Pharmacogenetics: The New Science of Personalizing Treatment
Drug therapy is the mainstay for managing most allergic diseases when avoidance of the offending allergen is impossible or is of limited effect. An important principle that guides the choice of one drug over another is the variation in drug responses between individuals. Why do drugs work well in some patients but not in others? This may be the result of diagnostic error, differences in disease severity, poor drug adherence, age, poor assessment of response and concomitant environmental exposures. Importantly, 60-80% of variations in drug response may be genetic. Currently, the only way a physician can deal with the variability in drug responsiveness is by trying another drug belonging to a different class, i.e. by using trial and error. The ability to distinguish responders from non-responders to a pharmacological agent in order to guide drug therapy will reduce the wasted time and effort required to tailor a drug treatment to an individual's needs, and at the same time, ensure that the right drug is given to match the disease process involved and to minimize side-effects. For specific drugs, individual patients show consistent responses over time and in relation to both efficacy and safety. Genetic variation accounts for much of this.
Genetic variation can occur at many levels, including drug absorption, distribution, metabolism, 'receptor' target and elimination. Single-nucleotide polymorphisms (SNPs) in critical molecules that govern these processes are now being identified at an alarming rate as the Human Genome Project begins to deliver on its promise. SNPs may cause a change in protein structure and function, the level of protein expression, or might influence the assembly of the final messenger RNA template from which the protein is synthesized (alternative splicing). Increasingly, SNPs are being identified in intronic regions (i.e. between coding exons) that influence the stability of the mRNA with an impact on the protein that ensues. SNPs in exons may either produce no change in the amino acid coded for (e.g. AGA → AGG both encode arginine and are referred to as 'conservative' SNPs), whereas others result in a new amino acid being substituted with consequent changes in protein structure and function (e.g. AGA → GGA results in arginine being replace by glycine and are referred to as 'non-conservative'). There are now many examples in which amino acid substitutions result in altered protein functions to influence drug uptake (e.g. P-glycoprotein transporter), metabolism (e.g. cytochrome P450 enzymes) and excretion (e.g. iron channels). However, most interest in allergic disease has centred around SNPs that influence the drug target to alter efficacy.
Many clinical studies have now demonstrated that β2-adrenoceptor SNPs influence the response of asthmatic airways to bronchodilator treatment. In particular, the asthmatic patients who carry Gly16 are more prone to acquire bronchodilator desensitization (resistance). Children who are homozygous or heterozygotes for Arg16 show greater responses to β2-adrenoceptor bronchodilators. Israel et al. examined whether the β2-adrenoceptor genotype influences the response of asthmatic patients to regular versus as-required short-acting salbutamol. Those who possessed the Arg16 homozygous allele and who were receiving regular salbutamol had a significantly lower morning peak expiratory flow when compared with the Arg16 homozygate individuals who took salbutamol as required. As those with the Gly16 variants will already have their β2-adrenoceptor downregulated, it is suggested that regular β2 agonist treatment induces a greater degree of receptor desensitization in those with the Arg16 variant, resulting in reduced endogenous β2-adrenoceptor tone first thing in the morning, and therefore, a lower peak expiratory flow reading. Another somewhat uncommon (1-2% frequency) SNP in the β2-adrenoceptor at amino acid 164 in the fourth transmembrane spanning domain reduced the ability of salmeterol, a long-acting β2-adrenoceptor agonist, to bind to its 'exosite', thereby markedly decreasing its duration of action.
A further illustration of the pharmacogenetics applied to allergic disease is the variable response to glucocorticosteroids. Although no SNPs have yet been shown to occur in the corticosteroid receptor gene, an alternatively spliced form (glucocorticoid receptor β), which is functionally inactive as a transcription factor, has been shown to occur with a higher frequency in corticosteroid-insensitive individuals with severe asthma.
The leukotriene pathway has also provided good examples of the importance of genetic influences. A repeat length polymorphism in the promoter of the 5-lipoxygenase enzyme on chromosome 10 modifies transcription factor binding and results in a reduced clinical response to a 5-lipoxygenase inhibitor, but appears not to influence the genetic susceptibility to asthma. A polymorphic variation in the leukotriene C4 synthase gene has been shown to be associated with aspirin-intolerant asthma. The SNP involved (-444 A → C) in the promotor of the enzyme gene on chromosome 5q creates a new transcription AP2 binding site. The same SNP causes reduced lung function in asthmatic children, and appears to influence the efficacy of cysteinyl leukotriene receptor antagonists. Those patients with the C allele generate more leukotrienes and are more responsive to leukotriene receptor antagonists.
These fascinating obervations go some way towards explaining drug response variability. However, many of the studies describing these effects are small and are inadequately powered to gauge the full impact of a specific polymorphic variant on a treatment response. In addition, it is highly likely that combinations of SNPs (haplotypes) are more likely to influence function, especially if these occur in different molecules along the same pathway.
The wide variations that occur in SNPs in populations from different countries or between different parts of the same country are likely to be of major importance in determining why certain drugs work better in some nationalities than in others, and also in explaining the wide variations in side-effects. What is now needed is for the pharmaceutical industry to embrace the challenges created by this new gene-environment interface in order to move towards tailoring drug treatments to a specific patient's needs. Not only will pharmacogenetics improve drug targeting in those most likely to benefit from them (and therefore improve adherence to treatment) but there will also be fewer side-effects. The future looks promising, but this will not be realized until pharmacogenetics is built in to drug trials both in the design phase and in helping stratify treatment responses.
