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W Ollier

Publications and source records attributed to W Ollier.

At least 19 recordsLinked to original sources
PubMed2006

Linkage to nodal osteoarthritis: quantitative and qualitative analyses of data from a whole-genome screen identify trait-dependent susceptibility loci.

OBJECTIVE: To identify susceptibility loci for nodal osteoarthritis. METHODS: A genome screen at an average marker spacing of 9.29 cM was carried out on 558 people from 202 families, of whom 491 had nodal osteoarthritis. All genotyped people were graded for the incidence and severity of distal interphalangeal (DIP) nodes, and radiographs from 354 people were graded for joint-space narrowing (JSN) and osteophytes (OSTs). Age-regressed indices for DIP nodes, JSN and OSTs were calculated using these phenotypic data. Affected sibling pair (ASP) and quantitative trait analyses were carried out using MERLIN. RESULTS: The data analysis identified suggestive linkage to loci on chromosomes 3 (for JSN and OST), 4 (for JSN), 8 (for DIP), 11 (for radiographic osteoarthritis) and 16 (for JSN). Both the ASP and quantitative analyses identified the loci on chromosomes 4 and 11. The loci on chromosomes 3 and 16 overlap with those previously identified for large-joint osteoarthritis. Of the loci identified by the quantitative analyses with the logarithm of the odds of linkage >1.5, two were linked to more than one trait, whereas nine were linked to single traits: one for DIP, six for JSN and two for OST. CONCLUSION: The ASP and quantitative analyses of the cohort with nodal osteoarthritis suggest that multiple susceptibility loci for osteoarthritis influence the traits, which combine to form the osteoarthritis phenotype, and that these loci may not act exclusively on the joints of the hand.

Cohort Studies↗
PubMed2006

Rapid cost-effective subtyping of meticillin-resistant Staphylococcus aureus by denaturing HPLC.

The importance of meticillin-resistant Staphylococcus aureus (MRSA) in hospital-acquired infection is widely acknowledged. The UK government has stated that MRSA bloodstream infection rates will have to be halved by 2008. Such radical improvements will require advances on several fronts. Screening for MRSA in high-risk patients on arrival at hospital allows isolation of carriers and reduces transmission to staff and other patients. Concurrent subtyping of MRSA could also inform outbreak investigations and long-term epidemiological studies. The variability within the staphylococcal protein A, or spaA, gene-repeat region can be used as a marker of short- and long-term genetic variation. A novel application is described of denaturing HPLC (DHPLC) for rapid, inexpensive characterization of spaA gene amplification products, without the need for DNA sequence determination. The method allowed rapid and precise sizing of spaA gene-repeat regions from 99 S. aureus strains and was combined with heteroduplex analysis, using reference PCR products, to indicate the spa type of the test isolate. The method allowed subtyping of strains in less than 5 h from receipt of a primary isolation plate. When applied to an outbreak that occurred during this study, the authors were able to demonstrate relatedness of the isolates more than 5 days before results were received from a reference laboratory. If combined with direct amplification from swabs, DHPLC analysis of spaA gene variation could prove extremely valuable in outbreak investigation and MRSA surveillance.

Chromatography, High Pressure Liquid↗
PubMed2006

Influence and interactions of cathepsin D, HLA-DRB1 and APOE on cognitive abilities in an older non-demented population.

