Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-12-10
2002-04-30
Eyler, Yvonne (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023500, C536S024310, C536S024330
Reexamination Certificate
active
06379890
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to systems and methods for screening patients for their susceptibility and severity of asthma. More specifically, this invention relates to determining a patient's susceptibility or potential severity of asthma by analysis of the IL-4 receptor.
2. Description of the Related Art
Asthma is a chronic inflammatory disorder and, in genetically-susceptible individuals, this inflammation leads to increased airway responsiveness to a variety of stimuli, and recurrent airway obstruction. It is the most common chronic disease of childhood and the most common reason for pediatric hospital admission. Although it is clear that both environmental and genetic influences are important in the development of asthma, the pathogenesis of this disease remains unclear.
Several candidate genes and loci have been linked to asthma and atopy, including IL-4, HLA complex, Fc&egr;RI&bgr;, &bgr;2 adrenergic receptor and chromosomal regions such as the cytokine cluster on 5q31-32, supporting the polygenic nature of these complex diseases. Delineating the genes which contribute to the development of asthma, and dissecting the mechanisms by which these genes alter the host response to environmental challenge (antigen, viral, etc.) are keys steps to furthering our knowledge of the pathogenesis of asthma.
IL-4 and IL-13 are cytokines produced by Th2 cells, mast cells and basophils, and together with signals from co-stimulatory molecules, they induce B cells to produce IgE class antibodies. Recently, a novel interleukin-4 receptor alpha chain (IL-4R&agr;) allele has been linked to susceptibility of atopy in humans (Hershey et al.,
The Association of Atopy with a Gain
-
of
-
Function Mutation in the &agr; Subunit of the Interleukin
-4
Receptor, N. Engl. J. Med
., 337, 1721-1725).
The allelic variation reported in
Hershey
resulted from an adenine to guanine substitution at nucleotide 1902 of the IL-4 receptor &agr; cDNA, predicting a change from glutamine (Q) to arginine (R) at position 576 in the cytoplasmic domain of the IL-4R&agr;. This new allele is termed the “R576” allelic variation.
Because asthma can become progressively more severe over time, it is important to determine individuals that are susceptible to the disease at a young age. In addition, in individuals that have been diagnosed with asthma, it is clinically important to predict the severity of their disease over time. Thus, what is needed in the art is a mechanism for determining whether an individual is at risk for asthma. In addition, a mechanism for predicting the severity of an individual's asthma as the individual ages is also needed. The present invention fulfills such a need.
SUMMARY OF THE INVENTION
Embodiments of the present invention relate to the discovery that allelic variations of the Interleukin-4 receptor gene that led to increased receptor signaling were genetic predictors for asthma. Moreover, these increased receptor signaling mutations were also predictive of the severity of asthma in individuals having asthma.
More specifically, we discovered that the R576 IL-4R&agr; allele plays a role in the development of asthma. In addition we discovered that the presence of the R576 IL-4R&agr; allele impacts on the severity of asthma in affected individuals. Our experiments illustrated that the presence of the R576 allele correlated with the severity of asthma in humans.
Specifically, an individual that is homozygous for the R576 allele is at a greater risk for severe asthma when compared to an individual that is either heterozygous for the R576 allele, or only possesses the wild-type IL-4 receptor gene (e.g.: homozygous for the wild-type gene). Because there are currently no known genetic markers for severity of asthma, this discovery has tremendous therapeutic potential.
In addition we have identified other allelic variants of the IL-4 receptor alpha chain. Individuals that were homozygous for IL-4 receptor variants that provided an increased level of receptor signaling were found to have more severe asthma than those individuals that were heterozygous for the receptor variant, or homozygous for the wildtype allele.
Accordingly, embodiments of this invention related to methods of determining whether an individual is at risk for asthma by analyzing the genetic makeup of the individual. Those individuals that are homozygous for an IL-4 receptor allele that provides increased receptor signaling are more at risk for asthma than individuals that only carry the wildtype IL-4 receptor allele.
In addition, those individuals that have already been diagnosed with asthma can use embodiments of the present invention to predict how severe their asthma might become over time. As reported below, we have discovered that the severity of an individuals asthma is correlated with the presence or absence of the IL-4 receptor alleles that provide increased receptor signaling.
REFERENCES:
patent: 5654139 (1997-08-01), Lappalainen et al.
Deichmann K. et al. Biochem. Biophys. Res. Commun. vol. 231, 1997. pp. 696-697. Common Polymorphisms in the Coding Part of the IL-4 Receptor Gene.*
Deichmann K. et al. Clin. Exp. Allergy. vol. 28, 1998 pp. 151-155. Linkage and Allelic Association of Atopy and Markers Flanking the IL-4 Receptor Gene*
Hershey, et all., The Association Of Atopy With A Gain-Of-Function Mutation in the &agr;Subnuit of the Interleukin-4 Receptor. The New England Journal of Medicine, vol. 337:24:1722-1725 (1997).
Hershey, et al., Association of Atopy With A Novel IL-4 Receptor Alpha Chain Allele. Abstract:6268. (1998).
Rosa-Rosa, et al., The R576 IL-4 Receptor &agr; Allele Correlates With Asthma Severity. J. Allergy Clin. Immunol. vol. 104:5:1008-1014 (1999).
Database WPI, Derwent Publications Ltd., London, GB; AN 2000-091352, XP-002138771;A Method for Judgment of Atopic Constitution;JP 11 332567 A (Daiichi Pharm Co Ltd), Dec. 7, 1999 Abstract.
Courtesy Copy of International Search Report mailed Jun. 14, 2000.
Hershey et al., The Association of Atopy with a Gain-of-Function Mutation in the &agr; Subunit of the Interleukin-4 Receptor, N. Engl. J. Med., 337, 1721-1725, 1997.
Children's Hospital Medical Center
Eyler Yvonne
Prasad Sarada C
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