Autosomal dominant (Beukes) premature degenerative osteoarthropathy of the hip joint maps to an 11-cM region on chromosome 4q35.
Explore the source record for details and available documents.
Chromosomes, Human, Pair 4↗
Biomedical subjects
J Worthington
Publications and source records attributed to J Worthington.
Combined sib-TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis.
Rheumatoid arthritis (RA) is a common disease of unknown aetiology which usually causes progressive destruction of the joints. Familial aggregation, twin studies and segregation analyses suggest that there is a genetic component to RA and the HLA-DRB1 locus in the major histocompatibility complex on chromosome 6 has been shown to be linked to, and associated with, RA susceptibility. It is likely that other genes with weaker effects are also involved, which may be difficult to detect using conventional parametric and non-parametric linkage methods. We have implemented the combined sib-TDT and TDT, in addition to parametric and non-parametric linkage methods, to investigate the candidate genes of the interleukin-1 (IL-1) gene cluster on chromosome region 2q13, since IL-1 is an important cytokine in the control of the inflammatory response that is central to RA pathology. Several tightly linked IL-1 cluster markers yielded suggestive evidence for linkage in the combined TDT in those families in which affected siblings did not share two HLA-DRB1 alleles identical by descent. The evidence was significant in those with severe disease, as assessed by the presence of bone erosions. In contrast, there was no evidence of linkage using non-parametric linkage analysis, but parametric analysis revealed weak evidence of linkage when marker-trait disequilibrium was incorporated into the analysis. The data provide preliminary evidence for linkage of genes of the IL-1 cluster to RA and suggest a possible role for this region in severe erosive disease.
Arthritis, Rheumatoid↗
Absence of association between interleukin 1 alpha and oligoarticular juvenile chronic arthritis in UK patients.
OBJECTIVE: To determine whether interleukin 1 alpha (IL-1alpha) polymorphisms are associated with UK oligoarticular juvenile chronic arthritis (JCA). PATIENTS AND CONTROLS: A well-characterized population of 164 UK Caucasian oligo-JCA patients and a control panel of 173 unrelated healthy UK Caucasian individuals. METHODS: The IL-1alpha promoter mutation at -889 was examined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The cases and controls were also genotyped for an IL-1alpha intronic microsatellite repeat. RESULTS: No association was observed between IL-1alpha polymorphisms and UK oligoarticular JCA patients. In particular, no association between IL-1alpha polymorphisms and chronic anterior uveitis was found. CONCLUSIONS: IL-1alpha is not associated with oligoarticular JCA in UK patients. This differs markedly to findings for IL-1alpha in Norwegian JCA patients.
Adult↗
Integrated microsatellite markers suitable for genetic studies of cytokine genes.
A panel of 13 highly informative dinucleotide repeats which are genetic markers for 17 cytokine genes and receptors is described. The marker panel is designed for use in fluorescence based semi-automated genotyping, with primers designed and labelled such that all 13 markers can be analysed in a single lane of a gel. Cytokine and cytokine receptors have a potential role in many diseases and pathological processes. Evidence suggests that cytokine production in vivo is influenced by polymorphisms within regulatory sequences of these genes. Genetic investigation of disease genes often requires genotyping of very large numbers of individuals. This panel of markers will, therefore, provide a useful tool to those wishing to undertake family-based linkage analysis studies of cytokine genes or large-scale association studies.
Alleles↗
A new polymorphism in the promoter of the interleukin 5 receptor alpha subunit (IL-5RA) gene.
Explore the source record for details and available documents.
Alleles↗
Complement C4B null allele status confers risk for systemic lupus erythematosus in a Spanish population.
Genetic susceptibility to systemic lupus erythematosus (SLE) may vary amongst different populations. In UK patients, genes encoded in the HLA class II (DQA*0501/DRB1*0301) and class III [C4A*Q0 and tumour necrosis factor (TNF) polymorphisms] subregions appear to contribute to disease susceptibility. We have examined HLA-DRB1, C4 and TNF microsatellites in 50 Spanish SLE patients and 48 matched controls. HLA-DRB1*0301 was increased in patients but did not achieve statistical significance (41% vs. 25.5%). C4A*Q0 was not increased in patients, but C4B*Q0 allele frequency was significantly increased compared with the controls (29% vs. 6%; OR: 6.0). TNF c2 microsatellite allele frequency was also increased in SLE patients. The C4B null allele (C4B*Q0) appears to play an important role in SLE susceptibility in the Spanish population.
