete edentulism is the terminal outcome of a multifactorial process involving biological factors and patient-related factors. It continues to represent a tremendous global health care burden, and will for the foreseeable future. The purpose of this review is to determine what comorbid factors exist for the completely edentulous patient. METHODS: This literature review evaluated articles obtained via the National Library of Medicine's PubMed website, using keywords of edentulism with various combinations of the terms comorbidity, incidence, health, nutrition, cancer, cardiovascular health, diabetes, osteoporosis, smoking, asthma, dementia, and rheumatoid arthritis. Abstracts were selected and screened, and selected full-text articles were reviewed. Articles were limited to those with adequate patient cohorts and a minimum of 2-year follow-up data. RESULTS: Edentulism was found to be a global issue, with estimates for an increasing demand for complete denture prostheses in the future. Completely edentulous patients were found to be at higher risk for poor nutrition, coronary artery plaque formation (odds ratio 2.32), to be smokers (odds ratio 2.42), to be asthmatic and edentulous in the maxillary arch (odds ratio 10.52), to being diabetic (odds ratio 1.82), to having rheumatoid arthritis (odds ratio 2.27), and to having certain cancers (odds ratios varying from 1.54 to 2.85, depending on the type of cancer). Chronic residual ridge resorption continues to be the primary intraoral complication of edentulation, and there appear to be few opportunities to reduce bone loss in the edentulous patient. CONCLUSIONS: While the completely edentulous patient seems to be at risk for multiple systemic disorders, whether development of these disorders is causal or casual has not been determined. To minimize the loss of residual alveolar ridges, exemplary complete denture therapy, along with the establishment of routine recall systems, should be the ultimate goal of treatment of this patient cohort.
20127436 [Chlorambucil treatment of Behçet's syndrome. Retrospective evaluation of two cases]. 2010 Jan BACKGROUND: Behçet's syndrome rarely occurs in North America and Central Europe (incidence: 1 : 500,000), whereas it is more frequently seen in Japan and Mediterranean countries (incidence: 1 : 10,000). The diagnosis is based on the detection of symptoms and clinical signs. Orogenital aphthosis, anterior and posterior uveitides that frequently cause loss of vision are considered to be primary symptoms. Dermatologic manifestations, i.e., erythema nodosum, vascular lesions (angio-Behçet's syndrome), gastrointestinal ulcers and neurologic involvement, can be observed. HLA B5 is found in some of the patients with Behçet's syndrome. Administration of chlorambucil, a cytotoxic compound, is an effective form of treatment of symptoms and complications of Behçet's syndrome. CASE REPORTS: The present article describes the course of a female and a male patient who were 39 and 23 years old when Behçet's syndrome was diagnosed for the first time. Treatment with chlorambucil was started in the early 1990s and continued for a period of 9 1/2 and 3(3/4) years, respectively, with the symptoms remitting during and after this therapy. Approximately 10 years after the start of treatment with chlorambucil, the patients' symptoms changed. The female patient who was first diagnosed having Behçet's syndrome at the age of 39 years developed rheumatoid arthritis with joint destruction. Her symptoms could be controlled in the long term by oral administration of prednisone, at doses below the Cushing threshold combined with methotrexate. The male patient who was first diagnosed having Behçet's syndrome at the age of 23 years developed systemic vasculitis remitting during low-dose treatment with prednisone. CONCLUSION: Immunosuppressive therapy with chlorambucil administered over several years often induces remission of Behçet's syndrome. However, both case reports indicate that symptoms can change from Behçet's syndrome to systemic vasculitis or rheumatoid arthritis.
20018068 A comparison of case-only designs for detecting gene x gene interaction in rheumatoid arth 2009 Dec 15 We compare and contrast case-only designs for detecting gene x gene (G x G) interaction in rheumatoid arthritis (RA) using the genome-wide data provided by Genetic Analysis Workshop 16 Problem 1. Logistic as well as novel multinomial and proportional odds models that do not depend on the specification of additive or dominant models for susceptibility loci were applied to the case-only sample. We identified 519 significant interactions (p < 1 x 10-4 in at least one test). All methods detected unique significant interactions; 169 were common to more than one model and only 21 were common to all models. Results emphasize that categorization of the genetic variables and choice of regression model are critical and hugely influential in the identification of G x G. Porportional odds and multinomial methods provide new tools for identification of G x G interactions.
20018015 Elastic-net regularization approaches for genome-wide association studies of rheumatoid ar 2009 Dec 15 The current trend in genome-wide association studies is to identify regions where the true disease-causing genes may lie by evaluating thousands of single-nucleotide polymorphisms (SNPs) across the whole genome. However, many challenges exist in detecting disease-causing genes among the thousands of SNPs. Examples include multicollinearity and multiple testing issues, especially when a large number of correlated SNPs are simultaneously tested. Multicollinearity can often occur when predictor variables in a multiple regression model are highly correlated, and can cause imprecise estimation of association. In this study, we propose a simple stepwise procedure that identifies disease-causing SNPs simultaneously by employing elastic-net regularization, a variable selection method that allows one to address multicollinearity. At Step 1, the single-marker association analysis was conducted to screen SNPs. At Step 2, the multiple-marker association was scanned based on the elastic-net regularization. The proposed approach was applied to the rheumatoid arthritis (RA) case-control data set of Genetic Analysis Workshop 16. While the selected SNPs at the screening step are located mostly on chromosome 6, the elastic-net approach identified putative RA-related SNPs on other chromosomes in an increased proportion. For some of those putative RA-related SNPs, we identified the interactions with sex, a well known factor affecting RA susceptibility.