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Biomedical subjects

A G Wilson

Publications and source records attributed to A G Wilson.

At least 19 recordsLinked to original sources
PubMed2006

The Genetics of Generalized Osteoarthritis (GOGO) study: study design and evaluation of osteoarthritis phenotypes.

PURPOSE: The primary goal of the Genetics of Generalized Osteoarthritis (GOGO) study is to identify chromosomal regions associated with increased susceptibility to generalized osteoarthritis (OA). Here we describe the study design and phenotype of the 2728 participants from the 1145 families recruited for this study. METHODS: GOGO is an investigator-initiated collaboration involving seven clinical academic sites and sponsored by GlaxoSmithKline. Family ascertainment was carried out between 1999 and 2002. A qualifying family required self-reported Caucasian ethnicity and at least two affected siblings with clinical hand OA. We hypothesized that this clinical phenotype would facilitate identification of participants with multijoint radiographic OA (rOA) in and beyond the hand. The "gold standard" case definition, however, was based on rOA (Kellgren-Lawrence grade > or =2) involving > or =3 hand joints distributed bilaterally and including at least one distal interphalangeal joint, with two of the three involved joints within a joint group (distal interphalangeal, proximal interphalangeal, or carpometacarpal). Radiographs of hips, knees and spine were also obtained. Additional siblings and living parents from qualifying families, both affected and unaffected, were invited to participate. RESULTS: A total of 2706 participants had complete clinical and radiological examination data. Of these, 2569 participants met clinical examination criteria for affected status; while 1963 (73%) participants met the prespecified radiographic criteria for affected status. This corresponded to a total of 707 families with at least two affected siblings that met the hand rOA criteria. Of those individuals with rOA of the hand, the frequency of rOA at other sites was highest for the knee (51%) and spine (54%), and less common for the hip (25%). Concordance rates among hand affected siblings were greatest for spine (36%) followed by knee (31%) and hip (9%); a total of 53% of the affected sib pairs were concordant for specific patterns of generalized rOA involving the hand and large joints (knees, hips or spine). CONCLUSIONS: GOGO represents a large multicenter collection of families with multiple joint OA that have been characterized both clinically and radiographically. The GOGO study will employ a comprehensive strategy for genetic screening based upon both qualitative and quantitative radiographic trait analyses, circulating biomarkers in a quantitative trait-based analysis, fine mapping, and candidate gene analysis. This sample should provide sufficient power to detect linkage to OA associated genes.

Adult↗
PubMed2006

Autoantibodies in rheumatoid arthritis: a review.

Emerging insights into the importance of B cells in the pathogenesis of rheumatoid arthritis (RA) as highlighted by the efficacy of B cell depletion is one factor that has contributed to the upsurge of interest in the potential role of autoantibodies both as disease markers and with respect to a pathogenic role. Since the initial description of rheumatoid factor (RF), a large number of both disease-specific and non-specific autoantibodies have been described in patients with RA including antibodies to type II collagen (CII), immunoglobulin binding protein (BiP) and antibodies directed at citrullinated peptides (anti-CCP) and other citrullinated proteins such as vimentin (anti-Sa) . Despite some overlap the serological profile of RA does appear to be distinct from other diseases such as SLE . Although the precise mechanisms responsible for the formation of these antibodies have not been well defined their presence must reflect the interaction between T and B cells believed to be relevant to the pathogenesis of RA. The specificity of the association of such factors as anti-CCP and anti-BiP with RA may reflect unique pathogenic events leading to the processing and presentation of the "cryptic self" . Ease of measurement and stability make autoantibodies attractive diagnostic and prognostic markers particularly in early disease when it may be difficult to distinguish self-limiting synovitis from persistent disease . The purpose of this article is to provide an overview of the current state of knowledge of the spectrum of autoantibodies thus far characterised in individuals with rheumatoid arthritis, and discuss their diagnostic, prognostic and pathogenetic relevance.

Arthritis, Rheumatoid↗
PubMed2006

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases.

The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype-phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (P<0.001) was seen, whereas B-associated transcript (BAT)2 (P<0.001) and leucocyte-specific transcript (LST)1 (P<0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1(*)15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.

Autoimmune Diseases↗
PubMed2006

Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review.