Alleles↗
Two novel biallelic polymorphisms in the IL-2 gene.
We have detected two novel single nucleotide polymorphisms in the IL-2 gene, at positions -330 and +166 relative to the transcription start site. The +166 change occurs within the leader peptide and does not affect amino acid sequence. The -330 polymorphism has two common alleles, making it an ideal marker for genetic association studies.
5' Untranslated Regions↗
Linkage of cytokine genes to rheumatoid arthritis. Evidence of genetic heterogeneity.
OBJECTIVE: To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis (RA) in affected sibling pair families stratified for specific clinical features. METHOD: Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from: INF alpha, INF gamma, INF beta, IL1 alpha, IL1 beta, IL1R, IL2, IL6, IL5R, IL8R, BCL2, CD40L, NOS3, NRAMP, alpha 1 anti-trypsin, and alpha 1 anti-chymotrypsin, using fluorescence based automated technology. Linkage was examined by defining allele sharing sibling pairs. This was assessed by maximum likelihood-inheritance by descent methods. RESULTS: An increase in allele sharing was seen for IL5R in female sibling pairs (LOD 0.91, p = 0.03), for INF gamma in sibling pairs with an affected male (LOD 0.96, p = 0.03) and most significantly for IL2 in sibling pairs where one or both were persistently seronegative (LOD 1.05, p = 0.02). CONCLUSION: Weak evidence of linkage of RA to IL5R, IFN gamma, and IL2 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease.
Arthritis, Rheumatoid↗
Variation in emergency department use of cervical spine radiography for alert, stable trauma patients.
OBJECTIVE: To, assess the emergency department use of cervical spine radiography for alert, stable adult trauma patients in terms of utilization, yield for injury and variation in practices among hospitals and physicians. DESIGN: Retrospective survey of health records. SETTING: Emergency departments of 6 teaching and 2 community hospitals in Ontario and British Columbia. PATIENTS: Consecutive alert, stable adult trauma patients seen with potential cervical spine injury between July 1, 1994, and June 30, 1995. MAIN OUTCOME MEASURES: Total number of eligible patients, referral for cervical spine radiography (overall, by hospital and by physician), presence of cervical spine injury, patient characteristics and hospitals associated with use of radiography. RESULTS: Of 6855 eligible patients, cervical spine radiography was ordered for 3979 (58.0%). Only 60 (0.9%) patients were found to have an acute cervical spine injury (fracture, dislocation or ligamentous instability); 98.5% of the radiographic films were negative for any significant abnormality. The demographic and clinical characteristics of the patients were similar across the 8 hospitals, and no cervical spine injuries were missed. Significant variation was found among the 8 hospitals in the rate of ordering radiography (p < 0.0001), from a low of 37.0% to a high of 72.5%. After possible differences in case severity and patient characteristics at each hospital were controlled for, logistic regression analysis revealed that 6 of the hospitals were significantly associated with the use of radiography. At 7 hospitals, there was significant variation in the rate of ordering radiography among the attending emergency physicians (p < 0.05), from a low of 15.6% to a high of 91.5%. CONCLUSIONS: Despite considerable variation among institutions and individual physicians in the ordering of cervical spine radiography for alert, stable trauma patients with similar characteristics, no cervical spine injuries were missed. The number of radiographic films showing signs of abnormality was extremely low at all hospitals. The findings suggest that cervical spine radiography could be used more efficiently, possibly with the help of a clinical decision rule.
Adolescent↗
Multipoint analysis of quantitative traits.
