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Biomedical subjects

J M Hopkin

Publications and source records attributed to J M Hopkin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Atopy phenotype in subjects with variants of the beta subunit of the high affinity IgE receptor.

BACKGROUND: Fc epsilon RI plays a central role in atopy, thus genetic variants of Fc epsilon RI-beta may alter receptor function to enhance atopic responses and may manifest as a more severe atopic phenotype and more symptomatic atopic disease. The immunological and clinical features of atopy in children with and without the Leu 181 variant of Fc epsilon RI-beta were compared. METHODS: Sixty British nuclear families, including 10 families with the Fc epsilon RI-beta variant Leu 181, recruited via a young proband with atopic asthma were analysed for atopic parameters including total IgE, specific IgE, and clinical atopic disorder. RESULTS: Compared with other children (combined atopic and non-atopic subjects), maternally inherited Leu 181 was associated with increased levels of total IgE (odds ratio (OR) 4.82, 95% confidence interval (CI) 1.02 to 27.66, p < 0.01) and a positive IgE response to grass pollen allergen (OR 7.45, 95% CI 1.56 to 35.52, p < 0.005) but not wheeze (OR 1.97, 95% CI 0.56 to 7.69), asthma (OR 2.25, 95% CI 0.65 to 7.85), or required medications (OR 0.95, 95% CI 0.29 to 3.14). There were trends for each atopic parameter to be more marked in atopic children with maternally inherited Leu 181 than in atopic children without Leu 181. Children with maternal Leu 181 had significantly raised eosinophils but there was no difference in basophil levels compared with other atopic children. CONCLUSIONS: The Leu 181 variant of Fc epsilon RI-beta, or another identified variant in linkage disequilibrium, may promote the development of atopy.

Adolescent↗
PubMed1997

Functional analysis of histamine release from basophils and mast cells in subjects with the Ile-181-->Leu variant of Fc epsilon RI-beta.

1. Atopy is a genetically heterogeneous disorder, but there is now strong evidence that one important locus is on chromosome 11q13. Fc epsilon RI-beta at that location has been identified as a candidate gene and variants have been associated with atopy in population studies. 2. No information is available on the functional consequences of any of these variants, and defining this may prove difficult because of the complexity of the atopy phenotype and because Fc epsilon RI beta is expressed on a range of cells with different functions, including basophils, mast cells, eosinophils and antigen-presenting Langerhan's cells. 3. We have conducted a qualitative study of mast cell and basophil histamine release in nine atopic individuals with Ile-181-->Leu mutation of Fc epsilon RI beta, and ten unrelated similarly atopic individuals without Ile-181-->Leu mutation. There were non-significant trends for Ile-181-->Leu-positive atopic subjects to produce wheal responses at lower allergen challenge in skin prick tests, and to release more histamine from basophils following in vitro allergen challenge. 4. The data do not provide decisive evidence of functional differences between atopic subjects with Ile-181-->Leu and other atopic individuals; more discriminating functional experiments are required.

Adult↗
PubMed1996

Association between genetic variants of mast-cell chymase and eczema.

BACKGROUND: Atopy is a common syndrome underlying asthma, rhinitis, and eczema, and is characterised by high immunoglobulin E (IgE) responses to common antigens. IgE and mast-cell chymase (MCC-a serine protease secreted by skin mast cells) have a key role in atopic or allergic inflammation of the skin. The gene for MCC is located within a cluster of genes for cellular proteases on chromosome 14q11.2. We aimed to identify variants of MCC and another gene within this complex, and assess whether there is a genetic association between variants of MCC and atopic disorders-particularly eczema. METHODS: We randomly selected 100 controls and recruited patients-100 in each group-with atopic asthma, non-atopic asthma, atopic rhinitis, and atopic eczema. PCR amplification was used to test genomic DNA for an association between allelic polymorphisms in MCC and a flanking gene (CGL1, for the cathepsin-G-like protein) on chromosome 14q11 and asthma, rhinitis, and eczema. FINDINGS: We found a significant association between a BstXI polymorphism in MCC and eczema (odds ratio 2.17 [95% CI 1.21-3.88], p = 0.009), but no association with atopic asthma, rhinitis, or non-atopic asthma. There was no association between an Mboll polymorphism in CGL1 and any of the atopic disorders. INTERPRETATION: These findings suggest that variants of MCC may be one source of genetic risk for eczema.

