Tackling childhood asthma Pharmacogenetics

Child hood asthma is part of our national health care challenge. An estimated 9.6 million children (13.1 percent) under the age of 18 have been diagnosed with asthma. It is hoped that pharmacogenomics can make treatment a bit more successful for those with asthma. The question so far has been how?

In their 2010 paper Kondo et al. describe the beginnings of a clinical workflow, based on the consolidation of a number of genetic/therapeutic correlation studies. The authors suggest that a combination of clinical evaluation steps combined with a knowledge of specific allelic subtypes  carried by the patient could provide more effective therapeutic choices. The authors point out that there are ethical considerations when genetic information is recorded and detailed. But what they provide is a remarkably simple workflow chart integrating pharmacogenomic information with clinical observation.

I have asked the Tox 1401 students to describe at least one of the gene polymorphisms and mutations from this paper, so read on in the comments if you would like to learn specifics.

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35 thoughts on “Tackling childhood asthma Pharmacogenetics

  1. LEUKOTRIENE C4 SYNTHASE; LTC4S
    It is mapped that the LTC4S gene to chromosome 5q35. Generally, leukotrienes are potent proinflammatory mediator synthesized from membrane derived arachidonic acid after activation of certain granulocytes. Specifically, the cysteinyl leukotrienes are associated with bronchial asthma. CYSLTR1 and CYSLTR2 are receptors form the LTC4 thus, the CYSLTR-selective pharmacologic antagonists are used in the treatment of asthma. This gene is especially activated when aspirin-intolerant asthma is present. It is characterized by adverse respiratory reactions to aspirin and other NSAIDS. Aspirin causes bronchoconstriction by triggering these genes known as the cysteinyl-leukotriene by removing PGE(2)- dependent inhibition in aspirin- intolerant asthma (AIA) patients. The expression of LTC4S is increased by 5 fold and 18-fold compared to aspirin-tolerant asthmatics and nonasthmatic (control). This lead to a conclusion that AIA patients encompass a polymorphism involving the regulation of LTC4S expression thus, the overproduction of cysteinyl-leukotrienes leads to bronchoconstriction. Vast studies have identified this information finding that aspirin given to AIA patients has not increased urinary output of LTCC4 but, this significance was abundant in the carriers of the -444C allele. This was an indication for something more when more studies were conducted essentially indicating that the
    -444C allele resulted in increased reported gene expression thus, the overexpression of LTC4S
    were more predisposed for AIA.

    http://omim.org/entry/246530

    • Even though aspirin causes bronchoconstriction in patients with asthma, do you think that it would have any of these effects in non-asthma patients? What happens to patients when there is no increase in urinary output, but an increase of aspirin in the body?

  2. TBX21 – (TBET)

    In regards to the paper on asthma in children, I have chosen one of the gene polymorphisms and mutations to explore, TBX21. Also known as T-Box expressed in T cells or just TBET, this gene is responsible for controlling the expression of the Th1 cytokine, interferon-gamma. TBX21 is a Th1-specific T-box transcription factor. Zhang and Yang (2000) concluded that both mouse and human TBX21 genes contain 6 exons. The TBX21 gene expression associates itself with the IFNG expression (Interferon gamma) in Th1 and natural killer (NK) cells. Finotto et al. observations have shown that the reduced expression of the Th1 factor (in this case TBX21) is associated with asthma. The comparison showed TBX21 in T cells from airways of nonasmathic patients and T cells in patients with asthma. The loss of TBX21 seems to be associated with asthma. In 2002, Finotto et al. concluded that “mice with a targeted deletion of the Tbet gene and severe combined immunodeficient mice receiving CD4(+) cells from Tbet knockout mice spontaneously demonstrated multiple physiologic and inflammatory features characteristic of asthma.” The alteration or deletion of the TBX21 gene is indeed associated with the symptoms of asthma.

    http://omim.org/entry/604895?search=TBX21&highlight=tbx21

    • This is really interesting because our T cells are associated with immunity and this will probably help understand more biological pathways associated.