Cathepsin D (CTSD), human leukocyte antigen DRB1 (HLA-DRB1) and apolipoprotein E (APOE) have all been associated with cognitive ability in both demented and non-demented individuals. CTSD is a pleiotrophic protein whose functions include the processing of proteins prior to presentation by HLA. Several studies have also reported that a functional exon 2 polymorphism in the CTSD gene interacts with APOEepsilon4 resulting in an increased risk of developing Alzheimer's disease (AD). We have previously reported that the CTSD exon 2 polymorphism regulates fluid intelligence. In this study, we extend this finding to other cognitive domains and investigate interactions with APOE and HLA-DRB1. Using a cohort of 766 non-demented volunteers, we found that the CTSD exon 2 T allele was associated with a decrease in several cognitive domains that comprise processing speed [random letters (RLs) test, P = 0.012; alphabet-coding task (ACT), P = 0.001], spatial recall (SR) (P = 0.016) and an additional test of fluid intelligence (P = 0.010). We also observed that the HLA-DR1 was associated with enhanced cumulative recall ability (P = 0.006), and conversely HLA-DR5 was associated with diminished delayed verbal recall and SR abilities (P = 0.014 and P = 0.003, respectively). When analysed independently, APOEepsilon4 did not influence any cognitive domains. In contrast, CTSD T/APOEepsilon4-positive volunteers scored lower on tests of fluid intelligence (P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall (P = 0.029). Scores were lower for all these tests than when CTSD and APOE were analysed independently. This supports previous findings in AD that have also reported an epistatic interaction. In addition, we found that CTSD T/HLA-DR2-positive volunteers had reduced processing speed (ACT, P = 0.040; RL, P = 0.014) and had significantly lower cumulative and SR abilities (P = 0.003 and P = 0.001, respectively). Biological interaction between these two proteins has previously been shown where HLA-DR2 binds more readily to the myelin basic protein (MBP) compared with other DR antigens, preventing MBP cleavage by CTSD.

Aged↗
PubMed2005

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population.

Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P=0.002, AH2 P=0.014), the test of semantic memory (P=0.010) and general cognitive ability (P=0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly.

Aged↗
PubMed2005

Attention deficit hyperactivity disorder with reading disabilities: preliminary genetic findings on the involvement of the ADRA2A gene.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) and reading disability (RD) tend to co-occur and quantitative genetic studies have shown this to arise primarily through shared genetic influences. However, molecular genetic studies have shown different genes to be associated with each of these conditions. Neurobiological studies have implicated noradrenergic function in the aetiology of ADHD that is comorbid with RD. This paper examines the neurobiological evidence and presents preliminary testing of the hypothesis that the ADRA2A receptor gene is contributing to ADHD and comorbid RD. METHODS: One hundred and fifty-two children (140 boys, 12 girls) of British Caucasian origin, aged between 6 and 13 years and with a diagnosis of ADHD, were recruited. The children's reading ability was tested. Children were identified as having ADHD or ADHD plus RD (n=82). DNA was available for 110 parent child trios and 42 parent child duos. Genotyping was undertaken for an ADRA2A polymorphism. RESULTS: For those with ADHD plus RD there was evidence of association with the alpha 2A adrenergic receptor (ADRA2A) polymorphism with the G allele being preferentially transmitted. CONCLUSIONS: The preliminary evidence together with other neurobiological research findings suggests that the ADRA2A gene may contribute to comorbid ADHD and RD and needs to be properly examined.

Adolescent↗
PubMed2004

Orthopaedic intervention in early rheumatoid arthritis. Occurrence and predictive factors in an inception cohort of 1064 patients followed for 5 years.

OBJECTIVES: To assess the occurrence of and predictive factors for orthopaedic surgery in an inception cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 5 yr in nine regions in England. METHODS: Standard clinical, laboratory and radiological assessments and all interventions were recorded at baseline and yearly in RA patients (less than 2 yrs symptoms) prior to the use of disease-modifying drugs. RESULTS: One thousand and sixty-four patients completed 5 yr of follow-up. Two hundred and sixty-four orthopaedic procedures for RA were performed in 181 (17%) patients at a median of 36.5 months from baseline. Seventy-five (7%) had replacements of major joints. Risk factors at baseline for large joint replacement surgery were a low haemoglobin concentration [odds ratio scores (OR) 3.4, 95% confidence interval (CI) 2.1-5.8] and high scores for erythrocyte sedimentation rate (ESR) (OR 3.2, CI 1.8-5.3), disease activity (DAS) (OR 2.1, CI 1.2-3.5) and Larsen X-rays (OR 2.6, CI 1.4-4.8). For hand or foot joint surgery (4%), risk factors included female gender (OR 3.2, CI 1.3-7.6), joint score (OR 2.3, CI 1.2-4.3), erosions (OR 2.3, CI 1.1-4.8), DAS (OR 2.4, 1.3-4.5) and Health Assessment Questionnaire score (OR 1.9, CI 1.0-3.6). No significant associations were seen for tendon, soft tissue or other minor procedures (6%). The HLA-DRB1 RA shared epitope was associated with any type of orthopaedic surgery (OR 1.7, CI 1.1-2.7). CONCLUSIONS: Eleven per cent of RA patients treated with conventional drug therapy for 5 yr underwent large- or small-joint surgery, an outcome which could be compared against that for new disease-modifying drugs. Risk factors varied according to type of surgery, but included standard clinical and laboratory measures. In order to reduce the eventual need for surgery, a therapeutic target in the first year of RA is the suppression of disease activity, as measured by haemoglobin and ESR. These are useful details for clinicians, health professionals and patients.

