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Biomedical subjects

R Donn

Publications and source records attributed to R Donn.

At least 19 recordsLinked to original sources
PubMed2006

Association of HLA-DRB1*13 with susceptibility to uveitis in juvenile idiopathic arthritis in two independent data sets.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease of childhood. Uveitis is the commonest eye complication of JIA, potentially leading to eye surgery and/or visual loss. JIA is a complex genetic trait with well-established HLA-DRB1 associations. The aim of this study was to investigate the involvement of HLA-DRB1 in JIA-associated uveitis. METHODS: A set of 130 UK Caucasian simplex families consisting of healthy parent(s) and a child affected with juvenile oligoarticular idiopathic arthritis (of which 31 had developed uveitis) had previously been screened for multiple markers in the major histocompatibility complex region. Associations with uveitis were investigated through haplotype pattern mining (HPM) and the extended transmission disequilibrium test (ETDT). A further set of 228 UK Caucasian patients with long-standing JIA were fully genotyped for HLA-DRB1 using PCR with sequence-specific primers. Associations of HLA-DRB1 alleles in patients with uveitis (n = 50) were examined individually using the chi 2 test. RESULTS: In the first cohort, HPM identified significant associations of HLA-DRB1*13 with uveitis in juvenile oligoarthritis (P = 0.002). The ETDT confirmed overtransmission of this allele in the families (empirical global P = 0.018). In the second cohort, the significant association of uveitis with HLA-DRB1*13 was replicated (P = 0.0002, odds ratio 3.4, 95% confidence interval 1.7-6.5). CONCLUSIONS: This study has established the HLA-DRB1*13 association with uveitis in JIA. Further work is necessary in order to explore the prognostic potential of this marker.

Alleles↗
PubMed2005

The type 1 diabetes susceptibility gene SUMO4 at IDDM5 is not associated with susceptibility to rheumatoid arthritis or juvenile idiopathic arthritis.

OBJECTIVES: Linkage and association of rheumatoid arthritis (RA) and rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) has previously been demonstrated to the type 1 diabetes (T1D) locus, IDDM5, on chromosome 6q25. An association of a methionine-to-valine polymorphism (rs237025, 163A --> G, M55V) in the SUMO4 gene within IDDM5 has recently been described in T1D. The objective of this study was to test the hypothesis that SUMO4 is a general autoimmune susceptibility gene by investigating whether the SUMO4 polymorphism is associated with RA and/or JIA. METHODS: The SUMO4 SNP was genotyped in 875 RA patients, 668 JIA patients and 484 healthy controls using a TaqMan allelic discrimination assay. Allele and genotype frequencies were compared between cases and controls using the chi2 test. Analyses were also carried out with RA patients stratified by gender, age at onset, RF status, the presence of erosive disease and shared epitope status, while JIA patients were stratified by their International League of Associations for Rheumatology (ILAR) subgroup. RESULTS: No deviation from Hardy-Weinberg equilibrium was detected in either set of cases or controls. No association was observed between rs237025 and RA (chi2 = 0.17, P = 0.93), or with any RA subset. Similarly, there was no association between this SNP and JIA (chi2 = 0.21, P = 0.90), or with any ILAR subgroup. CONCLUSIONS: The M55V substitution in the SUMO4 gene is not associated with susceptibility to RA or JIA in the UK population studied. However, other candidate genes mapping within IDDM5 remain to be investigated.

Aged↗
PubMed2004

Toll-like receptor 4 gene polymorphisms and susceptibility to juvenile idiopathic arthritis.

OBJECTIVES: To determine if polymorphisms within the Toll-like receptor 4 (TLR4) gene are associated and linked with juvenile idiopathic arthritis (JIA). To investigate any possible gene-gene (epistatic) interaction between TLR4 and macrophage migration inhibitory factor (MIF) gene polymorphisms. METHODS: 313 simplex families (each containing one affected JIA proband) were genotyped. Two known functionally important single nucleotide polymorphisms (SNPs) within the TLR4 gene (Asp299Gly and Thr399Ile) were typed by SNaPshot ddNTP primer extension and capillary electrophoresis. Single point and multipoint transmission disequilibrium tests (TDT) were carried out through the extended TDT and TDT phase packages for the two TLR4 SNPs. Epistatic interaction between TLR4 haplotypes and the previously JIA associated MIF CATT(7)-MIF-173*C promoter haplotype was investigated by chi(2) test and unconditional logistic regression in Stata version 7. RESULTS: No distortion from random inheritance was observed by single point analysis for TLR4 Asp299Gly (p = 0.89) or TLR4 Thr399Ile (p = 0.40). Similarly, no distortion in transmission was seen when the TLR4 haplotypes were studied (p = 0.54). Additionally, no evidence for gene-gene interaction between TLR4 polymorphisms and the previously associated MIF gene polymorphisms was found (p = 0.40). CONCLUSIONS: No linkage or association was seen for Asp299Gly or Thr399Ile SNPs of TLR4 with JIA susceptibility. No evidence of an epistatic interaction between these TLR4 polymorphisms and MIF polymorphisms was found.

