In class we have discussed a number of pharmacogenomic studies as well as the genes that we might examine in such cases. Asthma is a condition that effects millions of people, with increased diagnosis of asthma among a number of populations, including children. For asthma there are a number of approaches, some of which are based on the steroids and hormones that we discussed in class. Many of these treatments have pharmacogenomic indicators, and the number of these biomarkers have been growing.
This paper examines the process of making decisions based on pharmacogenomic data. It also serves as a nice review of the approaches to astma treatment. The process is nicely summed up in figure 3:
For your response to this paper I want you to choose one of the “Gene polymorphisms and mutations (Pharmacogenetics)” listed at the bottom of this chart. Then choose one of the classes of therapy that go with that gene polymorphism. For instance you might choose “beta 2 agonists” and “ADRbeta 2 R16G(R)”. Next, find a reference that ties these two items together, I suggest that you use OMIM, search with the gene polymorphism listed.
For your response I want you to provide the literature reference that supports the connection listed in the paper, and a summarry of the connection. For my “beta 2 agonists” and “ADRbeta 2 R16G(R)” example you can find the allele variants and references here.
Gillespie Lab 
The beta-2-adrenergic receptor agonists are most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. Gly 16 is believed to be associated with increased agonist-promoted downregulation of ADRB2 as compared with arg 16. A form of receptor with glu 27 had been shown to be resistant to down regulation when compared with gln 27, but only when coexpressed with arg 16. In a study of 190 asthmatics, it was found that the homozygous arg 16 genotype of the ADRB2 gene was positively associated with an acute response to treatment, but was also associated with a significant decrease in response after regular use of beta-agonists. Therefore, I used the reference Israel, E (Effect of Polymorphism of the beta-2-adrenergic receptor on response to regular use of albuterol in asthma) to further elaborate on the study of pharmacogenetics.
In this article, it was demonstrated that regular se of B-agonists can produce distinct effects on airway function in patients with specific polymorphisms of the B-adrenergic receptor. And regulatory use can result in reduced A.M. and P.M. peak expiratory flow in patients homozygous for the Arg 16 allele because patients homozygous for the Gly 16 allele did not experience such allele. Lastly, the polymorphisms at amino acid 27 of the B-adrenergic receptor did not alter the response to regular B-agonist use in the patients observed. Also, the regular albuterol use was associated with a decline in A.M. and P.M. peak expiratory flow in patients who are B16-Arg/Arg. This suggests that patients with B16-Arg/Arg polymorphism may be at risk for adverse effects, when using B-agonists regularly. It is demonstrated that the homozygous arginine genotype at position 16 of the B-AR can influence the response to use of a B-agonist. The altered response occurs only with regular use. Most asthmatics increase their B-agonist use during exacerbations. Almost 15% of the population seems too be homozygous for Arg 16 and the findings suggest that these individuals have a better chance of benefitting from not using B-agonists. Additionally, they (candidates) could also be used as experiment for anti-inflammatory agents.
This research supports the larger theme drawn in the paper about asthma because it tends to go into a deeper search for the causative genes of asthma and variation in causes of disease within individuals. Therefore, the research summarized above shows some intriguing factors which affect the group of people when B-agonists are used regularly. Hence, the studies in this paper also indicate the non-effectiveness of ADR beta 2 when collaborated with B2 agonists and suggests that it should not be used within individuals due to risk factors associated with it.
In this paper we have looked at the pharmacogenetics of asthma, and it’s hope to help predict the response to certain treatments that have been developed to control it. Since the feautures of patients and the causes of disease vary, personalized medicine is important for a cure to asthma. Based on a persons genotype, personalized treatment can be developed so it can best treat the asthma and reduce the risk of the drug itself.
It has been found that ICS or inhaled corticosteroids are very effective for asthma patients. The pharmocagenetics of ICS involves a gene known as TBX21 and a corticotropin-releasing hormone recpetor gene known as CRHR1. This ICS gene therapy reacts differently towards heterozygous and homozygous individuals. Particularly those individuals that have the heterozygous TBX21 gene, show an improvement and more sesnsitvity in the response to the ICS therapy.
The reference i used shows that having the TBX21 gene generally means inheriting mild asthma at an early age. The use of aspirin in these individuals show a prevalence of 10-20%. Aspirin causes bronchoconstriction in those that have aspirin-intolerant asthma. However, in all patients however, aspirin removes PGE(2)-dependent suppression.
In this paper, researchers wanted to determine the different genes that could be held responsible for the condition of asthma. Conclusions were shared in this review paper that there are a lot more than just a few genes that cause asthmatic conditions in people, mainly because there are so many different types of asthma. There are many polymorphisms that affect different areas of asthma related treatments. Today, a lot of people are treated for their asthma with Inhaled corticosteroids or ICS. Although this type of medication is known to be effective, there are still some people in which treatment with inhaled corticosteroids has no effect.