Adult↗
PubMed2004

Polymorphisms in the tumour necrosis factor gene are not associated with severity of inflammatory polyarthritis.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a powerful inflammatory mediator in rheumatoid and other types of inflammatory arthritis. Polymorphisms within the TNFalpha gene have previously been investigated to determine their role in the aetiopathogenesis of rheumatoid arthritis (RA), but it is unclear whether reported associations are with susceptibility to, or severity of, disease. OBJECTIVE: To examine the association between both individual TNFalpha single nucleotide polymorphisms (SNPs) and haplotypes with the development and severity of erosions by 5 years in patients with inflammatory polyarthritis (IP). METHODS: 438 patients from the Norfolk Arthritis Register observational inception cohort of patients with IP were x rayed 5 years after disease onset. They were genotyped for nine SNPs mapping to the TNFalpha gene, using a SNaPshot primer extension assay. Haplotypes were constructed in patients with IP, who were compared for the presence and extent of erosions at 5 years. RESULTS: No association between individual TNFalpha SNPs or haplotypes in the patients who developed erosions at 5 years compared with those who remained non-erosive was found. Restricting analysis to patients who satisfied ACR criteria for RA by 5 years did not affect the conclusions. CONCLUSION: The TNFalpha gene does not seem to be associated with severity as assessed by erosive outcome at 5 years in patients with IP.

Arthritis↗
PubMed2002

Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein-Barr virus proteins in oligoarticular juvenile idiopathic arthritis.

OBJECTIVE: To evaluate whether abnormal T cell recognition may be generated by exposure to exogenous antigens presenting sequence homology with epitopes contained in self HLA alleles, and if such recognition may be part of the mechanisms that fuel inflammation in autoimmune diseases associated with certain HLA alleles. METHODS: Cytotoxic responses of peripheral blood mononuclear cells to 9-mer peptides derived from HLA molecules (DRB1*1101, DRB1*0801, or DPB1*0201) associated with oligoarticular juvenile idiopathic arthritis (JIA) or homologous peptides derived from Epstein-Barr virus (EBV) proteins (Bolf1 or Balf2) were analyzed in patients with oligoarticular JIA and in healthy controls matched for HLA-DRB1*1101, DRB1*0801, or DPB1*0201. Production of proinflammatory cytokines in culture supernatants was determined by enzyme-linked immunosorbent assay. RESULTS: T cell cytotoxic responses and production of proinflammatory cytokines in response to stimulation with self HLA-derived peptides were found only in patients with oligoarticular JIA, and not in controls. Patients with oligoarticular JIA, but none of the healthy controls, had EBV-self HLA cross-reactive T cells. CONCLUSION: Our data suggest a disease- and allele-specific mechanism of autoimmunity in oligoarticular JIA. This mechanism may be part of the pathogenesis of the disease, and could be the basis of one of the likely multiple candidates for antigen-specific immunotherapy approaches in the future.

