[0003] Asthma may be identified by recurrent wheeze and intermittent air flow limitation. An asthmatic tendency may be quantified by the measurement of bronchial hyper-responsiveness 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 air flow (PD20) or the slope of the curve between the initial air flow measurement and the last dose given (slope).

[0004] In the atopic 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?Rl). 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 destabilisation of the cell membrane and release of inflammatory mediators. This results in mucosal inflammation, wheezing, coughing, sneezing and nasal blockage.

[0005] 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.

[0006] Genetic associations with atopy have been demonstrated. WO 95/05481 discloses that variants of the gene encoding the ?-subunit of the high-affinity receptor for IgE (Fc?RI?) are associated with atopy. It teaches a method for diagnosing atopy which is based upon the demonstration of the presence or absence of one of two variants in a specific portion of the DNA sequence of the gene encoding Fc?RI?, located near the commencement of exon 6 of the Fc?RI? gene on chromosome 11. A further variant has also been found in which the unusual variant sequence is in the coding sequence for the C-terminal cytoplasmic tail of Fc?Rl? (11).

[0007] The known polymorphisms do not account for all of the genetic factors which predispose to asthma. In particular, asthma is not necessarily an atopic disease. Identification of further genetic polymorphisms linked to asthma will allow the identification of children at risk of asthma before the disease has developed (for example immediately after birth), with the potential for prevention of disease.

[0008] Tumour necrosis factor (TNF, also known as TNF?) is a potent pro-inflammatory cytokine that is found in increased concentration in asthmatic airways (4) and in lavage fluid from asthmatic lungs (5). Increased secretion of TNF by peripheral blood lymphocytes or monocytes has also been established in association with the HLA-DRB1*03 genotype (8). The TNF locus is located within the major histocompatibility complex (MHC) between the MHC class III genes and HLA-B. Located downstream of the TNF gene and in tandem arrangement with it is the lymphotoxin ? gene (LT?, which was originally designated TNF?). Unlike the highly polymorphic class I and class II HLA genes, the coding portions of the TNF? and LT? genes only show a very low degree of polymorphism.

[0009] The TNF? and LT? loci have been investigated in association with autoimmune diseases such as systemic lupus erythematosus (SLE). It has been suggested that an increased level of TNF secretion is associated with allele 1 of a NcoI polymorphism in the LT? gene (9) and with allele 2 of a TNF promoter variant at position -308 (10). These polymorphisms are known as LT? NcoI*1 and TNF-308*2 respectively. However, there has been some doubt about the significance of these polymorphisms. In particular, it has been suggested that the TNF?-308 polymorphism is not relevant to TNF? gene regulation (15, 16).

[0010] Several polymorphic microsatellite sequences within the human TNF/LT locus have also been mapped and characterised (12) and used in a cell typing study (13).

[0011] It has now been discovered that, surprisingly, unusual genetic variants in or linked to the TNF? gene are predictive of asthma. Furthermore, it has been found that the unusual variants are predictive of bronchodilator and inhaled or oral steroid usage in asthmatic individuals. The variants are therefore useful to predict the clinical course of disease (e.g. severe as opposed to mild) or the response to particular treatments, as well as in a diagnostic tool, This information will be of use in relation to both individuals and population, and will be of interest to the insurance industry as well as to the healthcare and pharmaceutical industries.

[0012] These unexpected findings make possible new diagnostic and therapeutic strategies.

[0013] The present invention therefore provides a method for diagnosing an individual as being asthmatic, or of having a predisposition to asthma, which method comprises demonstrating in the individual the presence or absence of an unusual variant form of a polynucleotide sequence in the MHC region of chromosome 6p, said unusual variant form associated with an increased secretion of TNF. In particular, the variant may be located in the TNF?/LT? locus, including regulatory regions for the TNF? and LT? genes. FIG. 1 shows a physical map of the human TNF?/LT? locus and the locations of various polymorphisms using nomenclature as it appears in the literature. The variant may be for example allele 1 of the NcoI polymorphism in the LT? gene, or it may be allele 2 of the TNF promoter polymorphism at position -308. Both of these variants have been described in detail previously in references 10 and 14, the contents of which are incorporated herein by reference. The method according to the invention may involve identifying the presence or absence of two or more such variants. 
 
 
 

 -   3 Bottles of the herbal formulation containing 14 Herbs in granule form. Each bottle contains 400 grams of the herbal formulation in granule form.

Dosage : 10 grams taken twice a day - once after breakfast and once after dinner.

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 -   1 Bottles of the herbal formulation containing 14 Herbs in granule form. Each bottle contains 200 grams of the herbal formulation in granule form.

Dosage : 10 grams taken twice a day - once after breakfast and once after dinner.

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We will ship the herbal formulation BREATHE EAZY to reach your home/office anywhere in the world within 10 days from the date of ordering.

 -   3 Bottles of the herbal formulation containing 14 Herbs in granule form. Each bottle contains 200 grams of the herbal formulation in granule form.

Dosage : 10 grams taken twice a day - once after breakfast and once after dinner.

U.S.$49/- All Inclusive (Free Shipping)

(Total shipped weight is 1.6 Pounds. Shipping cost is borne by us)

We will ship the herbal formulation BREATHE EAZY to reach your home/office anywhere in the world within 10 days from the date of ordering.
 

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This  Herbal   product  is not  meant  to  diagnose ,treat  or  cure  any  ailment  and  it  does  not  replace  the  need  of  a  regular  doctor  . The   therapeutic  properties  of  the  individual  Herbs  have  not been  evaluated  by  FDA  -  USA.