Progress in spondylarthritis. Progress in studies of the genetics of ankylosing spondylitis

The advent of high-throughput SNP genotyping methods has advanced research into the genetics of common complex genetic diseases such as ankylosing spondylitis (AS) rapidly in recent times. The identification of associations with the genes IL23R and ERAP1 have been robustly replicated, and advances have been made in studies of the major histocompatibility complex genetics of AS, and of KIR gene variants and the disease. The findings are already being translated into increased understanding of the immunological pathways involved in AS, and raising novel potential therapies. The current studies in AS remain underpowered, and no full genomewide association study has yet been reported in AS; such studies are likely to add to the significant advances that have already been made.

Non-major-histocompatibility-complex genetics of ankylosing spondylitis

There is strong evidence from twin and family studies indicating that a substantial proportion of the heritability of susceptibility to ankylosing spondylitis (AS) and its clinical manifestations is encoded by non-major-histocompatibility-complex genes. Efforts to identify these genes have included genomewide linkage studies and candidate gene association studies. One region, the interleukin (IL)-1 gene complex on chromosome 2, has been repeatedly associated with AS in both Caucasians and Asians. It is likely that more than one gene in this complex is involved in AS, with the strongest evidence to date implicating IL-1A. Identifying the genes underlying other linkage regions has been difficult due to the lack of obvious candidates and the low power of most studies to date to identify genes of the small to moderate magnitude that are likely to be involved. The field is moving towards genomewide association analysis, involving much larger datasets of unrelated cases and controls. Early successes using this approach in other diseases indicates that it is likely to identify genes in common diseases like AS, but there remains the risk that the common-variant, common-disease hypothesis will not hold true in AS. Nonetheless, it is appropriate for the field to be cautiously optimistic that the next few years will bring great advances in our understanding of the genetics of this condition.

Progress in the genetics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthropathy. In addition to being strongly associated with HLA-B27, a further 13 genes have been robustly associated with the disease. These genes highlight the involvement of the IL-23 pathway in disease pathogenesis, and indicate overlaps between the pathogenesis of AS, and of inflammatory bowel disease. Genetic associations in B27-positive and -negative disease are similar, with the main exception of association with ERAP1, which is restricted in association to B27-positive cases. This restriction, and the known function of ERAP1 in peptide trimming prior to HLA Class I presentation, indicates that HLA-B27 is likely to operate in AS by a mechanism involving aberrant peptide handling. These advances point to several potential novel therapeutic approaches in AS.

Genetics of ankylosing spondylitis

Ankylosing spondylitis is a common inflammatory rheumatic disease. Both susceptibility to and clinical manifestations of the disease are highly heritable. Although some genes, notably HLA-B27, have been implicated in susceptibility to the disease, the genetics of the condition are complex and many more genes involved in the condition await discovery.

Genetics of ankylosing spondylitis and rheumatoid arthritis: Where are we at currently, and how do they compare?

Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are common, highly heritable conditions, the pathogenesis of which are incompletely understood. Gene-mapping studies in both conditions have over the last couple of years made major breakthroughs in identifying the mechanisms by which these diseases occur. Considering RA, there is an over-representation of genes involved in TNF signalling and the NFκB pathway that have been shown to influence the disease risk. There is also considerable sharing of susceptibility genes between RA and other autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, autoimmune thyroid disease and celiac disease, with thus far little overlap with AS. In AS, genes involved in response to IL12/IL23, and in endoplasmic reticulum peptide presentation, have been identified, but a full genomewide association study has not yet been reported.

The genetics of osteoporosis: Future diagnostic possibilities

The risk of developing osteoporosis is determined by the interaction of several mostly unknown genes and environmental factors. Genetic studies in osteoporosis have largely focussed on association studies of a small number of candidate genes, with few linkage studies performed, and large areas of the genome remaining unexplored. Identifying the genes involved in osteoporosis would be a major advance in our understanding of the causation of the disease, and lead to advances in diagnosis, risk prediction, and potentially preventive and therapeutic measures.