Inhaled corticosteroids act as a signal that binds to the CRHR1 receptor. CRHR1 stands for corticotrophin releasing hormone receptor. The purpose of this particular receptor is to increase lung function when a signal, corticotrophin releasing hormone, binds to the receptor. This specific type of hormone is what is found inside of the inhaled corticosteroid which is why they function so well. When a person is having an asthma attack and use an ICS inhaler, the hormone is being brought through the lungs right to the receptor sites. When the signal binds to these receptor sites, it acts as a mediator to a stress present, in case the inflammation and closing of the bronchi in the lungs. There has been found to be different variants of the CRHR1 receptor which tends to cause problems with treatment in some patients. Most of the time, inhaled corticosteroids increased the lung function up to four times. In the case of certain variants however, there is no effect with taking an inhaled corticosteroid.
The idea of tailor made medication or personalized medication I think is very important. People shouldn’t have to rely on going to use an ICS inhaler and find out that its not working to know that they have the variant that has no effect or to have to worry about an ICS inhaler working only part of the time. By having personalized mediation, it would take the worry out of asthma patients in the sense that they will know that their specific treatment will work every time for their asthma attacks. All people are different and even though asthma is a generalized disease, it is caused by so many different polymorphisms in genes. In order to fully be able to treat asthma, you need to have a treatment that will ensure that you will be helped in an asthma attack. By having personalized medication, I also think that the quality of life of an asthma patient will be increase. They will know their treatment will work and wont have side effects from it not functioning properly such as a constant cough that they cant get rid of. One of my good friends has a mild case of asthma but recently it has gotten worse. Doctors put them on an one of these steroid inhalers which is the usual treatment to asthma as a precaution since they have had increase coughing and shortness in breath which is a symptom of an attack coming. It would be fine if the inhaler helped but it hasn’t. They still have coughing fits and I know they are annoyed that their treatment doesn’t seem to work. With personalized medication, they would be cure of these side effects such as coughing fits, making life more enjoyable. (Reference used was ” CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1; CRHR1 on OMIM)
This paper discusses several different genes that play a role in the development of bronchial asthma and atopic dermatitis. Although a review, the authors present several genetic mutations and factors that lead to asthma. One they discussed specifically is the LTC4S gene located on chromosome 5q35. This gene has been associated with allergic diseases such as asthma. LTC4S stands for leukotriene C4 synthase, which catalyzes the synthesis of leukotriene C4 (LTC4). Leukotrienes are fatty molecules that promote inflammation in people with asthma. In addition to this LTC4 plays a role in synthesizing cysteinyl leukotrienes, which contract bronchial and vascular smooth muscle, increase blood vessel permeability, and increase mucus production, all of which are factors that cause the symptoms of asthma. Cysteinyl leukotrienes have been tied to causing bronchial asthma. Studies have also found that single nucleotide polymorphism on the LTC4S gene causes aspirin induced asthma, a form of asthma that occurs when the patient takes aspirin or other nonsteroidal anti-inflammatory drugs, which promotes the production of cysteinyl leukotrienes.
In order to fight the effects of leukotrienes in those suffering from asthma, medications are made that act as leukotriene receptor antagonists, or LTRAs. CysLTs have two receptors, CYSLTR1 and CYSLTR2, and when bounded together, they create the physical symptoms of asthma. The paper mentions a medication known as montelukast, which acts as an LTRA by preventing cysteinyl leukotrienes from reaching and binding to their receptors.
Since so many genes play a role in causing asthma, it may be difficult for a physician to know what kind of medication to prescribe in order to control asthma. How can you tell if the person’s asthma is being caused by cysteinyl leukotrienes or corticosteroids? By discovering which gene is causing a person’s asthma, the idea of personalized medicine will become more real and will help the sufferer feel much better because they’ll be using a medicine that is treating the true cause of their disease.
Reference: “+246530 LEUKOTRIENE C4 SYNTHASE; LTC4S” on OMIM
Studying the pharmacogenetic of asthma has allowed scientists to identify numerous gene polymorphisms and mutations associated with the disease. In a Japanese study, numerous types of medicine were used to treat asthma patients with genetic mutations many were proven to be effective. One type of medicine in particular is the inhaled corticosteroids (ICS) which acts as a corticotrophin-releasing hormone (CRH) that binds to the corticotrophin releasing hormone (CRHR1) receptor.