Complete multipoint analysis as implemented by MAPMAKER/SIBS was used to identify the chromosomal regions with the strongest evidence of linkage. Three different quantitative sib-pair methods were compared. For each trait the maximum lod/Z score was used to implicate a chromosomal region. For trait Q5, chromosome 5, the analysis was repeated in a second data set to test for replication of the result from the first data set. The initial screen was carried out using complete parental information and the first sibling pair from each nuclear family. The effect of removing the parental genotypes and the use of multiple independent sibs was examined in the second data set for Q5, chromosome 5.
Chromosome Mapping↗
Allelic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles among women with rheumatoid arthritis and systemic lupus erythematosus.
OBJECTIVE: To investigate linkage disequilibrium between HLA-DRB1 disease susceptibility alleles and microsatellite markers close to the prolactin gene, among women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and normal controls. METHODS: DNA from 89 women with RA, 76 women with SLE, and 94 controls was typed for HLA-DRB1 status and D6S422 and D6S285, 2 highly polymorphic microsatellite markers close to the prolactin gene. RA patients were stratified by DRB1*0401 status, and SLE patients were stratified by *0301 status. RESULTS: There was an excess frequency of D6S422*1 among SLE patients with DRB1*0301 (odds ratio [OR] 3.1). The frequency of this allele was also slightly in excess among RA patients with DRB1*0401 (OR 1.9). D6S285*5 was also in excess among female RA patients with DRB1*0401 (OR 3.5), and was slightly increased among female SLE patients with DRB1*0301. None of these alleles were found to be increased among *0401-positive or *0301-positive controls. CONCLUSION: These data indicate that there may be linkage disequilibrium between HLA-DRB1 alleles and microsatellite marker alleles close to the prolactin gene among women with RA and SLE. This suggests the possibility of extended haplotypes encoding for HLA-DRB1 susceptibility and high prolactin production, which contribute to susceptibility to both RA and SLE.
Alleles↗
Variation in ED use of computed tomography for patients with minor head injury.
STUDY OBJECTIVE: To determine the frequency of utilization, yield for brain injury, incidence of missed injury, and variation in the use of computed tomography (CT) for ED patients with minor head injury. METHODS: This retrospective health records survey was conducted over a 12-month period in the EDs at seven Canadian teaching institutions. Included in this review were adult patients who sustained acute minor head injury, defined as witnessed loss of consciousness or amnesia and a Glasgow Coma Scale score of 13 or greater. Data were collected by research assistants who were trained to select cases and abstract data in a standardized fashion according to a resource manual. Subsequently, patient eligibility was reviewed by the study coordinator and principal investigator. RESULTS: Of the 1,699 patients seen, 521 (30.7%) were referred for CT, and 418 (79.8%) of these scans were negative for any type of brain injury. Overall, 105 (6.2%) of these patients sustained acute brain injury, including 9 (.5%) with an epidural hematoma Cochran's Q test for homogeneity demonstrated significant variation between the seven centers for rate of ordering CT (P < .0001), from a low of 15.9% to a high of 70.4%. All five cases of "missed" hematoma occurred at the institutions with the highest and third highest rates of CT use. After controlling for possible differences in case severity and patient characteristics at each hospital, logistic regression analysis revealed that five of seven hospitals were significantly associated with the use of CT (respected odds ratios [OR], .4, .5, .5, 3.2, and 4.7). Three of the centers (two with the highest ordering rates) showed significant heterogeneity in the ordering of CT among their attending staff physicians, from a low of 6.5% to a high of 80.0%. CONCLUSION: There was considerable variation among institutions and individual physicians in the ordering of CT for patients with minor head injury. Although emergency physicians were selective when ordering CT, the yield of radiography was very low at all hospitals. None of the cases of "missed" intracranial hematoma came from the lowest ordering institutions, indicating that patients may be managed safely with a selective approach to CT use. These findings suggest great potential for more standardized and efficient use of CT of the head, possibly through the use of a clinical decision rule.
Adolescent↗
Small fish in a big pond.
Explore the source record for details and available documents.
Arthritis, Rheumatoid↗
TNF microsatellite a2, b3 and d2 alleles are associated with systemic lupus erythematosus.