Adolescent↗
PubMed2004

Linkage and association studies of discoidin domain receptor 1 (DDR1) single nucleotide polymorphisms (SNPs) in juvenile oligoarthritis.

OBJECTIVES: Multiple independent juvenile oligoarthritis susceptibility loci have been identified within the major histocompatibility complex (MHC), including HLA-A, HLA-DRB1 and an as yet unlocalized effect in the centromeric class I region. The discoidin domain receptor 1 (DDR1) gene resides within this region and codes for a receptor tyrosine kinase that plays an important role in regulating cell attachment to collagen, chemotaxis, proliferation and matrix metalloproteinase (MMP) production. DDR1 expression in chondrocytes has not been investigated. The objectives of this study were to investigate expression of DDR1 in healthy chondrocytes and to identify linkage and association of this candidate gene with juvenile oligoarthritis. METHODS: A set of 135 simplex juvenile idiopathic arthritis families consisting of one affected child and healthy parent(s) and 199 healthy unrelated individuals were genotyped for six single nucleotide polymorphisms (SNPs) within the DDR1 gene using the primer extension SNaPshot trade mark method. Single-point and multipoint transmission disequilibrium tests were carried out with the ETDT and TDTPHASE packages. Allele frequency comparisons between cases and controls were carried out with the chi(2) test. DDR1 expression was investigated in normal articular cartilage by RT-PCR and immunofluorescence methods. RESULTS: No linkage and association with any of the six SNPs or their haplotypic combinations were observed in the families studied. No significant differences were observed in allele frequencies between patients and controls. DDR1 expression was found in normal articular cartilage by RT-PCR and by immunofluorescence. CONCLUSIONS: The DDR1 SNPs examined are not involved in susceptibility to juvenile oligoarthritis.

Arthritis, Juvenile↗
PubMed2003

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis.

The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)(n) repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years. The MIF-173*C allele (OR 1.7, 95% CI 1.3-2.4, P=1.8 x 10(-4)) and the CATT(7) allele (OR 1.5, 95% CI 1.0-2.1, P=0.02) were found to be associated with increased susceptibility to IP. Furthermore, presence of the haplotype containing both associated polymorphisms was associated with a three-fold increase risk of developing IP. No association with disease severity or activity either at baseline or by 5 years was detected for either of the promoter polymorphisms studied. In conclusion, MIF is a susceptibility gene for the development of IP. The same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk. The promoter polymorphisms of MIF, investigated in this study, do not influence the severity of disease outcome by 5 years.

Adult↗
PubMed2002

Juvenile idiopathic arthritis classified by the ILAR criteria: HLA associations in UK patients.

OBJECTIVE: To determine the HLA associations with juvenile idiopathic arthritis (JIA) and its subgroups as defined by the International League of Associations for Rheumatology (ILAR) classification criteria. METHODS: Five hundred and twenty-one UK Caucasian JIA patients and 537 UK Caucasian controls were typed for HLA class II alleles. Phenotype and haplotype frequencies were compared between all JIA cases and controls and between the seven ILAR-defined JIA subgroups. RESULTS: Three haplotypes (DRB1*08-DQA1*0401-DQB1*0402; DRB1*11-DQA1*05-DQB1*03; DRB1*1301-DQA1*01-DQB1*06) were associated with increased risk and one (DRB1*04-DQA1*03-DQB1*03) with decreased risk of JIA. However, in each case the frequencies also varied between JIA subgroups. CONCLUSION: This study categorically demonstrates that there are multiple HLA class II associations with JIA. It has also, for the first time, defined these associations in the seven different ILAR subgroups in UK JIA cases. Although there are a number of common associations, each ILAR subgroup exhibits different patterns of HLA associations, suggesting that the ILAR classification system does define genetically distinct groups of patients.

Adolescent↗
PubMed2002

Tumour necrosis factor receptor II polymorphism and juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a complex polygenic disorder. The encouraging outcome of anti-tumour necrosis factor (TNF) treatment, as well as serological studies, has implicated TNF and its receptors (TNFRI and TNFRII, or TNFRSF1B) in the pathogenesis of JIA. The purpose of this study was to investigate the exon 6 TNFRII single nucleotide polymorphism (SNP) in a well-defined UK cohort of JIA patients, using case-control association analysis. METHODS: A total of 435 patients, spanning seven JIA subgroups, and 261 healthy individuals were screened for the polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: No significant differences were observed between the SNP allelic or genotypic frequencies of patients and controls, or between JIA subgroups. CONCLUSIONS: This TNFRII exon 6 SNP does not seem to be associated with susceptibility to JIA.

Antigens, CD↗
PubMed2001

Characterization of a prolactin gene polymorphism and its associations with systemic lupus erythematosus.