CRHR1 receptor plays a key in mediating how the body reacts to stress and anxiety. It is expressed in numerous areas in the brain like the anterior pituitary and cerebellum. Activation of this receptor may encourage production of adenalate cyclase, involved in the formation of cyclic AMP. The binding between CRH and CRHR1 receptor is important for lung function especially for asthma patients experiencing decrease in lung function. ICS contains CRH making it an effective medicine to increase lung function. When ICS are inhaled, CRH are brought to the receptor sites in the lungs, once the CHR binds to CRHR1 receptors, it acts as a mediator that suppresses stress by opening the bronchi.
However, a genetic variation in CRHR1 can increase the effect of ICS. Those homozygous for the variant, experience a tremendous increase, up to four times the lung function capacity of those lacking the variant. I personally feel that personalized medicine is the future frontier of medicine because it can enable doctors to select a treatment that is gear towards the individual, predict the risk of unpleasant effects as well as patient’s response before the treatment.
REFERENCE: 122561 CORTICOTROPIN-RELEASE HORMONE RECEPTOR 1; CRHR1 Gene map locus 17q12-q22
In this review paper, it discusses and lists the numerous genetic, environmental, pharmacogenetic factors that cause asthma in children. In order to treat and cure asthma fully, we might need to create a personalized medicine and we need to be aware of the pharmacogenetic aspect in order to do so. One type of gene polymorphisms and mutations that cause asthma is in the LTC4S gene. LTC4S stands for leukotriene C4 synthase. Just as its name states, its function is to synthesize leukotriene C4 (LTC4) through the conjugation of leukotriene A4 (LTA4) and a reduced glutathione. LTC4, also called cysteinyl leukotrienes, is associated with the proinflammatory responses in the body, such as the contraction of the bronchial and vascular smooth muscles and the increase of mucus secretion. Therefore, a polymorphism in the LTC4S gene can cause asthma through an increase of bronchoconstriction. Polymorphism in the LTC4S gene is sometimes correlated with aspirin sensitive asthma (AIA) because the aspirin triggers the production of the cysteinyl leukotrienes. According to Sanak et al. a polymorphism in the promoter of the LTC4S gene, specifically -444A-C, is linked to the cause of AIA.
The treatment that the authors recommend for those who have a polymorphism in the LTC4S gene, especially those who have the A/C and C/C genotype, is leukotriene receptors antagonists or LTRA. LTRA is an oral medication that is used to relax the bronchial smooth muscles and it is anti-inflammatory. An example of LTRA is Montelukast, which is sold as Singulair®.
To think that we are predisposed to certain diseases is frightening. We can prevent or control the environmental factors, but we cannot really control what is in our genes or to prevent the mutations to occur. Also, if there is so much kinds of defects that can cause asthma, imagine how much research we still need to perform to investigate what genetic factors cause the other kinds of disease. Then the doctors need to remember the kinds of medicine to prescribe since there is so much different causes of asthma. It seems like an endless process.
Reference: “246530: LEUKOTRIENE C4 SYNTHASE; LTC4S” on OMIM
This research paper investigates different genes and factors that may play a role in asthma and other such allergic diseases. Investigating the different genes in a pharmacogenetics context will help develop personalized medicine for asthma patients. Many different genes were found related to asthma as it is a hereditary disease. Many different genetic polymorphisms and mutations are involved, and thus there are a variety of asthmas. One of the polymorphisms discussed on the chart were IL-13 R110Q and Th2 cytokine inhibitor.
The reference paper I used was INTERLEUKIN 13; IL13. In this paper differences and similarities between IL-13 and IL-4 were investigated. It states that polymorphisms in their signaling may be the cause of allergies and asthma. Thus their signaling pathways can be used and targeted for treating asthma patients. Acidic mammalian chitinase is induced by a Th2 and IL-13 pathway. This enzyme is expressed in high quantities in patients with allergy. Asthma is a T helper 2 disorder and so the enzyme quantities can be neutralized by inhibiting the specific pathways of IL-13. These pathways are specifically found in the epithelium and in macrophages of individuals with asthma. The AMCase enzyme expression was much higher in tissue samples taken from asthma patients as compared to tissue samples from individuals without asthma. IL-13 type 1 receptor in contrast to type 2 receptors function primarily in regulating the development of the T helper 2 cell. IL-13 type 2 receptor function in the regulation of cells in the airways. The R110Q variant was found mostly in populations in Japan and Britain.
Reference (*147683 INTERLEUKIN 13; IL13)
This paper is about asthma and the very popular topic, personalized medicine. Asthma is a fairly common complication that has been around for a long period of time; overtime scientists were able to derive which gene polymorphisms were responsible for this complication. Although some better than others, depending on the exact type of asthma one has, various medical treatments have been put forth one of the most common being the corticosteroid inhaler but the problem is that because there are various types of asthma some treatments do not work on some patients. I actually have a cousin with asthma who was issued the pump and it was ineffective on multiple occasions and that’s why this specifically caught my attention. According to the paper it was found that people with the IL-4 589T allele showed some type of corticosteroid resistance which would hinder the helpful effects of the inhaler.