Genetics and the pathogenesis of ankylosing spondylitis

Purpose of review The field of genetic research in ankylosing spondylitis (AS) is advancing rapidly. The purpose of this review is to outline recent findings, particularly, in regard to genetic studies of the major histocompatibility complex (MHC) and the non-MHC genes IL23R, ERAP1, and killer cell immunologlobulin-like receptor (KIR) complex, in AS. Recent findings: Convincing evidence has been reported for the existence of further non-B27 MHC genes involved in AS. Strong, replicated association has been reported with IL23R and ERAP1 and AS. The IL23R finding strongly implicates the TH17 lymphocyte system in AS aetiopathogenesis. Suggestive evidence of a role for KIR gene polymorphism in AS exists, but definitive findings are awaited. Summary: The findings suggest that further genome-wide studies in large case-control cohorts are likely to be very productive in this disease. The IL23R findings and subsequent immunological investigations suggest that targeted intervention in the TH17 system is likely to have major therapeutic benefit, as it does in the genetically related diseases, inflammatory bowel disease and psoriasis.

Genetics of ankylosing spondylitis

Purpose of Review Over the past 3 years, several new genes and gene deserts have been identified that are associated with ankylosing spondylitis (AS). The purpose of this review is to discuss the major findings of these studies, and the answers they provide and questions they raise about the pathogenesis of this common condition. Recent Findings: Five genes/genetic regions have now definitively been associated with AS [the major histocompatibility complex (MHC), IL23R, ERAP1, 2p15 and 21q22]. Strong evidence to support association with the disease has been demonstrated for the genes IL1R2, ANTXR2, TNFSF15, TNFR1 and a region on chromosome 16q including the gene TRADD. There is an overrepresentation of genes involved in Th17 lymphocyte differentiation/activation among genes associated with AS and the related diseases inflammatory bowel disease and psoriasis, pointing strongly to this pathway as playing a major causative role in the disease. Increasing information about differential association of HLA-B27 subtypes with disease suggests a hierarchy of strength of association of those alleles with AS, providing a useful test as to the validity of different potential mechanisms of association of HLA-B27 with AS. The mechanism underlying the association of the gene deserts, 2p15 and 21q22, suggests the involvement of noncoding RNA in AS etiopathogenesis. Summary: The increasing list of genes identified as being definitely involved in AS provides a useful platform for hypothesis-driven research in the field, providing a potential alternative route to determining the underlying mechanisms involved in the disease to research focusing on HLA-B27 alone.

Genetic studies of chondrocalcinosis

Purpose of review Our understanding of the causation of the chondrocalcinosis and other disorders characterized by ectopic mineralization is rapidly increasing, and genetic studies have contributed substantially to recent major advances in the field. This review will discuss what is known about the genetics of chondrocalcinosis and what we have learned from genetic studies to date. Recent findings: Chondrocalcinosis is one of a family of conditions associated with ectopic mineralization. This family also includes disorders of mineralization of bone and spinal and other ligaments, and vascular calcification. There has been increasing evidence of the key role of transport and metabolism of inorganic pyrophosphate (PPi) in control of mineralization, and as the likely explanation for the association of a variety of genetic variants with chondrocalcinosis and ectopic mineralization elsewhere. This may be an overly simplistic view of this family of conditions, with recent evidence suggesting that, for example, ANKH variants may not all predispose to chondrocalcinosis by effects on PPi transport, but may also influence chondrocyte maturation. Summary: Understanding the control of the process of mineralization and its tissue specificity are important steps in the search for rational therapies for these conditions.