  3. CYTOCHROME P450, SUBFAMILY I, POLYPEPTIDE 2, usually known as a CYP1A2 gene, is in charge of making an enzyme called 21-hydroxylase, which is part of the cytochrome P450 gene family of enzymes. It is found that more than 20 clinically used drugs are partly or predominantly metabolized by CYP1A2 including caffeine, theophylline, imipramine, clozapine, and propranolol. Especially, Caffeine is often used in studies as a marker for CYP1A2 activity, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by CYP1A2, and its clearance is increased by 56% in smokers (medscape). On the other hand, theophylline is a kind of medication that is similar to caffeine when it comes to the issue of asthma. It is believed that theophyline is to ease the symptoms of asthma by relaxing the muscles, making the breathing tubes wider so that making it easier to breathe. Although long-acting theophylline last up to 24 hours, it can cause some serious side effects from taking too much. According to American Thoracic Society, the most common ones can be headache, dizziness, heartburn, and stomach pain. In particular, the dosage should be regulated when it comes to children.
    In addition, cigarette smoking has also been shown to increase CYP1A2 activity. And what happens is that theophylline’s clearance increases by 51% in children exposed to the secondhand smoke of parents who smoke about 20 cigarettes daily due to the fact that theophylline is highly metabolized by CYP1A2.

    • Very good post I liked how you linked the genetic factor to the environmental factor of secondhand smoke.

      • If excessive Theophyline is consumed, why does a person feel so many side effects? Can you take a counteracting drug to reduce the side effects?

    • I too looked up this gene. I really like how you touched on so many different medications and uses for this drug. I did not realize that there were so many.

  4. Asthma and atopy are both caused by an interaction between genetic and environmental factors. Genetic cause might be the characteristic pattern of polymorphism in multiple genes that involve in the regulation of the allergic reaction. There are many genes that has an effect for atopy and asthma have been described one of them is LTC4S (leukotriene C4 synthase) genes. Leukotriene C4 synthetase LTC4S A-444C (AA). Leukotrienes are pro-inflammatory mediators and are implicated in bronchial asthma, CYSLTR1 and CYSLTR2 are receptors for LTC4; selective CYSLTR are used for the cure of asthma.
    The gene structure is described as 2.52 kb long and contains five exons and is found in multiple transcription initiation sites in the 5-prime flanking region of the LTC4S gene, and charted to chromosome 5q35. Crystal structure of human LTC4S and glutathione-complexed has a homotrimer in which each monomer is comprised of 4 transmembrane segments.
    Mutant allele is a risk factor for aspirin-induced asthma and is referred to it as adverse respiratory reaction. Bronchoalveolar fluid has been demonstrated high in patients with active asthma; in aspirin-intolerant patients asthma aspirin causes bronchoconstriction by targeting cysteinyl-leukotriene production the study says it might be because of taking away PGE(2)-dependent inhibition. LTC4S expression in AIA patients was up 5 fold and 18 fold compared to aspirin tolerant of asthmatics and nonasthmatic controls patients. AIA patients might have a polymorphism that involves the regulation of LTC4S expression resulting it to overproduction of cysteinyl-leukortienes and leading to bronchoconstriction.

    • I liked how you explained what happens in aspirin- intolerant patients when they take aspirin and also why it could be that they react in an adverse way.

  5. Interleukin 4 Receptor Alpha, or IL-4Ra, is a gene that plays a large role in IgE production. Polymorphisms of IL-4Ra have been linked to the development of childhood asthma. The receptor is located on the cell membrane and effects signal transduction pathways for cytokines. The receptor has several transmembrane domains for this purpose. Polymorphisms in this gene create a faulty receptor which causes overproduction of IgE. The Ile50Val mutant variant the polymorphism that is associated with this overproduction of IgE. It is linked to atopic asthma, but there is no known association between this variant and atopic asthma. An overabundance of IgE is a problem because IgE contributes to the allergic reaction. There is a strong association between an excessive amount of mite-specific IgE, that is, IgE that provokes an immune response when mites are inhaled, and childhood asthma. The mutant variant creates excessive IgE by exhibiting upregulated uptake of its ligand, IL-4, which results in increased activation of Stat6, which increases IgE production.

    • Very Good post. I like how you explain the pathology of how the IgE’s were produced.