The idea of personalized medicine plays a huge role in this whole situation for the mere fact that everyone is different although most medicine address the average infected population the exceptions must be taken into consideration as well. There are many gene variables that influence the effect of corticosteroids on an individual, those genes being ones such as the TBX21 gene and the CRHR1 gene. An example would be that individuals who possess heterozygous TBX21 genes show a better response to the steroid than individuals who possess the homozygous version of the gene. Corticotrophin releasing hormone receptor (CRHR1) is the other very important influential gene and this gene along with the steroid is supposed to cause a significant increase in lung performance. Similar to the TBX21 gene depending on the variant of the CRHR1 gene can increase the effect of the corticosteroid by four fold with this gene or have no effect at all. The positive side is that there are more treatments available for different people however it is not cost efficient nor is it a good thing for the body to be delivering chemicals inside of an individuals body that are not inducing the intended effect.
Reference:
*122561
MGI, Links
CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1; CRHR1
In this paper it introduces the recent treatments and management on bronchial asthma and many other factors which cause the disease. Like the other common diseases, asthma has sufficient evidences to prove the cause of the disease is mostly hereditary. The production of antibodies IgEs are responsible for the allergic reactions in our bodies. The genetic defects in the ownregulation of IgE production are closely associated with IL-12 or IL-18 signaling. There are also many gene polymorphisms and mutations involve in the cause of the disease, and thus form a variety of different asthmas. One of the polymorphism and mutation that cause asthma is at the IL-13 R11OQ gene.
The gene function of IL-13 is to produce sufficient amount of IgGs and IgEs on the cell surface. Although cytokine IL-13 is independent of IL-14 from its activity, but both of the cytokines share a common signaling pathway. IL4 induced CD23 expression on B cells, enhanced CD72, surface IgM, and class II MHC antigen expression, and induced germline IgE heavy-chain gene transcription in highly purified B cells. The specific signaling pathway for IL-13 and IL-14 is mainly target for the treatment of allergy and asthma. An enzyme called acidic mammalian chitinase is discovered a large amounts within patients with allergic reactions. This enzyme is induced by the T-helper-2 specific and it is to inhibit the IL13 pathway activation and other chemokine inductions. Studies shown that the enzyme (AMCase) is an important mediator of the Th-2 disorders such as asthma due to the fact that the Th2 inflammation and hyperresponsiveness taken from mice inhibits IL13 pathway activation and chemokine induction, and it is mostly found in the epithelial cells and macrophages in the tissue samples. There are two receptors for the IL13. The type one receptor is more reactive when dealing with Th2 development and the type two receptor is not found in the T cells and it is responsible for regulating cell that mediate airway hypersensitivity and mucus secretion. The R11OQ variant is associate asthma in populations as Britain and Japan with ninety-five percent confidence level.
Reference (147683 INTERLEUKIN 13; IL13)
In “Pharmacogenetics of asthma in children” the researchers stated that asthma is caused by a combination of genetic and environmental factors, and therefore they suggest a personalized medicine for asthma treatment. In the article, they mention some genes polymorphisms that cause asthma and some of the treatments and medication that are being used. The TBX21 (T-bet) gene and the corticotropin-releasing hormore receptor 1 (CRHR1) gene are two these gene polymorphisms where inhaling corticosteroids has proven to be effective. In an article called “TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids” which was used as a reference in the original article, the researcher studied airway responsiveness (PC20 ) of children with asthma for four years and found a correlation between genetic variation in TBX21 and corticosteroids, which lead to improvement in asthma condition. Their results proved that a nonsynonymous SNP in the TBX21 gene enhances the effects of inhaled corticosteroid usage in PC20 of asthmatic children.
I found an article from PubMed called”Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids” that discusses ICS and CRHR1 gene. Here, researchers tried to find association between changes in lung function from the biological actions of corticosteroids. After analyzing three populations who used inhaled corticosteroids as the primary therapy for asthma, they found that individuals who were homozygous for the variant CRHR1 gene showed a double to quadruple lung function response to corticosteroids as compared to those who lack the variants. The researchers therefore suggest that CRHR1 have pharmacogenetic effects in influencing asthmatic response to corticosteroids.
This paper focuses on the different genes that are thought to be responsible for developing asthma. There are so many different types of asthma, so they believe many different genes contribute to its development. There are several mutations and gene polymorphisms discussed that lead to asthma. One is the LTC4S gene which stands for leukotriene C4 synthase and is on chromosome 5q35. It converts LTA4 to LTC4 by conjugation to reduced glutathione. Leukotrienes are mediators in asthma that are released by eosinophils, and macrophages. LTC4 makes cysteinyl leukotrienes which increase the production of mucus, and contract bronchial and smooth muscle.