BACKGROUND: Interleukins and cytokines play an important role in the pathogenesis of many solid cancers. Several single nucleotide polymorphisms (SNPs) identified in cytokine genes are thought to influence the expression or function of these proteins and many have been evaluated for their role in inflammatory disease and cancer predisposition. The aim of this study was to evaluate any role of specific SNPs in the interleukin genes IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 in predisposition to breast cancer susceptibility and severity. METHODS: Candidate single nucleotide polymorphisms (SNPs) in key cytokine genes were genotyped in breast cancer patients and in appropriate healthy volunteers who were similar in age, race and sex. Genotyping was performed using a high throughput allelic discrimination method. Data on clinico-pathological details and survival were collected. A systematic review of Medline English literature was done to retrieve previous studies of these polymorphisms in breast cancer. RESULTS: None of the polymorphisms studied showed any overall predisposition to breast cancer susceptibility, severity or to time to death or occurrence of distant metastases. The results of the systematic review are summarised. CONCLUSION: Polymorphisms within key interleukin genes (IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 do not appear to play a significant overall role in breast cancer susceptibility or severity.

Aged↗
PubMed2006

Cytokine pharmacogenetics.

Genetic variation plays a significant role in the normal functioning of the immune system, and also in the interaction between many common drugs and cellular pathways. With a growing number of cytokine-based therapies now in mainstream clinical use, the prospect of targeting these agents to the individuals likely to benefit from them most is an appealing one. This review outlines the potential clinical impact of cytokine pharmacogenetics in targeting these therapies to individuals with favourable genetic profiles. The use of such approaches may have important pharmacoeconomic benefits and lead to improved therapeutic profiles for these treatments.

Animals↗
PubMed2005

Antiferritin antibodies discovered by phage display expression cloning are associated with radiographic damage in rheumatoid arthritis.

OBJECTIVE: Several autoantibodies have been described in individuals with rheumatoid arthritis (RA), leading to interest in the use of such antibodies as diagnostic or prognostic markers in RA as well as in their relevance to disease pathology. The objective of this study was to use a phage display expression cloning system to identify novel autoantibody targets in RA. METHODS: We used immunoscreening of a phage-displayed complementary DNA (cDNA) library to isolate a cDNA clone encoding the ferritin heavy chain polypeptide. Antiferritin antibody levels in patients with early and established RA, healthy controls, and disease controls were measured by enzyme-linked immunosorbent assay. Antibody-positive and antibody-negative individuals were compared with respect to disease severity as measured by the modified Larsen score, demographic variables, rheumatoid factor status, and carriage of HLA-DRB1 shared epitope alleles. RESULTS: Antiferritin antibodies were present in 60 (16%) of 366 patients with established RA, 23 (19%) of 118 patients with early RA, 2 (2.7%) of 73 healthy blood donors, 2 (2.1%) of 94 individuals with osteoarthritis, and 2 (2.1%) of 97 patients with systemic lupus erythematosus (P < 0.01, RA patients versus healthy and disease controls). Antiferritin antibodies were more common in men than in women (28.4% versus 12.2%; P < 0.001), and antiferritin levels were associated with the severity of joint damage (P = 0.01). CONCLUSION: Antiferritin antibodies are observed in a subset of patients with RA, are present early in the disease course, and are associated with the severity of radiographic damage. Further studies are required to explore their potential as diagnostic and prognostic markers in RA.

Adult↗
PubMed2004

Articular hypermobility is a protective factor for hand osteoarthritis.