    • There is also response that is involved in regulating IgE production, chemokine and mucus production at sites of allergic inflammation. And in certain cell types, IL-4Ra can signal through activation of insulin receptor substrates.

  6. Asthma is a chronic disease which affects many is is common among children. This disease impairs one ability in certain activities as an attack causes difficulty breathing and if not given immediate attention it can be fatal. There are many speculations and links to why asthma arises in those affected. Smoking and living in urban areas where air pollution is very high are factors that have been associated with the high number of asthma patients. Most asthma patients are usually treated at home with an inhaler when an attack strikes however severe attacks may require additional medical attention and the person having the attack may need to be rush to the emergency room before it is too late.
    Newer studying have been trying to see if there is any genetic correlation in the disease.The receptor gene IFN-gR1 has been linked to many disorders including heart disease and asthma as well as other allergic reaction diseases. It has been found that a nuclelotide substitution in this gene has some relation to allergic reactions causing diseases such as asthma. Characterized as Leu467 Pro this substitution was found in only six of eighty nine patients with allergic reactions including asthma it was not found in the seventy two patients with no allergies. Ige’s are one of the five type of antibodies found in the immune system and is associated in with allergic reactions. When an antibody bind to its corresponding antigen a response is mounted. In the case of asthma when the antigen would be what is called a trigger as when it is detected in the body Ige(s) are then made and the response would be the persons difficulty of breathing. It was found that in these six patients with the Leu467 pro substitution that there was a high level of Iges thus linking this substitution to the allergic response.

    • Good point. And I do agree on how the environment, especially air pollutants, can affect asthma patients.

    • Great response, I searched Leu 467 Pro and read that there was a difference in the L467P frequency between the allergic patients and the non-allergic subjects. The 6 patients with L467P got allergic diseases such as bronchial asthma, and L467P revealed a linkage between allergic diseases and L467P. Serum IgE levels of the patients with L467P were higher than those of the non-allergic subjects.

    • Does this mean that anyone without a mutation in this gene will not have an allergy that may lead to asthma. This is a very interesting gene because it proves that asthma is also genetic and not just environmental. I like your post, you write very well.

  7. Asthma usually becomes more active around the time allergy season arrives, because environmental factors is one of the most prevalent triggers of an asthma attack. However, genetic factors also play a huge part in asthma especially do to polymorphisms on specific genes.
    One polymorphism discussed in the paper, Pharmocogenomics of asthma in children by Naomi Kondo, etc., was the polymorphism on the IL-13 gene. This gene normally encodes an immunoregulatory cytokine that is involved in several stages of B-cell maturation and differentiation. The cytokine works to down-regulate macrophage activity, which in turn cause the inhibition of the production of pro-inflammatory cytokines and chemokines. The cytokines that are produced from this process are found to be critical in the pathogenisis of the allergen- induced asthma.

    • This makes sense and I liked how it was basic enough to understand but I think that you could have explained what exactly a cytokine or a chemokine is. If a person didn’t know what those things were this could be very confusing for them to read.

  8. The gene polymorphism that I chose to research was the gene ALOX5 (Arachidonate 5-lipoxygenase), located on chromosome 10. It encodes a member of the lipoxygenase gene family and also synthesized leukotrienes, fatty signaling molecules. These leukotrienes play an important role when it comes to inflammatory conditions such as allergies. There are some mutations in the promoter region of this gene. These mutations can cause a weakened response to antileukotriene drugs, which are used to treat asthma. The ALOX5 gene is also associated with some types of cancer. For example, ALOX5 is a regulator for leukemia stem cells. If the gene is not present, then the chronic myeloid leukemia tested in mice is not induced which leads to non-functioning leukemia stem cells.

    • I liked your response that it included ALOX5’s role in both asthma and cancer.
      Does ALOX5 have any direct associations with asthma besides its response to drugs used to treat asthma?

  9. Research has shown that allergic diseases such as bronchial asthma and atopic dermatitis may develop due to both genetic and environmental factors. In addition, there is ample evidence that indicates that asthma is heredity. This leads to the correlation of the development of asthma and other allergic disorders with some genes. There are four categories of genes that control the expression of allergic disorders. They included antigen recognition, IgE production, production and release of mediators, and events on target organs.