Patients with asthma and aspirin sensitivity have greater cysteinyl leukotriene production to the effects of inhaled cysteinyl leukotrienes than people that are aspirin-tolerant. The receptors for LTC4 are CYSLTR1 and CYSLTR2. CYSLTR-selective pharmacologic competitors are important to treat asthma. LTC4S which catalyzes the synthesis of LTC4 is done by joining LTA4 and GSH. This is synthesized by glutathione synthetase. Studies have shown that patients with the A-A type have lower cysteinyl-leukotriene levels in the presence of corticosteroids compared to others. This has possibility to help in the assessment of combined corticosteroid and antileukotriene therapy in asthma. Leukotriene receptor antagonists or LTRA can help with the mutations in the LTC4S gene, such as Montelukast which blocks the action of leukotriene by binding to the receptor and reducing bronchocontsriction.
Reference (246530, “Leikotriene C4 Synthase; LTC4S” on OMIM)
This article discusses the genetic aspects of predisposition to and development of asthma in children. The scientists performed several studies, as well as research on the topic and several genetic factors have been linked to asthma. They found that around seventy nine genes out of one hundred were asthma related genes. Also, HLA genes and asthma have been reported to have an association with the development of bronchial asthma. One treatment several people use to help treat there asthma are inhaled steroid products, known as ICS. They work by binding to the CRHR1 receptor, which increases lung expansion to facilitate breathing. As we know, a person who has asthma has difficulty breathing, so a medication that can operate in this manner is very effective. Although mostly effective, it has been found that ICS steroid inhalers are not always effective, and my also cause side effects in some patients.
One of the treatments I chose to focus on in this summer is the polymorphism 5IL-13 R110Q, and the therapy associated with it CH2 cytokine inhibitor. The article states that “IgE production is upregulated by Th2 cytokines, particularly interleukin-4 (IL-4), and is downregulated by Th1 cytokines, particularly interferon-g (IFN-g). Interleukin-12 (IL-12) and interleukin- 18 (IL-18) are the cytokines that induce IFN-g and downregulate IgE production. The way that TH2 cytokine inhibitors would work as a treatment for asthma is by interfering with interleukins such as IL-13. The airways of individuals with asthma contain inflammatory cells, which consists of white blood cells such as T’s and esinophils. One of the T lymphocytes TH2 help to regulate the IgE response, a response of the immune system that deals with allergens. Several cells, and cytokines are manufactured and released by the TH2 lymphocytes, which contribute to the development of asthma, and the complications that come with it. Therefore, by finding a method of treatment that can inhibit or counter-act the actions of these lymphocytes would be a way to help treat asthmatics. Corticosteroids such as ICS help to inhibit the TH2 cytokine responses.
OMIM http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124092
This article has to do with asthma and its causes due to environmental and genetic factors. The authors focus on the genetic and pharmacogenetics of asthma in children. The authors dissect and present the genes that seems to cause asthma. In addition they present the pharmacogenetics, personal medication for those who suffer from asthma especially since it varies from one person to another. The gene polymorphism I chose was TBX21 and H33Q with the class of therapy ICS. I actually suffer from asthma, but only when I’m out of breath, mostly from running. In high school I used to run track and cross country and at times I’d get short of breath and I’d use an inhaler which is the therapy of ICS; a corticotropin-releasing hormore receptor. This is why I chose to look into it. TBX21 and H33Q are poly-morphed genes that promote asthma. This article doesn’t go into much detail about the relationship between TBX21 and H33Q and ICS but that Caucasian children there was proof of improvement when the ICS therapy was used to those who were diagnosed with asthma due to the gene TBX21 and H33Q.I got onto PubMed and found an article that related both TBX21 and H33Q with ICS. “Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21 H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment.” It was an experiment based on the therapy ICS and how it’s affect its varies in individuals. “Genetic factors have been shown to be potential predictors of responsiveness to ICS. We aimed to evaluate those pharmacogenetic effects on asthma control in further detail.” They set up an experiment with an asthma control and the unknown with the four genetic polymorphisms: beta2-adrenergic receptor (ADRB2), adenylate cyclase 9 (ADCY9), neurokinin receptor 2 (NK2R) and T-box 21 (TBX21). They concluded that NK2R G231E G>A and TBX21 H33Q C>G are genetic predictors of response to ICS. Also an important factor is that this study was done to Korean patients. In the end the two poly-morphed genes I chose in relation to the therapy of ICS correlate with each other. ICS is a therapy that fights asthma in patients, but in the end every person is different and every body reacts differently to medicine. Which is why there such a wide variety to personalized medicine. Sooner or later everything is going to be personalized!