Medical Data Access Accountability in EHR Systems, A Practical Perspective

The world has experienced a large increase in the amount of available data. Therefore, it requires better and more specialized tools for data storage and retrieval and information privacy. Recently Electronic Health Record (EHR) Systems have emerged to fulfill this need in health systems. They play an important role in medicine by granting access to information that can be used in medical diagnosis. Traditional systems have a focus on the storage and retrieval of this information, usually leaving issues related to privacy in the background. Doctors and patients may have different objectives when using an EHR system: patients try to restrict sensible information in their medical records to avoid misuse information while doctors want to see as much information as possible to ensure a correct diagnosis. One solution to this dilemma is the Accountable e-Health model, an access protocol model based in the Information Accountability Protocol. In this model patients are warned when doctors access their restricted data. They also enable a non-restrictive access for authenticated doctors. In this work we use FluxMED, an EHR system, and augment it with aspects of the Information Accountability Protocol to address these issues. The Implementation of the Information Accountability Framework (IAF) in FluxMED provides ways for both patients and physicians to have their privacy and access needs achieved. Issues related to storage and data security are secured by FluxMED, which contains mechanisms to ensure security and data integrity. The effort required to develop a platform for the management of medical information is mitigated by the FluxMED's workflow-based architecture: the system is flexible enough to allow the type and amount of information being altered without the need to change in your source code.

Mobile medical applications for melanoma risk assessment: False assurance or valuable tool?

With the smartphone revolution, consumer-focused mobile medical applications (apps) have flooded the market without restriction. We searched the market for commercially available apps on all mobile platforms that could provide automated risk analysis of the most serious skin cancer, melanoma. We tested 5 relevant apps against 15 images of previously excised skin lesions and compared the apps' risk grades to the known histopathologic diagnosis of the lesions. Two of the apps did not identify any of the melanomas. The remaining 3 apps obtained 80% sensitivity for melanoma risk identification; specificities for the 5 apps ranged from 20%-100%. Each app provided its own grading and recommendation scale and included a disclaimer recommending regular dermatologist evaluation regardless of the analysis outcome. The results indicate that autonomous lesion analysis is not yet ready for use as a triage tool. More concerning is the lack of restrictions and regulations for these applications.

Medical free-text to concept mapping as an information retrieval problem

Concept mapping involves determining relevant concepts from a free-text input, where concepts are defined in an external reference ontology. This is an important process that underpins many applications for clinical information reporting, derivation of phenotypic descriptions, and a number of state-of-the-art medical information retrieval methods. Concept mapping can be cast into an information retrieval (IR) problem: free-text mentions are treated as queries and concepts from a reference ontology as the documents to be indexed and retrieved. This paper presents an empirical investigation applying general-purpose IR techniques for concept mapping in the medical domain. A dataset used for evaluating medical information extraction is adapted to measure the effectiveness of the considered IR approaches. Standard IR approaches used here are contrasted with the effectiveness of two established benchmark methods specifically developed for medical concept mapping. The empirical findings show that the IR approaches are comparable with one benchmark method but well below the best benchmark.

Determinants of the citation rate of medical research publications from a developing country

Background The number of citations received by an article is considered as an objective marker judging the importance and the quality of the research work. The present study aims to study the determinants of citations for research articles published by Sri Lankan authors. Methods Papers were selectively retrieved from the SciVerse Scopus® (Elsevier Properties S.A, USA) database for 10 years from 1st January 1997 to 31st December 2006, of which 50% were selected for inclusion by simple random sampling. The primary outcome measure was citation rate (defined as the number of citations during the 2 subsequent years after publication). Citation data was collected using the SciVerse Scopus® Citation Analyzer and self citations were excluded. A linear regression analysis was performed with ‘number of citations’ as the continuous dependent variable and other independent variables. Result The number of publications has steadily increased during the period of study. Over three quarter of papers were published in international journals. More than half of publications were research studies (55.3%), and most of the research studies were descriptive cross-sectional studies (27.1%). The mean number of citations within 2 years of publication was 1.7 and 52.1% of papers were not cited within the first two years of publication. The mean number of citations for collaborative studies (2.74) was significantly higher than that of non-collaborative studies (0.66). The mean number of citations did not significantly change depending on whether the publication had a positive result (2.08) or not (2.92) and was also not influenced by the presence (2.30) or absence (1.99) of the main study conclusion in the title of the article. In the linear regression model, the journal rank, number of authors, conducting the study abroad, being a research study or systematic review/meta-analysis and having regional and/or international collaboration all significantly increased the number of citations. Conclusion The journal rank, number of authors, conducting the study abroad, being a research study or systematic review/meta-analysis and having regional and/or international collaboration all significantly increased the number of citations. However, the presence of a positive result in the study did not influence the citation rate.

Genetics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.