Adolescent↗
PubMed1995

Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample.

OBJECTIVE: To establish the prevalence of Fc epsilon RI-beta polymorphisms Leu181 and Leu181/Leu183 on chromosome 11q13 in the general population and to examine whether when maternally inherited they confer a risk of atopy. DESIGN: A population based survey for measures of atopy (skin prick test reactions, specific IgE titres, total serum IgE concentration), bronchial hyperresponsiveness, and carriage of Fc epsilon RI-beta Leu181 and Leu181/Leu183. SETTING: The rural coastal town of Busselton, Western Australia. SUBJECTS: 1004 members of 230 two generation families identified through adults aged under 55. RESULTS: Fc epsilon RI-beta Leu181/Leu183 was identified in 45 subjects (4.5%). All 13 children who had inherited the variant maternally were atopic. Six had asthma and nine rhinitis. The odds ratio of a positive skin prick test reaction to house dust mite or grass pollen in these children compared with the other 523 children was 7.37 (95% confidence interval 1.62 to 33.60). The 95% confidence interval for the odds ratio of a positive specific IgE response (radio-allergosorbent test) was 3.00 to infinity, and the odds ratio for bronchial hyperresponsiveness was 3.70 (1.21 to 11.60). By contrast, the eight children who had derived the variant paternally had negative skin prick and radioallergosorbent test results and did not have increased bronchial responsiveness. CONCLUSION: Fc epsilon RI"' beta Leu181/Leu183 when inherited maternally identifies a genetic risk factor for atopy and bronchial hyperresponsiveness.

Adolescent↗
PubMed1995

A genetic map of chromosome 11q, including the atopy locus.

Atopy is a common and genetically heterogeneous syndrome predisposing to allergic asthma and rhinitis. A locus linked to the atopy phenotype has been shown to be present on chromosome 11q12-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of the region, using 15 markers to span approximately 27 cM, and integrate previously published maps. Under a model of maternal inheritance, the atopy locus is placed within a 7-cM interval between D11S480 and D11S451. The interval contains the important candidate gene FCERIB.

Alleles↗
PubMed1994

Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor.

The beta-subunit of the high-affinity IgE receptor (Fc epsilon RI-beta) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of Fc epsilon RI-beta, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that Fc epsilon RI-beta, subject to maternal modification, may be the atopy-causing locus on chromosome 11q.

Amino Acid Sequence↗
PubMed1994

A 2.8 Mb YAC contig in 11q12-q13 localizes candidate genes for atopy: Fc epsilon RI beta and CD20.

An important locus for Atopy (familial asthma, hay fever and eczema) has been localized to the 11q12-q13 region with the minimum recombination fraction around the CD20 gene. We have constructed a 2.8 megabase (Mb) Yeast Artificial Chromosome (YAC) contig of the candidate region using 15 STSs. A total of seven genes have been mapped within this interval in the order cen-OSBP-TCN1-GIF-Fc epsilon RI beta-CD20-CD5-PGA-q(ter) and can be covered by a minimum of eight YAC clones. Contig integrity was assayed with fluorescence in-situ hybridization (FISH) and the mapping of YAC ends on somatic cell and radiation hybrid panels. A long range restriction map of the contig has been constructed to establish the order of and distance between loci. Two promising candidates for the atopy locus, the beta subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI beta) and CD20, a molecule involved in B cell differentiation, have been placed within the contig.

Antigens, CD↗
PubMed1994

HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens.