In this article, scientists discuss how the clinical features of patients with asthma and the cause for this disease tends to vary. Asthma has been known to be a result of genetic and environmental factors. However the reason for its development differentiates for each individual and personalized medicine is necessary for quality of life and asthma cure. One of the main pharmaceuticals utilized to treat asthma are inhaled corticosteroids (ICS). This form of treatment is very effective for asthma in adults as well as children. This paper discusses how there are reports concerning the parmacogenetics of corticosteroids because people with severe asthma tend to show no response to treatment with ICS. However, the TBS21 (T-bet) gene (His 33 Gln) and the corticotropin-releasing hormore receptor1 (CRHR1) gene are important for the pharmacogenetics of
ICS.
Reference:*122561
MGI, Links
CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1; CRHR1
This paper tells us about allergic diseases, like bronchial asthma and atopic dermatitis, develop as a result of a combination of genetic and epigenetic factors.
Beta2-agonists acts by binding to the Beta2-agonists receptor named ADRbeta2, a cell surface G-protein-coupled receptor. The Beta2-agonists receptor has several polymorphisms in the coding region such as Arg 16, Glu 27 Glu, and Thr 164 Ile, where Arg 16, Glu 27 Glu are functionally important.
The beta-2-adrenergic receptor agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. It had been reported that gly16 is associated with increased agonist-promoted downregulation of ADRB2 as compared with arg16. A form of the receptor with glu27 had been shown to be resistant to downregulation when compared with gln27, but only when coexpressed with arg16. In a group of 269 children in a longitudinal study of asthma, Martinez et al. (1997) performed spirometry before and after administration of albuterol and correlated the findings with the genotypes of these 2 polymorphisms. Two polymorphisms showed marked linkage disequilibrium, with 97.8% of all chromosomes that carried arg16 also carrying gln27. When compared to homozygotes for gly16, homozygotes for arg16 were 5.3 times and heterozygotes for the polymorphism arg16 to gly were 2.3 times more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between glu27 and response to albuterol.
I found this paper really easy to understand but also I found it very difficult to respond to. Now I realize how helpful the discussion in class is cause I got completely lost writing this respond.
Reference:
+109690 Beta-2-Adrenergic Receptor; ADRB2
Asthma is a very serious allergic disease, which from a number of studies has been concluded to be a hereditary condition. This disease does not occur from only one gene, but rather from a genetic accumulation of genes that have suffered mutations. These genetic accumulations have been found to change depending on which ethnic group an individual is from. But from all of these genes that can cause asthma this paper focused more on those genes related to the development of asthma, in accordance with the various stages of allergic reaction and development: LTC4S A-444C, LTC4S A-444C, IL-13 R110Q, ALOX5, MRP1, CYP1A2 -3594, ADRb2 R16G, TBX21 H33Q, CRHR1. Luckily, thanks to pharmacogenetics, scientists have been able to produce anti asthmatic drugs that work on a single gene, or on two at a time, effectively. These drugs depend on the gene and how the deficiency of that gene can be controlled with the drug, for example there are four types of classifications for asthma: antigen recognition, IgE production, production and release of mediators, and events on target organs.
The gene I am going to focus on is the ALOX5. This gene has been suggested to have an important role in inflammation and immediate hypersensitivity. The mutations that occur in this particular gene can lead to defects in the production or release of mediators, which scientists have already found a treatment for. These mediators are known as leukotrienes. These leukotrienes are formed from a biosynthetic pathway which its first enzyme is the protein that comes from the ALOX5 gene. So if a mutation where to occur on the gene’s transcription factor binding regions or on the protein encoding sequence, the resulting product formed would be deficient. And since these leukotrienes area what control inflammation of the veins if this molecule is not synthesized properly it leads to severe allergic reactions which is what asthmatics suffer from. That is why scientists use leukotriene antagonist’s therapy. This drug inhibits leukotrienes from causing an extreme inflammation and since it does not have side effects it is commonly used in children.
Asthma is a very serious allergic disease, which from a number of studies has been concluded to be a hereditary condition. This disease does not occur from only one gene, but rather from a genetic accumulation of genes that have suffered mutations. These genetic accumulations have been found to change depending on which ethnic group an individual is from. But from all of these genes that can cause asthma this paper focused more on those genes related to the development of asthma, in accordance with the various stages of allergic reaction and development: LTC4S A-444C, LTC4S A-444C, IL-13 R110Q, ALOX5, MRP1, CYP1A2 -3594, ADRb2 R16G, TBX21 H33Q, CRHR1. Luckily, thanks to pharmacogenetics, scientists have been able to produce anti asthmatic drugs that work on a single gene, or on two at a time, effectively. These drugs depend on the gene and how the deficiency of that gene can be controlled with the drug, for example there are four types of classifications for asthma: antigen recognition, IgE production, production and release of mediators, and events on target organs.