OBJECTIVE: Hyperprolactinemia is associated with systemic lupus erythematosus (SLE), but the mechanism is unknown. Prolactin is expressed in T lymphocytes and is under the control of an alternative promoter region. We characterized a G/T single-nucleotide polymorphism (SNP) at position -1149 of this promoter and assessed its prevalence in patients with SLE. METHODS: Electrophoretic mobility shift assays (EMSAs) were performed to determine DNA protein complex formation in the prolactin promoter. Transient transfection of reporter gene constructs containing the G/T promoter alleles into the Jurkat T cell line were used to determine transcription activity. Peripheral blood lymphocytes (PBLs) were treated in vitro with phytohemagglutinin (PHA) to determine levels of prolactin messenger RNA (mRNA). RESULTS: EMSAs indicated that binding of a GATA-related transcription factor was altered by the G/T SNP at position -1149. Transient transfection studies in Jurkat cells showed that the G allele consistently produced higher promoter activity. PHA treatment of PBLs in vitro induced a greater increment of prolactin mRNA from patients with the GG(-1149) genotype than from those with the TT(-1149) genotype. Disease association studies in a cohort of SLE patients demonstrated an increased frequency of the prolactin -1149 G allele compared with control subjects. CONCLUSION: We found a functionally significant polymorphism that alters prolactin promoter activity and mRNA levels in the lymphocytes. Altered local prolactin production by immune cells may contribute to disease progression by affecting T cell function.

Alleles↗
PubMed2001

HLA-DRB1 and disease outcome in multiple sclerosis.

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.

Adult↗
PubMed1998

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↗
PubMed1997

A dysfunctional allele of the mannose binding protein gene associates with systemic lupus erythematosus in a Spanish population.

OBJECTIVE: To determine dysfunctional mannose binding protein (MBP) status of Spanish patients with systemic lupus erythematosus (SLE) and to determine whether MBP and complement C4 null alleles contribute in an additive way to SLE susceptibility. METHODS: The frequencies of MBP alleles (characterized by polymorphisms at codon 54 and codon 57 of exon 1) were determined by the amplification refractory mutation system-polymerase chain reaction in 50 Spanish patients with SLE and 49 matched controls. Mutant genotypes for the codon 54 mutation were confirmed using a Ban I restriction enzyme digest method. Complement C4 allotyping was achieved by agarose gel electrophoresis of neuraminidase/carboxypeptidase B digested plasma samples followed by immunofixation and staining. RESULTS: At least one dysfunctional MBP allele, unable to activate complement, was present in 52% of patients with SLE and in 31% of controls (OR = 2.4, 95% CI 1.1-5.6). Complement C4 null alleles (either C4A or C4B) were present in 61% of patients and 43% of controls (OR = 2.1, 95% CI 0.9-4.9). A dysfunctional MBP allele and C4 null allele were present in 41% of patients and 16% of controls (OR = 3.2, 95% CI 1.2-8.1). CONCLUSION: The presence of a dysfunctional MBP allele is a risk factor for developing SLE in this Spanish population and may affect susceptibility in an additive way with C4 null alleles.

Acute-Phase Proteins↗
PubMed1995

HLA-DPB1*0201 is associated with particular clinical features of rheumatoid arthritis.

AIMS: to determine the effect of HLA-DPB1 status on rheumatoid arthritis (RA) susceptibility and disease expression. METHODS: HLA-DPB1 alleles were identified in 158 RA patients and 106 controls using PCR-sequence specific oligonucleotide probing. HLA-DPB1 allele frequencies were compared between patient and control groups and the strength of associations assessed using odds ratios and with 95% confidence intervals (CI). Associations observed in the total RA group were confirmed using a relative predispositional effect (RPE) analysis. RESULTS: an association between DPB1*0201 and RA was observed (OR 1.8, 95% CI 1.0-3.4). By contrast, negative associations were found with DPB1*0301 (OR 0.5, 95% CI 0.3-1.0) and DPB1*1101 (OR 0.06, 95% CI 0.001-0.5). These associations were confirmed using RPE analysis. On further analysis the increase in DPB1*0201 and decrease in DPB1*0301 frequencies in RA was found to be independent of DR4 status. The association of DPB1*0201 with RA appears to be most pronounced in male patients (OR 3.3, 95% CI 1.3-8.3), seronegative patients (OR 2.6, 95% CI 0.9-7.3) those with non-erosive disease (OR 2.6, 95% CI 0.9-7.3) or in patients with high titre antinuclear antibodies (OR 2.4, 95% CI 0.8-7.1). CONCLUSIONS: HLA-DPB1 alleles may be associated with the pattern of disease expression in certain RA patients and in some cases confer protection against disease.

Adult↗
PubMed1991

Distribution of type X collagen mRNA in normal and osteoarthritic human cartilage.

The function of collagen X, a unique homotrimer synthesised by hypertrophic chondrocytes, is not known but its localisation and transient expression at sites of calcification suggest that it is likely to be associated with events in the early stages of endochondral bone formation. Osteoarthritis (OA) is a disorder characterised by new bone formation but the role of type X collagen in its pathogenesis is unclear. A 700-bp restriction fragment encoding most of the C-terminal non-collagenous domain and part of the 3'-untranslated region of the human collagen X gene has been used for in situ hybridisation studies on human OA joints removed from hip and knee replacement operations and the results compared with immunohistochemical localisation of type X collagen gene product. Collagen X gene expression was detected in chrondrocytes present in OA tissue in areas where there appeared to be a re-initiation of the endochondral bone formation process including osteophytes and areas of subchondral bone sclerosis.

Antibody Specificity↗