In order to test for human histocompatibility leucocyte antigens (HLA) class II restriction of IgE responses, 431 subjects from 83 families were genotyped at the HLA-DR and HLA-DP loci and serotyped for IgE responses to six major allergens from common aero-allergen sources. A possible excess of HLA-DR1 was found in subjects who were responsive to Fel d I compared with those who were not (Odds Ratio (OR) = 2, P = 0.002), and a possible excess of HLA-DR4 was found in subjects responsive to Alt a I (OR = 1.9, P = 0.006). Increased sharing of HLA-DR/DP haplotypes was seen in sibling pairs responding to both allergens. Der p I, Der p II, Phl p V and Can f I were not associated with any definite excess of HLA-DR alleles. No significant correlations were seen with HLA-DP genotype and reactivity to any of the allergens. The results suggest class II HLA restriction is insufficient to account for individual differences in reactivity to common allergens.

Alleles↗
PubMed1994

Pneumocystis carinii pneumonia in thoroughbred foals: identification of a genetically distinct organism by DNA amplification.

Genetically distinct forms of Pneumocystis carinii infect several mammalian hosts. We report the amplification of P. carinii DNA from samples of two infected thoroughbred foal lungs by using primers designed from the sequence of a P. carinii mitochondrial rRNA gene; these primers also prime the amplification of P. carinii DNA from other hosts. The nucleotide sequence of part of the mitochondrial rRNA gene amplified from P. carinii infecting one of the foals was determined and found to be distinct from that of published rat-, rabbit-, ferret-, and human-derived P. carinii sequences.

Animals↗
PubMed1994

Granulomatous Pneumocystis carinii pneumonia: DNA amplification studies on bronchoscopic alveolar lavage samples.

Three HIV positive subjects presented with symptoms and radiographic changes suggestive of Pneumocystis carinii pneumonia. Methenamine silver staining of bronchoscopic alveolar lavage (BAL) fluid was negative (from one sample in one patient and two samples in the other two patients). Open lung biopsy was performed because of uncertain clinical progress and diagnosis; all three patients were found to have multiple pulmonary granulomata encasing numerous P carinii organisms. DNA amplification, using P carinii specific oligonucleotides, was performed on stored bronchoscopic BAL samples. P carinii specific amplification product was detected by ethidium bromide staining after electrophoretic separation on agarose gel in one case, and by the more sensitive technique of oligohybridisation in all three cases. In granulomatous P carinii pneumonia organisms are rarely identified in bronchoscopic alveolar lavage samples using histochemical staining, but are detectable by DNA amplification, although not at levels which can be readily distinguished from low, subclinical infection.

Adult↗
PubMed1993

The cloning and characterization of the arom gene of Pneumocystis carinii.

The arom gene, encoding a single polypeptide that catalyses five consecutive steps of the pre-chorismate aromatic amino acid biosynthetic pathway, has been cloned from the opportunistic pathogen Pneumocystis carinii. There is a single open reading frame of 4788 bp which includes an intron of 45 bp that does not introduce a stop codon into the sequence. Thus, the derived amino acid sequence consists of 1581 residues, which is highly homologous to all fungal AROM proteins studied to date. These data support the view that P. carinii is a fungus and imply that its aromatic amino acid biosynthesis is conventionally organized.

Alcohol Oxidoreductases↗
PubMed1993

Genetics of asthma.

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Antibody Formation↗
PubMed1993

Oropharyngeal samples for detection of Pneumocystis carinii by DNA amplification.

Pneumocystis carinii pneumonia is a major complication of T-lymphocyte immune deficiency. Restriction of the disease to the alveolar spaces and failure to culture R. carinii has hindered simple diagnostic methods. We have developed a specific DNA amplification method for P. carinii and shown diagnostic sensitivity and specificity exceeding 95% for pneumocystis pneumonia when applied to bronchoscopic lavage and hypertonic saline induced sputum. We here report application of DNA amplification to simple oropharyngeal samples in 31 HIV-positive patients with respiratory illness. P. carinii-specific DNA was detected in 10 of 18 (56%) patients with pneumocystis pneumonia by ethidium bromide stained gels and 14 of 18 (78%) patients by the more sensitive technique of oligoblotting. P. carinii DNA was not detected in samples from 13 patients with other respiratory diagnoses. An oropharyngeal sample offers a simple specimen for detecting P. carinii by DNA amplification; refinements of technique and calibration may allow its development for accurate diagnostic and epidemiological work.

AIDS-Related Opportunistic Infections↗