The gene I am going to focus on is the ALOX5. This gene has been suggested to have an important role in inflammation and immediate hypersensitivity. The mutations that occur in this particular gene can lead to defects in the production or release of mediators, which scientists have already found a treatment for. These mediators are known as leukotrienes. These leukotrienes are formed from a biosynthetic pathway which its first enzyme is the protein that comes from the ALOX5 gene. So if a mutation where to occur on the gene’s transcription factor binding regions or on the protein encoding sequence, the resulting product formed would be deficient. And since these leukotrienes area what control inflammation of the veins if this molecule is not synthesized properly it leads to severe allergic reactions which is what asthmatics suffer from. That is why scientists use leukotriene antagonist’s therapy. This drug inhibits leukotrienes from causing an extreme inflammation and since it does not have side effects it is commonly used in children.
Reference
152390
ARACHIDONATE 5-LIPOXYGENASE; ALOX5
I chose LTC4S, a.k.a LEUKOTRIENE C4 SYNTHASE; the article is +246530. Basically, leukotrienes help work agains bronchial inflammation in asthma patients. The CRHR1, a.k.a CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1; the article is 122561. Basically, CRHR1 is a hormone and neurotransmitter involved in stress response. Although I don’t understand the articles, it makes sense that if CRHR1 doesn’t function properly, then the LTC4S can’t be released to stop bronchial inflammation when the organism is in a stressful situation.
This paper discusses the genes that could possibly be responsible for asthma. When the offspring of parents with asthma is compared to those without the rate of asthma is higher. These offspring also contain a certain phenotype. The authors suggest that it is not just one gene but “multiple causative genes,” that may be responsible for asthma and allergic reactions. Genes from different ethnic groups can also be involved in asthma. This paper reports that HLA genes have be associated with bronchial asthma. HLA or human leukocyte antigen genes contain a large number of genes related to the immune system.
One of the many gene polymorphisms and mutations associated with asthma is the CRHR1 or corticotropin-releasing hormone receptor 1. “The corticotropin-releasing hormone receptor binds to corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress.”
Today many people treat their asthma with inhaled corticosteriods (ICS). Corticosteriods make it easier to breathe by reducing mucus and inflammation in the airway. The ICS bind to the CRHR1 receptor when it is inhaled. Another way of explaining this is that the corticotrophin releasing hormone in the ICS binds to the CRHR1 receptor in the lungs which opens that bronchi.
Hopefully we will progress smoothly and quickly to personalized medicine. Through this we will be able to give patients the medicine that will work best for the gene issue that they have. This will help ensure that everyone is receiving the treatment that will work best for them.
*122561 CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1; CRHR1
This study was done to prove how bronchial asthma and atopic dermatitis are influenced by the mixture of environmental and genetic factors. However, every individual reacts differently to the environmental factors and have different causes of disease so it would be more beneficial to everyone if their medicine is personalized. There are many studies that have been done to prove that multiple genes are the cause of asthma or allergic reactions because of the various pathogeneses for them. Once the personalized medicine is used therapeutically there is a sure possibility of an asthma cure and improvement of quality of life.
For one of the gene markers known as IL-13 R11OQ, the effective therapy that goes with the gene polymorphism is Th2 cytokine inhibitor. Apparently, asthma and allergic diseases have increased upon the children’s population because of the liberal use of antibiotics, the eradication of childhood infections, and the ‘cleaner lifestyle.’ Studies have shown that children who attend daycare and that have older siblings are less likely to develop any diseases like asthma mainly because of the increased exposure to infections. The point of exposing a child to germs at a young age is for the development of an immune response for these germs at an early age. The immune system development would balance out with the T helper (Th1) and Th2 cytokine producing cells. This study is mainly about how environmental factors are essential factors to the cause of gene polymorphisms and the advancing of asthma or allergic reactions.
I believe that trying to find something that we don’t already know is extremely difficult and tedious, especially when it is supposed to be found within a person’s billion base-paired genome. Maybe there will be machines to help scientists analyze the genome for them multiple genes that influence the development o the disease. Regardless, the fact that a combination of genes is the cause of an allergic reaction or asthma seems tedious.