    One of the many genes that have been identified with the development of asthma is LTC4S (leukotriene CA synthase). The gene’s locus has been mapped to chromosome 5q35. The gene itself is 2.53 KB long and contains five exons. LTC4S encodes a protein that is an enzyme that converts LTA4 (leukotriene A4) and glutathione to produce LTC4 (leukotriene C4). This enzyme catalyzes the first step in the biosynthesis of cysteinyl leukotrienes. Cysteinyl leukotrienes are potent biological compounds that have been derived from arachidonic acid. In addition, they act as mediators of bronchial smooth muscle contraction and increase mucous secretion, vascular permeability, and cellular infiltration in inflammatory conditions such as bronchial asthma. Receptors fro LTC4 and its metabolites include CYSLTR1 and CYSLTRS. Therefore, CYSLTR- selective pharmacologic antagonists are often used in the treatment of asthma.

    LTC4S is associated with asthma due to a single-nucleotide substitution. In addition, a single-nucleotide polymorphism (A-444C) in LTC4S has been associated with aspirin-sensitive asthma (AIA). AIA is a syndrome in which aspirin causes bronchoconstriction by triggering cysteinyl-leukotriene production and increased LTC4S in bronchial biopsies of AIA patients. However, recent studies have found no association with this polymorphism and AIA, but more research is needed.

  10. Asthma is caused by genetic and environmental factors. A number of studies have shown an increased prevalence of asthma among the offspring of subjects with asthma compared with the offspring of subjects without asthma. They are many genes that have been linked to asthma.
    One gene is LTC4S, or leukotriene C4 synthase. LTC4S is mapped on chromosome 5q35. LTC4S can mediate bronchial smooth muscle constriction and increase mucous secretion, vascular permeability, and cellular infiltration. LTC4S converts LTA4 to LTC4 by conjugation to reduced glutathione. Leukotriene are released by eosinophils, mast cells, and alveolar macrophages. A single-nucleotide promoter polymorphism (A-444C) in LTC4S has been associated with aspirin-intolerant asthma, a distinct clinical syndrome characterized by adverse respiratory reactions to aspirin and other nonsteroidal anti-inflammatory drugs. Aspirin caused bronchoconstriction in AIA patients by triggering cysteinyl-leukotriene production, probably by removing PGE(2)-dependent inhibition. The study by Cowburn et al. (1998) showed that LTC4A expression in AIA patients was increased 5 fold and 18-fold compared to aspirin-tolerant asthmatic and nonasthmatic controls. This study led to a conclusion that AIA patients have a polymorphism involving the regulation of LTC4S expression, which results in the overproduction of cysteinyl-leukortienes and leads to bronchoconstriction.

  11. There are genetic and environmental factors that trigger asthma in patients. A lot of research was done to prove that Asthma is hereditary; People were prone to have asthma if their parents had it versus those subjects that didn’t have the disease if their parents didn’t have it. There is a correlation between HLA genes and asthma. ILe50 is associated with atopic asthma but not with atopic asthma. If there is an increase in IgE there is an increased amount of Ile 50 present. There was a strong correlation amongst children. When data was collected from Mouse and Human cells, it shows that Ile50 upregulates receptors that are associated with IL4. Then there is a increase in cell proliferation and IgE production. Ile50 is a variant of IL-4Ra which upregulates the receptor response to IL4.

    • Interesting start but I’m not completely clear with the sentence about ILe50 and atopic asthma. Also is the cell proliferation related to asthma, perhaps the proliferation of the cells in question may be connected to asthma?

  12. The Beta-2 adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins, making it a G-protein-coupled receptor. These receptors binds epinepherine with a 30x greater affinity than it does nonepinephrine. In regards to the pharmacogenetics of Beta-2 agonists act by binding to the Beta-2 adrenergic receptors. This receptor has many polymorphisms in the coding region, including Arg 16 Gly and Gln 27 Glu. Patients who were homozygous for Arg 16 did worse cinically and had advers effects but those who were homozygous for Gly 16 did better clinically.

    • The best therapy would work according to the phenotypes and possibly the responsiveness of the patient individually. This is a great posting to be used for further additional information for the studying of specifically B-2 antagonists in therapy for asthma, or COPD or other respiratory-related illnesses.

