Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1998-02-25
2000-09-05
Horlick, Kenneth R.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
435 6, 435 911, 536 231, 536 235, 536 243, 536 2431, 536 2433, C12P 1934, C12Q 168, C07H 2104
Patent
active
061141518
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the diagnosis and therapy of atopy and to materials and methods relating thereto.
Atopy is in essence an excessive or misplaced immune response mediated by IgE antibodies in response to common environmental allergens. Common allergens sensitizing atopic individuals are grass and tree pollens, house dust, house dust mites (HDM), bacteria, fungi, feathers, hair, eggs, milk and chocolate. Atopy underlies hayfever, asthma, eczema, urticaria and certain gastro-intestinal disorders.
Asthma is an atopic condition of particular interest as it is becoming more prevalent. It now affects one child in seven in the United Kingdom (Strachan D. P., et al., Arch. Dis. Childhood 70, 174-178, 1994). Allergies/atopy underlies 95% of childhood asthma cases. Asthma may be identified by recurrent wheeze and intermittent airflow limitation. An asthmatic tendency can be quantified by the measurement of bronchial hyper-responsiveness (BHR) in which an individual's dose-response curve to a broncho-constrictor such as histamine or methacholine is constructed. The curve is commonly summarised by the dose which results in a 20% fall in airflow (PD20) or the slope of the curve between the initial airflow measurement and the last dose given (slope).
In an atopic immune response, IgE is produced by B-cells in response to allergen stimulation. These antibodies coat mast cells by binding to the high affinity receptor for IgE (Fc.epsilon.RI). When a multivalent allergen binds to an IgE coated mast cell, the cross-linking of adjacent IgEs by allergen initiates a series of cellular events leading to the destabilization of the cell membrane and release of inflammatory mediators. This results in mucosal inflammation, wheezing, coughing, sneezing and nasal blockage.
Atopy can be diagnosed by (i) a positive skin prick test in response to a common allergen; (ii) detecting the presence of specific serum IgE for allergen; or (iii) by detecting elevation of total serum IgE. Using these and other assays, a genetic linkage between generalised atopic IgE responses and chromosome 11q has been observed.
Previous studies have found linkage of atopy and bronchial hyper-responsiveness to markers on chromosome 11q13 (eg Cookson, W. O. C. M., et al., 1989 Lancet i pages 1292-1295.) and the beta-chain of the high affinity receptor for IgE (Fc.epsilon.RI.beta.) has been identified as a candidate gene for this linkage (Sandford, A. J., et al., 1993 Lancet 341, pages 332-334).
WO95/05481 provides further information on atopy and its diagnosis and treatment. In particular, it discloses variants of the gene encoding Fc.epsilon.RI.beta. which are associated with atopy and it teaches a method for diagnosing atopy which is based upon the demonstration of the presence or absence of one or two variants in a specific portion of the DNA sequence of the gene encoding Fc.epsilon.RI.beta.. The specific DNA sequence is located near the commencement of exon 6 of the Fc.epsilon.RI.beta. gene on chromosome 11q and two variants are described. The first variant (designated I181L) encodes a polymorphism in which there is a change of isoleucine to leucine at amino acid residue 181. The second variant (designated I181L/V183L) involves a double mutation that includes the change at residue 181 and the additional change of valine to leucine at residue 183. The amino acid residues 181 and 183 are positioned in the fourth transmembrane domain of Fc.epsilon.RI.beta.. The variants and polymorphisms are fully described in WO95/05481.
The polymorphisms I181L and I181L/V183L and associated polynucleotide variants have been described in British and Australian populations and are, in selected subjects, associated with atopy and atopic asthma (Shirakawa, T., et al. 1994 Nature Genetics 7, 125-9; and Hill, M. R. et al., 1995 Br. Med. J., 311, 776-779). However the two polymorphisms/variants I181L and I181L/V183L have in practice proved problematical to assay, there being a high false-negative rate for PCR-based tests.
Unexpectedly, the present applicants have found
REFERENCES:
Kuster et al JBC vol. 267, No. 18, pp. 12782-12787, 1992.
Shirakawa et al Nature Genetics vol. 7 pp. 125-130, 1994.
Hill and Cookson, "A new variant of the .beta. subunit of the high-affinity receptor for Immunoglobulin E (Fc.epsilon.RI-.beta. E237G): associations with measures of atopy and bronchial hyper-responsiveness", Human Molecular Genetics 5(7):959-962 (1996).
Shirakawa et al, "Association between atopic asthma and a coding variant of Fc.epsilon.RI-.beta. in a Japanese population ", Human Molecular Genetics 5(8):1129-1130 (1996).
Kuster et al, "The Gene and cDNA for the Human High Affinity Immunoglobulin E Receptor .beta. Chain and Expression of the Complete Human Receptor", The Journal of Biological Chemistry 267(18):12782-12787 (1992).
Newton et al, "Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS)", Nucleic Acids Research 17(7):2503-2516 (1989).
GenBank/Embl entry (accession No. M89796) Jan. 9, 1995.
Human Molecular Genetics, vol. 5, No. 7, Jul. 1996, pp. 959-962, Hill R. et al, "A new variant of the B subunit of the high-affinity receptor for immunoglobulin in E(FceRi-beta E237G): associations with measures of atropy and bronchial hyper-responsiveness".
Proceedings of the National Academy of Sciences of the USA, vol. 89, No. 8, Apr. 1989, pp. 2766-2770, Orita M. et al, "Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms".
Cookson William O. C.
Hill Michael R.
Horlick Kenneth R.
Isis Innovation Limited
Siew Jeffrey
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