REFERENCE:
#600807
ASTHMA, SUSCEPTIBILITY TO
Alternative titles; symbols
ASTHMA, BRONCHIAL
ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO
ASTHMA, PROTECTION AGAINST, INCLUDED
ASTHMA, DIMINISHED RESPONSE TO ANTILEUKOTRIENE TREATMENT IN, INCLUDED
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600807
Pharamcogenetics of asthma in children, by Kondo et al., emphasizes the importance of personalized medicine care as the next up-coming form of treatment for individual patients. Since the causes of diseases vary, medical researchers need to treat the diseases with medicinal drugs that are tailored to each patient’s needs. In the paper, it explains the genetics behind the pharmacogenetics of asthma and the possible guidelines for personalized medicine for asthma. I tried to focus on LTC4S and zafirlukast, a common therapy based on LTC4S.
Immunoglobin E (IgE) is one of types of antibodies that is related to allergens. When IgE binds with either eosinophils, master cells, and alveolarmacrophages, leukotrienes are released. In the process of making these leukotrienes, enzyme leukotrine C4 synthase( LTC4S) is produced. When LTC4S reacts with cysteinyl-leukotrienes, this reaction converts LTA4 to LTC4, which is an inflammatory mediator that tightens the smooth muscle in the bronchial tubes. If Cysteinyl-leukotriene is also present in large amounts, it will also cause the muscle in the bronchial tubes to contrict; this also increases mucous secretion, vascular permeability, and cellular infiltration.
To repress those allergic subsequence reactions, they can be treated by zafirlukast, which is one of the leukotriene receptor antagonists. According to the paper about zafirlukast by Dr. Dunn and Dr. Goa, this drug inhibits LTC4 and will not allow it to react with cysteinyl-leukotrienes and it will be more effective on both A/C and C/C genotypes.
I think that it is wise method to treat a disease based on the patience’s genetic character. Since many adults and children live with the pain of asthma, giving these patients personalized medicine treatment will help them breath easier without suffering.
Reference: Zafirlukast: an update of its pharmacology and therapeutic efficacy in asthma by Dunn CJ, Goa KL.
http://www.ncbi.nlm.nih.gov/pubmed/11270943
In this paper it is seen that the cause of many allergic diseases such as bronchial asthma and atopic dermatitis may be from the environment or even genetic reasons.
Gene polymorphisms and mutations that I chose was LTC4S, leukotriene C4 synthase. This gene is known for catalyzing the production of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH). With leukotriene the receptor binding metabolites would be LTD4 and LTE4. These metabolites are cysteinyl leukotrienes. After activation of certain granulocytes, the leukotrienes become very proinflammatory because they are strong lipid mediators.
Aspirin-intolerant asthma is a medical syndrome that’s classified by negative reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). The use of aspirin may eventually cause a bronchoconstriction in AIA in some people and with this come the making cysteinyl-leukotriene. Researchers Sampson and Cowburn came to the conclusion that the patients with AIA a high level of LTC4S gene in the bronchial biopsies. In the LTC4S, one promoter polymorphism was consistent in most of the patients that couldn’t take aspirin; this promoter was 444A-C. In AIA the rate that this promoter would occur was twice as much when compared to patients with asthma that are able to take aspirin for the syndrome.
Reference: 246530 LEUKOTRIENE C4 SYNTHASE; LTC4S; OMIM
IL-13 R110Q was chosen from the chart and showed to be responsive to Th2 Cytokine Inhibitor2 . Cytokines like TH2, according to Britannica online (http://www.britannica.com/bps/additionalcontent/18/36642975/Th2-Cytokine-Inhibitor-Suplatast-Tosilate-Inhibits-AntigenInduced-Mucus-Hypersecretion-in-the-Nasal-Epithelium-of-Sensitized-Rats) are involved in hypersecretion of mucous and allergic inflammation. The TH2 works to lower IgE serum levels therefore providing for less inflammation and issue breathing in the bronchioles. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600807
This article has to do with the environmental and genetic factors that induce asthma specifically in children. It has been found that specific gene traits can be the cause of asthma, and must be treated with the correct dosage and type of medication, as each person’s asthma may differ. The polymorphism TBX21 is the class of therapy ICS. A type of ICS could be an inhaler, which is a corticotrophin- releasing hormone receptor. Most people who have asthma, typically suffer from symptoms such as tight chest, hyperventilating, and shortness of breath; the feeling as if one cannot breathe. These can be induced by many reasons, such as physical activity, stress, humidity of air, etc.
This article has proven that TBX21 is a morphed gene that promotes asthma and children, Caucasian more or less, have shown improvement in symptoms when treated with ICS therapy.
“Genetic factors have been shown to be potential predictors of responsiveness to ICS.” When one is having an asthma attack, an inhaler is taken, releasing corticotrophin which once binds to the receptor site, different variants are used to suppress and mediate the symptom. The majority of the time, corticosteroids increase lung function up to four times as much as a normal asthma patient, which is an outstanding goal.
I chose this gene mutation because I personally suffer from asthma, but only sports induced. I found that the inhaler helped but only when taken at the right moments, in the correct manner.