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

Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular genetic studies are underway, with most researchers focusing on identifying susceptibility genes in clinical samples with ADHD. An alternative approach is to search for quantitative trait loci underlying the trait measure of ADHD in non-clinical samples. Positive findings of association of the dopamine transporter DAT1 480 bp allele (allele 10) and the DRD4 7 repeat allele with clinical ADHD have been previously reported. In this pilot study, we examined these polymorphisms in a selected population-based sample of twins (50 high scoring pairs, 42 low scoring pairs). There was a trend for an increase in the frequency of the dopamine receptor DRD4 7 repeat allele in the high-scoring concordant monozygotic twins (odds ratio=1.4). Although this result was not statistically significant, the frequency of the 7 repeat allele was similar to that reported for our clinic sample of ADHD patients drawn from the same geographical area. There was a non-significant trend for an increased frequency of the DAT1 allele 10 (odds ratio=1.3). These results suggest that a molecular genetic study based on a questionnaire-derived measure of ADHD in a non-clinical sample is feasible and the results appear to be comparable with those from studies of clinical cases. However, sample size and power are key issues to consider when using this approach.

Adolescent↗
PubMed2001

Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable childhood-onset psychiatric condition characterized by developmentally inappropriate inattention, hyperactivity, and impulsiveness. The pathophysiology of ADHD is currently unknown. However, the therapeutic effects of stimulant medication together with findings from animal and neuroimaging studies as well as from several molecular genetic studies of the dopamine receptor D4 gene and dopamine transporter gene have implicated involvement of the dopaminergic system. To test the dopaminergic hypothesis further, we have looked for association between ADHD and alleles of seven dopamine-related candidate genes using a family-based association approach in a sample of 150 children diagnosed with ADHD. We tested polymorphisms in genes encoding three dopamine receptors (DRD3, DRD4, and DRD5) and four dopamine-relevant enzymes: tyrosine hydroxylase [tyrosine hydroxylase (TH)], dopamine beta hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). We were unable to detect a significant association with any of the polymorphisms genotyped, although there was a trend for preferential transmission of the DRD5 148 bp marker allele and the MAOA 122 bp marker allele. We conclude that none of the alleles we have tested makes a major contribution to ADHD, although much larger samples are required to exclude small effects.

Adolescent↗
PubMed2001

[Influence of genetic variation in the major histocompatibility complex on head and neck cancer susceptibility].

BACKGROUND: While cigarette smoking and alcohol consumption are risk factors for squamous cell carcinomas (SCC) of the head and neck, genetic factors are also significant. The gene of tumor necrosis factor (TNF) is located in the major histocompatibility complex class III and the cytokine has pleiotropic actions some of which are anticarcinogenic. As this gene complex is polymorphic with microsatellite markers identified it is a further candidate for head and neck cancer susceptibility. METHODS: We used a case-control approach to study the influence of polymorphism at the A-D markers on susceptibility in 113 controls, 265 laryngeal and 123 oral cavity/pharyngeal SCC cases. Genotypes were identified on polyacrylamide gels in an automated DNA sequencer after amplification with fluorescently-labeled primers. RESULTS: We found no differences in allele frequencies between controls and oral cavity/pharyngeal SCC cases but the frequency of B3 was greater in the laryngeal SCC cases than controls (p = 0.004, odds ratio 2.8). Homozygosity for B3 conferred an increased risk of laryngeal cancer compared with controls (p = 0.021, odds ratio 10.8). CONCLUSIONS: The data provide the first evidence that allelism at MHC class III microsatellite markers is associated with risk to laryngeal SCC.

Aged↗
PubMed2001

Mannose binding lectin and FcgammaRIIa (CD32) polymorphism in Spanish systemic lupus erythematosus patients.

OBJECTIVE: Mannose binding lectin (MBL) and FcgammaRII (CD32) polymorphisms have both been implicated as candidate susceptibility genes in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the relationship of these polymorphisms with SLE. METHODS: We studied a cohort of 125 SLE patients from Barcelona, Spain and 138 geographically matched controls. Sequence-specific primer-polymerase chain reaction (SSP-PCR) amplification was used to determine CD32 and MBL structural polymorphisms. MBL haplotypes were established using sequence-specific oligonucleotide probing techniques. RESULTS: Patients carried the MBL codon 54 mutant allele more frequently than controls [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.2-4.0; P=0.007] and the haplotype HY W52 W54 W57 was found to be significantly lower in cases compared with controls (OR 0.6; 95% CI 0.4-0.9; P=0.016). CONCLUSION: The MBL gene codon 54 mutant allele appears to be a risk factor for SLE, whilst haplotypes encoding for high levels of MBL are protective against the disease. Differences between controls and patients were not significant when considering the FcgammaRIIa polymorphisms; similar results were observed for renal affectation.