OBJECTIVE: Very few studies have evaluated the association of articular hypermobility and radiographic osteoarthritis (OA) in humans. We assessed hypermobility and its relationship to radiographic hand OA in a family-based study. METHODS: A total of 1,043 individuals were enrolled in the multicenter Genetics of Generalized Osteoarthritis study, in which families were required to have 2 siblings with radiographic OA involving >/=3 joints (distributed bilaterally) of the distal interphalangeal (DIP), proximal interphalangeal (PIP), or carpometacarpal (CMC) joint groups, and OA in at least one DIP joint. Radiographic OA was defined as a score of >/=2 on the Kellgren/Lawrence scale in one or more joints within the group. The Beighton criteria for assessment of hypermobility were recorded on a 0-9-point scale. Hypermobility was defined as a Beighton score of >/=4, a threshold generally used to establish a clinical diagnosis of joint laxity. A threshold of >/=2 was also evaluated to assess lesser degrees of hypermobility. The Beighton score for the present was calculated based on clinical examination, and that for the past was based on recall of childhood hypermobility in the first 2 decades of life. The association of hypermobility and radiographic OA of the PIP, CMC, and metacarpophalangeal joints was evaluated in all participants and in men and women separately. Multiple logistic regression was used to examine the relationship of hypermobility with radiographic OA in each joint group, after adjusting for age and sex. The association of hypermobility and DIP OA was not evaluated, because evidence of DIP OA was required for study inclusion. RESULTS: Using a threshold Beighton score of 4, 3.7% of individuals were classified as hypermobile based on the present examination, and 7.4% were classified as hypermobile based on the past assessment. A significant negative association between present hypermobility and age was observed. In persons with hypermobility, the odds of OA in PIP joints was lower (for present, odds ratio [OR] 0.34, 95% confidence interval [95% CI] 0.16-0.71; for past, OR 0.43, 95% CI 0.24-0.78). Similar results were obtained using a threshold Beighton score of 2. The lower odds of PIP OA with hypermobility were significant after adjusting for sex and age (for present, OR 0.44, 95% CI 0.20-0.94; for past, OR 0.48, 95% CI 0.26-0.87). CONCLUSION: This study demonstrated a joint-protective effect of hypermobility for radiographic OA of PIP joints. In contrast to previous studies showing an association of hypermobility and CMC OA, in this cohort there was no evidence for increased odds of OA in any joint group of the hand in association with articular hypermobility.

Adult↗
PubMed2003

Notch4, a non-HLA gene in the MHC is strongly associated with the most severe form of alopecia areata.

Alopecia areata (AA) is a disorder primarily affecting the hair and nails in which associated autoimmune or atopic disease is common. Genetically, it is a complex trait with evidence of a role for genes of the major histocompatibility complex (MHC), the interleukin-1 cluster and chromosome 21 in the pathogenesis. The strongest association is with HLA class II alleles, although whether this indicates a direct contribution to the pathogenesis or results merely from linkage disequilibrium with nearby disease genes is unknown. Notch4 is a recently defined gene in the HLA class III region. Notch signalling is a direct determinant of keratinocyte growth arrest and entry into differentiation. A possible role for Notch in hair growth has been indicated by transgenic mouse findings that activation of the Notch pathway in the hair cortex leads to aberrant differentiation of adjacent hair-shaft layers. Notch4 is therefore a plausible candidate gene for AA. We have examined two polymorphisms in the coding sequence of the Notch4 gene at positions +1297 and +3063 in a case-control study of 116 AA patients and 142 ethnically matched, healthy control subjects. The initial analysis showed a significant association of AA in the overall data set with the Notch4(T+1297C) polymorphism (P<0.001) but not with Notch4(A+3063G). To confirm this association, we genotyped an additional 62 patients and found that the risk for disease was higher in Notch4(+1297C) homozygotes [odds ratio (OR) 3.43 (1.63, 7.19)] than in heterozygotes [OR 2.58 (1.57, 4.24)]. On classifying the patients by severity of disease, the association appeared to be confined to the severest form (alopecia universalis) [OR 4.02 (1.64, 9.88), P=0.0014]. These results support previous findings showing that different HLA susceptibility alleles are associated with mild and severe AA.

Alleles↗
PubMed2003

Identification of novel single nucleotide polymorphisms within the NOTCH4 gene and determination of association with MHC alleles.

Mapping of disease susceptibility loci within the MHC has been partly hampered by the high degree of polymorphism of the HLA genes and the high level of linkage disequilibrium (LD) between markers within the MHC region. It is therefore important to identify new markers and determine the level of LD between HLA alleles and non-HLA genes. The NOTCH4 gene lies at the centromeric end of the MHC class III region, approximately 335 kb telomeric of the DRB1 locus. The encoded protein is an oncogene that is important in regulating vascular development and remodelling. A recent report has linked polymorphisms within NOTCH4 with risk of developing schizophrenia. We have investigated if coding polymorphisms exist within this gene and have identified three single nucleotide polymorphisms; a synonomous T to C transition at +1297 (HGBASE accession number SNP000064386), a synonomous A to G transition at +3061 (SNP000064387) and an A to G transition at +3063 which results in a replacement of glycine with aspartic acid at amino acid 279 (SNP000064388). The allele frequencies of +1297T, +3061A and +3063G were 0.65, 0.66 and 0.66, respectively. Linkage disequilibrium was detected both between these markers and with MHC alleles. These findings can be used in the fine mapping of disease susceptibility alleles within the MHC.