We have investigated TNF microsatellite polymorphisms in SLE and their association with both HLA class II alleles and disease expression. A total of 91 Caucasoid SLE and 109 matched Caucasoid controls were recruited for this study. TNF microsatellites a, b and d were typed using fluorescent based semi-automated gene scanning. TNF a2, b3 and d2 allele frequencies were significantly increased in the SLE group compared to controls. These alleles were found to be part of an extended HLA-DRB1*0301 haplotype and have previously been associated with high TNF-alpha production. When the SLE group was analyzed according to presentation of certain clinical features, photosensitivity and Raynaud's phenomenon, the frequency of these alleles (TNF a2, b3 and d2) were also significantly increased. No significant increase in the allele frequencies of TNF a2, b3 and d2 was demonstrated in the group of patients with renal involvement. These data suggest that TNF microsatellite alleles are not independent of HLA associations in SLE and may be important in the expression of certain clinical features in SLE.
Alleles↗
Investigation of candidate disease susceptibility genes in rheumatoid arthritis: principles and strategies.
It has been estimated that a number of non-HLA susceptibility loci exist in rheumatoid arthritis (RA), each making relatively small contributions (lambda s < 2). Previous approaches for whole genome screening are unlikely to be sufficiently sensitive to detect such loci. As the pathology of RA already indicates several molecules that may be of potential importance in disease susceptibility, we propose an alternative approach, targeting candidate genes directly. Highly polymorphic dinucleotide markers within a candidate gene sequence or close to the gene can be used as markers, and the selection of the most appropriate markers is discussed. RA sibling pair families from the Arthritis and Rheumatism Council National Repository (n = 200) are used in linkage analysis studies. The data generated are analyzed using sib pair analysis methods to examine evidence of linkage. The interpretation of such results is also discussed, in particular, minimizing the possibility of type I errors, and the interpretation of negative results.
Arthritis, Rheumatoid↗
The sensitivity of different analytical methods to detect disease susceptibility genes in rheumatoid arthritis sibling pair families.
Our aim was to compare the sensitivity of 4 analytical methods to detect linkage to a known disease susceptibility locus, HLA-DRB1, in 100 rheumatoid arthritis sibling pair families with incomplete parental genotype information. Genotypes for the HLA-DRB1 and HLA-A loci were analyzed using (1) identity-by-descent (IBD), considering inheritance of maternal and paternal alleles separately; (2) maximum likelihood score-IBD (MLS-IBD), which infers missing parental genotypes; (3) identity-by-state (IBS), which does not require parental genotypes; and (4) transmission disequilibrium test (TDT), which uses affected offspring with a heterozygous parent. Due to the small number of informative meoisis for HLA-DRB1, the IBD analysis was not significant for linkage (p = 0.014). HLA-A was more informative (p = 0.0002). The MLS-IBD method for HLA-DRB1 (p = 0.00004) and HLA-A (p < or = 0.00001) was significant. Using IBS both loci gave highly significant evidence of linkage, (p < < 0.00001). The TDT detected HLA-DRB1*0401 as the allele associated with RA; no HLA-A allele was associated. Thus, sib pair families with limited parental genotypes can be used to detect disease susceptibility loci, but when selecting the method of analysis the informativeness of the markers should be taken into account.
Arthritis, Rheumatoid↗
Tumor necrosis factor microsatellite haplotypes are different in male and female patients with RA.
We investigated whether tumor necrosis factor (TNF) microsatellite polymorphisms are associated with sex and age at disease onset in rheumatoid arthritis (RA). A case-control study was used to compare the frequencies of TNF microsatellite alleles in 181 Caucasian RA cases and 251 controls. TNF microsatellite genotyping was performed using fluorescent based polymerase chain reaction (PCR) techniques and HLA-DR typing using PCR based sequence specific oligonucleotide probing. The association of TNF microsatellite alleles a6, b5, and d4 with RA was confirmed. These polymorphisms were more frequent in female patients. Male patients with RA with young age at onset had a different TNF microsatellite profile, TNFa2, b1, and c2 being the most frequent. TNF microsatellite polymorphisms are different in male and female patients with RA. This difference was more obvious in patients stratified according to age at onset. Sex and age at onset should be considered in studies of genetic factors in RA.
Adult↗