Acute-Phase Proteins↗
PubMed2001

Seronegative rheumatoid arthritis in elderly and polymyalgia rheumatica have similar patterns of HLA association.

OBJECTIVE: To examine whether polymyalgia rheumatica (PMR) and late onset rheumatoid arthritis have identical or similar HLA-DRB1 genetic associations. METHODS: Seventy five PMR cases without evidence of giant cell arteritis were available for study. One hundred seven RA cases were investigated, of which 62 had disease onset after age 60 years. All cases were compared with 145 ethnically matched controls. All cases and controls originated from Lugo, NW Spain. HLA-DRB1 typing was performed on DNA samples using PCR based molecular methods. RESULTS: Early onset RA (< or =40 yrs) was strongly associated with DRB1*04 (DRB1*0401 and *0404). In contrast late onset RA (> or = 60 yrs) was not associated with DRB1*04 but was associated with DRB1*01. Stratification of late onset RA cases by rheumatoid factor status revealed that DRB1*01 was only increased in seropositive RA cases. Late onset seronegative RA cases exhibited increased frequency of DRB1*13/*14; this was also observed in PMR cases where coexistence of GCA had been excluded. CONCLUSION: These data indicate that (1) HLA associations with RA differ with respect to age at disease onset; and (2) seronegative late onset RA and "isolated" PMR have a similar HLA-DRB1 association and may have an identical etiological basis.

Adolescent↗
PubMed2001

Linkage and association analysis of candidate genes in rheumatoid arthritis.

OBJECTIVES: To test for linkage and association to rheumatoid arthritis (RA) in multiplex families for polymorphic markers in candidate gene loci. Loci including the cytokine cluster on 5q31.1 and IL10, both previously investigated in RA, were included along with several other genes including ICAM-1, cMYC, the cytokine cluster on 17q11.2 and IL1RA. METHODS: One hundred eighty-five multiplex RA families were genotyped for 11 microsatellite markers close to candidate genes. Markers showing evidence of linkage and/or association to RA were tested in a further cohort of families (n = 99). RESULTS: A single microsatellite marker in the GSTM4 gene showed some evidence of linkage, LOD 1.6 (p = 0.006). However, there was no evidence of excess allele sharing in the second cohort of families tested. There was also evidence of association to RA, using the transmission disequilibrium test for a dinucleotide repeat in the IRF gene in the cytokine cluster on 5q31.1; this was not replicated in a second cohort of families. CONCLUSION: Our results do not provide evidence of a role for these genes in RA susceptibility.

Arthritis, Rheumatoid↗
PubMed2000

A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3' untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands.

Adult↗
PubMed2000

A single nucleotide polymorphism in exon 1 of cytotoxic T-lymphocyte-associated-4 (CTLA-4) is not associated with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an oligogenic disease for which only one susceptibility locus has been identified to date. Genes involved in T-cell regulation are potential candidates. Association to cytotoxic T-lymphocyte-associated-4 (CTLA-4) protein, a negative regulator of T-cell activation, has previously been described in a subset of German RA patients carrying the HLA DRB1*0401 subtype. Linkage and association with another oligogenic autoimmune disease, insulin-dependent diabetes mellitus, has also been described in a Spanish population. OBJECTIVE: To investigate the association of CTLA-4 with RA in Spanish and UK subjects. METHODS: Caucasoid UK RA patients (n=192), UK controls (n=96), Spanish RA patients (n=136) and Spanish controls (n=144) were typed for an A/G bi-allelic polymorphism in exon 1 of CTLA-4 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (enzyme). RESULTS: No significant differences in the frequency of the G allele or the GG genotype were found in either the UK or Spanish RA patients compared with controls. CONCLUSION: No significant evidence was found of an association between RA and CTLA-4.

Abatacept↗