Humans↗
PubMed2002

Association between two tumour necrosis factor intronic polymorphisms and HLA alleles.

The gene for tumour necrosis factor (TNF) lies at the telomeric end of the class III region of the major histocompatibility complex (MHC). Polymorphisms within this gene have been implicated in the genetic background of a large number of common human diseases. Recently two polymorphisms, TNF +489 and +691, have been described in the first intron of TNF (+489, G to A transition; +691, G deletion) and disease associations have been reported; however, the pattern of linkage disequilibrium with other MHC alleles has not been studied. We have therefore studied the association of TNF alleles with HLA-DR, -DQ and -B alleles in 216 healthy individuals from the north of England. The frequencies of the uncommon alleles were 0.08 (+489A) and 0.05 (+691Gdel). The +489A allele is associated with carriage of DRB1*1104, DQB1*0301, B18 and B35. The +691Gdel allele is associated with carriage of DRB1*13 *11, DQB1*0301 and B44. Knowledge of the pattern of association, indicating probable linkage disequilibrium, between these TNF alleles may be useful in studies aimed at determining the role of this locus in the genetic background of the large number of diseases which show genetic associations with MHC haplotypes.

England↗
PubMed2002

Toll-like receptors: their role in allergy and non-allergic inflammatory disease.

The human TLRs comprise an important and interesting group of receptors that regulate pathogen-related responses, and play as yet uncharacterized roles in the amplication of sterile inflammation. Signalling through these receptors, which are powerfully coupled in gene transcription processes, has powerful immunostimulatory and immunomodulatory effects. Exploitation of TLR signalling will probably lead to novel effective therapies for allergic disease, in the first instance through more efficient mechanisms of immunotherapy. The likelihood of adverse consequences of such treatments, though possible, may be minimized by use of conjugated vaccines.

Animals↗
PubMed2001

A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease.

Human Toll-like receptor 4 (TLR4) transduces proinflammatory cytokine release by human cells in response to lipopolysaccharide (LPS). This study tested the hypothesis that, if TLR4 is rate limiting for a successful response to bacterial LPS in humans, a human gene polymorphism that results in the amino acid substitution Asp299Gly and causes reduced expression and function of TLR4 should influence susceptibility to or severity of natural gram-negative infection. The allele frequency of the Asp299Gly polymorphism was 5.9% among 879 blood donors, 6.5% among 1047 patients with microbiologically proven meningococcal disease, and 4.1% among 86 patients who died of meningococcal disease. No significant differences were observed, including those analyzed after stratification of the infected population by age and by meningococcal serogroup. Therefore, this functional TLR4 polymorphism does not influence susceptibility to or severity of meningococcal disease.

Adolescent↗
PubMed2001

Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma.

PURPOSE: To determine the incidence and frequency of the Bcl-2/IgH rearrangement in the peripheral blood of normal individuals to define the potential complication this may pose for the molecular monitoring of disease in patients with follicular lymphoma (FL). MATERIALS AND METHODS: The incidence and frequency of the major breakpoint cluster region rearrangement in DNA extracted from peripheral blood or lymphoblastoid cell lines from 481 normal individuals was determined using a TaqMan real-time polymerase chain reaction assay (PE Applied Biosystems, Foster City, CA). RESULTS: Twenty three percent of samples were positive for the Bcl-2/IgH rearrangement, with approximately 3% of these at levels of more than 1 in 10(4) cells. CONCLUSION: The presence of circulating Bcl-2/IgH+ cells, other than those derived from the malignant clone, could confound the detection and quantitation of minimal residual disease in patients with FL, particularly at low levels of tumor burden.

Adult↗
PubMed2001

A candidate gene analysis of three related photosensitivity disorders: cutaneous lupus erythematosus, polymorphic light eruption and actinic prurigo.