  13. Cytochrome P450 located in subfamily I, polypeptide 2, encodes for the P450 enzyme. There are many forms of CYP1A2, this particular one is purified from human liver microsomes and purified to electrophoretic homogeneity. This gene is 7.8 kband contains 7 exons. Among all of the exons the first is the non coding exon, followed by exons conserved in the nucleotides and bases, and lastly are the regulatory elements. I found this information using OMIM.

  14. At one point as a child having to deal with Asthma myself I remember specifically how cold frigid weather would trigger my asthma, while at the same time my friends would be fine. Then around the start of spring during allergy season all my asthmatic friends would come to school, inhalers locked and loaded. I would often wonder during these moments why different factors triggered our asthma. It was clear that asthma was correlated to certain outside conditions but at the same time something internal is also important. Now I understand that this internal factor is genetics.
    In the article one type of gene which acts as an internal factor of childhood asthma is HLA. HLA was found to associate with bronchial asthma in particular. Furthermore this type of gene has been seen to relate to the severity of asthma in children.
    HLA is the human leukocyte antigen, the HLA gene is known to be in relation to many types of immune responses within the body. The gene codes for 6 different antigen proteins and also plays a major part in immune function and is highly variable in order to defend against pathogens through variability amongst the species.

  15. The ICS just mentioned was a common and effective medicinal use for treating asthma-mediated illness. The ICS was a Histone 33 GLN and the corticotropin-releasing hormone receptor along with the TBX 21 genes are collectively responding to the affected sites. The IL-4 T allele known for being associated with the ICS resistance, only impedes the responsiveness to asthma if a patient isn’t a heterozygous mix. This is extremely helpful when determining the best therapy simply because if a good percentage of patients are observed to be of heterozygous match then the ICS is best suited for their bodies. If not then the ICS resistance is present and the other two methods, DSCG or Leukotriene Mediators, might be of better relief. The TBX21 gene, was the shorter version name of the T-Box that’s involved in DNA-binding, the “encoder” for transcription factors so that the regulation of developmental processes can occur. This gene is the human ortholog of the TBX 21 mouse gene. The human ortholog also correlates with IFNG expression in Th1 cytokine and natural killer cells, suggesting a role for this gene in initiating lineage and development.

  16. Regarding How Complex is Life: February 27, 2012 – March 3, 2012
    From reading the paper, the new direction of targeting cancer pathways instead of specific genes is trying to establish a point of where the target pathway from which specific genes are starting to promote cancer growth, metastasize. The sooner to hit the pathway possibly, the sooner to destroy any further gene or cell reproduction or any continuance of mutation growth that can lead to cancer.
    The main disadvantages as noted from the paper was that the targeting of specific genes is a simple discrete pathway rather than a large complex network of genes that are placed in an order to cause cancer or genetic mutation.
    The H19 gene from the maternal allele, for example would show a pathway due to the many organs that this can target. The usage of network therapy would better serve, especially here because of the vast outlook from this gene and to the different organs. The more effective to reduce the tumors and prevent cancer is possible.

  17. Regarding 1st paper Watson and Crick: DNA molecular structure January 20, 2012
    The paper starts by explaining the research into DNA. The mechanical process discussed is the transcription. The transcript factor along with the enzyme polymerase has the attachment to the TATA box along with poly-A-tail and promoter in a codon region. This whole unit makes up a transcription unit in which a fresh strand complementary to the one with transcription unit. The same is for both RNA and DNA except of course on the pyrimidine units Uracil replacing thymine. The oligonucleotide is where the fibres and transcription unit all have the site of this process occurring. The oligonucleotide is made up of nitrogenous base, the sugar, and the phosphate molecule.
    The system works by the DNA fibers that hold up the structure. Mainly a long complex chain and busy with attachments such as the sugars and phosphate groups. The containment of the nitrogenous base is what keeps the stew sticking together!! A-T or C-G for DNA!! The coils form and wrap together to make a double helical structure.
    The theory was incredible and the idea and determination and detail from such a fresh thought was an overwhelming one for both scientists as this was the first precedent of the construction of a possible DNA molecule, the building block of life.

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