Drug therapy is the mainstay for managing most allergic diseases when avoidance of the offending allergen is impossible or is of limited effect. An important principle that guides the choice of one drug over another is the variation in drug responses between individuals. Why do drugs work well in some patients but not in others? This may be the result of diagnostic error, differences in disease severity, poor drug adherence, age, poor assessment of response and concomitant environmental exposures. Importantly, 60-80% of variations in drug response may be genetic. Currently, the only way a physician can deal with the variability in drug responsiveness is by trying another drug belonging to a different class, i.e. by using trial and error. The ability to distinguish responders from non-responders to a pharmacological agent in order to guide drug therapy will reduce the wasted time and effort required to tailor a drug treatment to an individual's needs, and at the same time, ensure that the right drug is given to match the disease process involved and to minimize side-effects. For specific drugs, individual patients show consistent responses over time and in relation to both efficacy and safety. Genetic variation accounts for much of this.
Genetic variation can occur at many levels, including drug absorption, distribution, metabolism, 'receptor' target and elimination. Single-nucleotide polymorphisms (SNPs) in critical molecules that govern these processes are now being identified at an alarming rate as the Human Genome Project begins to deliver on its promise. SNPs may cause a change in protein structure and function, the level of protein expression, or might influence the assembly of the final messenger RNA template from which the protein is synthesized (alternative splicing). Increasingly, SNPs are being identified in intronic regions (i.e. between coding exons) that influence the stability of the mRNA with an impact on the protein that ensues. SNPs in exons may either produce no change in the amino acid coded for (e.g. AGA → AGG both encode arginine and are referred to as 'conservative' SNPs), whereas others result in a new amino acid being substituted with consequent changes in protein structure and function (e.g. AGA → GGA results in arginine being replace by glycine and are referred to as 'non-conservative'). There are now many examples in which amino acid substitutions result in altered protein functions to influence drug uptake (e.g. P-glycoprotein transporter), metabolism (e.g. cytochrome P450 enzymes) and excretion (e.g. iron channels). However, most interest in allergic disease has centred around SNPs that influence the drug target to alter efficacy.
Many clinical studies have now demonstrated that β2-adrenoceptor SNPs influence the response of asthmatic airways to bronchodilator treatment. In particular, the asthmatic patients who carry Gly16 are more prone to acquire bronchodilator desensitization (resistance). Children who are homozygous or heterozygotes for Arg16 show greater responses to β2-adrenoceptor bronchodilators. Israel et al. examined whether the β2-adrenoceptor genotype influences the response of asthmatic patients to regular versus as-required short-acting salbutamol. Those who possessed the Arg16 homozygous allele and who were receiving regular salbutamol had a significantly lower morning peak expiratory flow when compared with the Arg16 homozygate individuals who took salbutamol as required. As those with the Gly16 variants will already have their β2-adrenoceptor downregulated, it is suggested that regular β2 agonist treatment induces a greater degree of receptor desensitization in those with the Arg16 variant, resulting in reduced endogenous β2-adrenoceptor tone first thing in the morning, and therefore, a lower peak expiratory flow reading. Another somewhat uncommon (1-2% frequency) SNP in the β2-adrenoceptor at amino acid 164 in the fourth transmembrane spanning domain reduced the ability of salmeterol, a long-acting β2-adrenoceptor agonist, to bind to its 'exosite', thereby markedly decreasing its duration of action.
A further illustration of the pharmacogenetics applied to allergic disease is the variable response to glucocorticosteroids. Although no SNPs have yet been shown to occur in the corticosteroid receptor gene, an alternatively spliced form (glucocorticoid receptor β), which is functionally inactive as a transcription factor, has been shown to occur with a higher frequency in corticosteroid-insensitive individuals with severe asthma.
The leukotriene pathway has also provided good examples of the importance of genetic influences. A repeat length polymorphism in the promoter of the 5-lipoxygenase enzyme on chromosome 10 modifies transcription factor binding and results in a reduced clinical response to a 5-lipoxygenase inhibitor, but appears not to influence the genetic susceptibility to asthma. A polymorphic variation in the leukotriene C4 synthase gene has been shown to be associated with aspirin-intolerant asthma. The SNP involved (-444 A → C) in the promotor of the enzyme gene on chromosome 5q creates a new transcription AP2 binding site. The same SNP causes reduced lung function in asthmatic children, and appears to influence the efficacy of cysteinyl leukotriene receptor antagonists. Those patients with the C allele generate more leukotrienes and are more responsive to leukotriene receptor antagonists.
These fascinating obervations go some way towards explaining drug response variability. However, many of the studies describing these effects are small and are inadequately powered to gauge the full impact of a specific polymorphic variant on a treatment response. In addition, it is highly likely that combinations of SNPs (haplotypes) are more likely to influence function, especially if these occur in different molecules along the same pathway.
The wide variations that occur in SNPs in populations from different countries or between different parts of the same country are likely to be of major importance in determining why certain drugs work better in some nationalities than in others, and also in explaining the wide variations in side-effects. What is now needed is for the pharmaceutical industry to embrace the challenges created by this new gene-environment interface in order to move towards tailoring drug treatments to a specific patient's needs. Not only will pharmacogenetics improve drug targeting in those most likely to benefit from them (and therefore improve adherence to treatment) but there will also be fewer side-effects. The future looks promising, but this will not be realized until pharmacogenetics is built in to drug trials both in the design phase and in helping stratify treatment responses.
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