BACKGROUND: Polymorphic light eruption (PLE) is a common inherited photosensitivity disorder, which may predispose to several related but distinct conditions, including subacute cutaneous lupus erythematosus (SCLE), discoid lupus erythematosus (DLE) and actinic prurigo (AP). OBJECTIVES: To examine specific candidate genes for shared susceptibility alleles between these related phenotypes. METHODS: Eighty-five caucasian patients with annular SCLE or DLE were recruited, in addition to 102 first-degree relatives. The prevalence of PLE in both the patient and relative groups was determined by detailed interview and clinical examination. Eighty-five patients with pure PLE and 59 patients with AP were also recruited. Candidate genes were analysed by typing of single nucleotide polymorphisms of IL10 (-1082 G/A and -819 C/T), FCGR2A (131 R/H), SELE (128 S/R), ICAM1 (241 G/R and 469 E/K), IL1A (+ 4845 G/T), IL1B (-511 C/T and + 3954 C/T), IL1RN (+ 2018 T/C) and TNF (-308 G/A) using polymerase chain reaction (PCR) with sequence-specific primers and 5'-nuclease PCR. RESULTS: A significant association was found between SCLE and the rare TNF -308 A allele when compared with patients with DLE (P = 0.043), PLE (P = 0.001), AP (P < 0.001) and healthy controls (P < 0.001). However, there was strong linkage disequilibrium between TNF -308 A and the HLA A*01, B*08, DRB1*0301 haplotype. A negative association was also found between SCLE and the IL1B + 3954 T allele (P = 0.039), but the significance was lost on correction for multiple testing. CONCLUSIONS: We have demonstrated the association of SCLE with the rare TNF -308 A allele, which may be pathogenic or, alternatively, a marker allele for the extended HLA A*01, B*08, DRB1*0301 haplotype that is associated with a number of autoimmune conditions. Although many of the other loci that we chose failed to demonstrate an association, a candidate gene approach remains the most logical one, and the most likely to yield positive results in the future.

Alleles↗
PubMed2001

Expression and activity of ADAMTS-5 in synovium.

ADAMTS proteinases, belonging to the adamalysin subfamily of metalloproteinases, have been implicated in a variety of cellular events such as morphogenesis, cell migration, angiogenesis, ovulation and extracellular matrix breakdown. Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) have been identified in cartilage and are largely responsible for cartilage aggrecan breakdown. We have shown previously that synovium, the membrane lining diarthrodial joints, generates soluble aggrecanase activity. We report here the expression, localization and activity of ADAMTS-5 from human arthritic and bovine synovium. ADAMTS-5 was expressed constitutively in synovium with little or no transcriptional regulation by recombinant human interleukin-1 alpha or all-trans-retinoate, factors previously shown to upregulate aggrecanase activity in cartilage. Aggrecanase activity generated by synovium in vitro and recombinant ADAMTS-5 cleaved aggrecan extensively, resulting in aggrecan fragments similar to those generated by chondrocyte-derived aggrecanases, and the activity was inhibited by heparin. ADAMTS-5 was immunolocalized in human arthritic synovium, where staining was mostly pericellular, particularly in the synovial lining and around blood vessels; some matrix staining was also seen. The possibility that synovium-derived ADAMTS-5 may play a role in cartilage aggrecan breakdown is discussed.

ADAM Proteins↗
PubMed2001

Maximizing use of the emergency department observation unit: a novel hybrid design.

STUDY OBJECTIVE: We sought to determine whether sharing an observation unit with scheduled procedure patients would maintain a more consistent unit census and patient/nurse ratio. A secondary objective was to determine the effect of this model on patient length of stay and discharge rates. METHODS: This retrospective, descriptive study was conducted in a high-volume suburban teaching hospital, using a "before-and-after" study design. A "pure" postprocedure unit became a "hybrid" observation postprocedure unit by displacing specific postprocedure patients to inpatient locations. Subsequently, the displaced patients were returned to the unit. On weekends, the unit operated as a pure observation unit. Hourly unit occupancy and census data were prospectively collected, and hourly patient/nurse ratios were calculated. Patient length of stay and discharge data were collected and compared in different settings. RESULTS: The 2 services showed a complementary census pattern that allowed the hybrid unit to maintain an average hourly patient/nurse ratio of 3.7 compared with the ratio of 2.5 for a pure observation unit. There was no difference in observation patient length of stay (14.8 hours versus 14.7 hours) or discharge rate (20.4% versus 18.1%) between weekdays and weekends. However, scheduled procedure patients experienced significantly shorter lengths of stay in the hybrid unit setting (4.3 hours) than in alternative inpatient locations (9.4 hours). CONCLUSION: The hybrid model showed better hourly census and nurse resource use rates, with no adverse effect on observation patients. However, scheduled procedure patient length of stay was shorter in this setting.

Bed Occupancy↗