One area of medicine that is receiving a lot of attention for potential application of genomics to individualized medical care is pharmacogenomics: the study of how genetic variation among individuals affects the response to medication therapy. The development of a genetic profile that predicts efficacy, toxicity, or an adverse drug reaction is likely to have clinical significance. It allows health care professionals to choose a drug from which the patient will benefit—by reducing the risk for an adverse event—or to decide on a dosage that ensures adequate therapy and minimizes complications.

The US Food and Drug Administration (FDA) has recognized the importance of pharmacogenetic variation in individual response to drug treatment by including pharmacogenetic information on the labels that come with a broad range of pharmaceuticals (Table 1). As with all other aspects of personalized medicine, however, the cost effectiveness of such testing must be proved if it is to become part of accepted medical care.

Table1. Gene- Drug Combinations for Which There Is Pharmacogenetic Information in Their US Food and Drug Administration Package Inserts ^*

There are two ways that genetic variation affects drug therapy. The first is the effect of variation on pharmacokinetics; that is, the rate at which the body absorbs, transports, metabolizes, or excretes drugs and/ or their metabolites. The second is the variation affecting pharmacodynamics; that is, differences in the way the body responds to a drug. This can involve biochemical, physiologic, and molecular effects of drugs on the body and can include receptor binding (including sensitivity) and chemical interactions.

The terms pharmacogenetics and pharmacogenomics can be used interchangeably, although historically pharmacogenetics referred to variations in a single gene influencing drug response and pharmacogenomics referred to the sum total of all relevant genetic variation that determine drug behavior.

Variation in Pharmacokinetic Response

Variation in Drug Metabolism: The Example of Cytochrome P- 450

The human cytochrome P- 450 proteins are a large family of at least 57 different functional enzymes, each encoded by a different CYP gene. The cytochromes P- 450 are grouped into 18 families according to amino acid sequence homology. They code for enzymes. Three of these families, CYP1, CYP2, and CYP3, are particularly active in the detoxification of exogenous chemicals (xenobiotics), such as drugs. Four cytochrome P- 450 genes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4/ 5) are especially important because the enzymes they encode are responsible for the metabolism of about 75 to 80% of all commonly used drugs (Fig. 1).

Fig1. Contribution of individual cytochrome P- 450 enzymes to drug metabolism. Modified with permission from Guengerich F: Cytochrome P450s and other enzymes in drug metabolism and toxicity, AAPS J 8:E101– E111, 2006.

For many drugs, the action of a cytochrome P- 450 is to begin the process of detoxification through a series of reactions (oxidation) that render the drug less active and easier to excrete. Some drugs, however, are themselves inactive prodrugs whose conversion into an active metabolite by a cytochrome P- 450 is required for the drug to have any therapeutic effect.

Many of the CYP genes important for drug metabolism (including CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) are highly polymorphic, with alleles that result in absent, decreased, or increased enzyme activity. variants affect the rate at which many drugs are metabolized, with real functional consequences for how individuals respond to drug therapy. As one example, CYP2D6, the primary cytochrome in the metabolism of more than 70 different drugs, has dozens of reduced, absent, or increased activity alleles, leading to normal, poor, intermediate, or ultrafast metabolism (see table on metabolizer phenotypes). Missense variants decrease the activity of this cytochrome; alleles with no activity are caused by splicing or frameshift variants. In contrast, the CYP2D6*1XN allele is actually a series of copy number variant alleles in which the CYP2D6 gene is present in three, four, or more copies on one chromosome. Predictably, these larger copy number variants produce high levels of the enzyme. There are dozens more alleles that do not affect the function of the protein and are considered to be wild type. various combinations of these four classes of alleles produce quantitative differences in metabolizing activity, resulting in four main phenotypes: nor mal (also called extensive) metabolizers, intermediate metabolizers, poor metabolizers, and ultrafast metabolizers (Fig. 2).

Fig2. Serum drug levels after repeated doses of a drug (arrows) in three individuals with different phenotypic profiles for drug metabolism. (A) Poor metabolizer accumulates drug to toxic levels. (B) Normal (extensive) metabolizer reaches steady- state levels within the therapeutic range. (C) Ultrafast metabolizer fails to maintain serum levels within the therapeutic range.

Depending on whether a drug is itself an active com pound or is a prodrug that requires activation by a cytochrome P- 450 enzyme to have its pharmacologic effect, poor metabolizers may either accumulate toxic levels of the drug or fail to have therapeutic efficacy because of poor activation of a prodrug. In contrast, ultrafast metabolizers are at risk for being undertreated by a drug with doses inadequate to maintain blood levels in the therapeutic range, or they may suffer overdose due to too rapid conversion of a prodrug to its active metabolite. For example, codeine is a weak narcotic drug that exerts most of its analgesic effect on conversion to morphine, a bioactive metabolite with a 10- fold higher potency. This conversion is carried out by the CYP2D6 enzyme. Poor metabolizers—quite common in some populations, carrying loss- of- function alleles at the CYP2D6 locus fail to convert codeine to morphine, thereby receiving little therapeutic benefit; in contrast, ultrafast metabolizers can become rapidly intoxicated with low doses of codeine. A number of children have died from codeine overdoses due to having an ultrafast metabolizer phenotype.

As with many forms of genetic variation, the frequency of many of the alleles in the cytochromes P- 450 differs among different populations (Table 2). For example, a slow metabolizing phenotype for CYP2D6 that is present in 1 in 14 individuals of European ancestry is rare in Asia and nearly absent in Native Americans and Pacific Islanders. Similarly, slow metabolizing alleles at CYP2C19 show striking population variability, with 1 in 33 individuals of European descent but nearly 1 in 6 Asians having slow metabolism. These differences in the frequency of poor and ultrarapid metabolizers are important for the delivery of individualized genetic medicine in heterogeneous populations.

Table2. Frequency of Poor CYP2D6 and CYP2C19 Metabolizers in Various Population Groups

Clinical pharmacogenetics—the use of genetic data to guide drug therapy decisions, is supported by professional societies such as the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Royal Dutch Association for the Advancement of Pharmacy– Pharmacogenetic Working Group (DPWG), the Canadian Pharmacogenomic Network for Drug Safety, and others. They established guidance on pharmacogenes to provide actionable recommendations for the use of genomic information in a consistent manner. Additionally, the FDA has recognized the importance of pharmacogenetic variation in individual response to drug treatment by including pharmacogenetic information on the labels that come with a broad range of pharmaceuticals (see Table 1). As with all other aspects of individualized medicine, further cost- effectiveness studies of such testing must be provided if it is to become part of accepted medical care.

Variation in Pharmacodynamic Response

Malignant Hyperthermia Malignant hyperthermia is a rare autosomal dominant condition in which there may be a dramatic adverse response to the administration of many commonly used inhalational anesthetics (e.g., halothane) and depolarizing muscle relaxants (e.g., succinylcholine). Soon after induction of anesthesia, a patient develops life- threatening fever, sustained muscle contraction, and attendant hyper catabolism. The fundamental physiologic abnormality in the disease is an elevation of the level of ionized calcium in the sarcoplasm of muscle. This increase leads to muscle rigidity, elevation of body temperature, rapid breakdown of muscle (rhabdomyolysis), and other abnormalities. The condition is an important, if not a common cause of death during anesthesia. The incidence is 1 in 50,000 adults undergoing anesthesia but for unknown reasons is 10- fold higher in children.

Malignant hyperthermia is most frequently associated with pathogenic variants in a gene called RYR1, encoding an intracellular calcium ion channel. However, variants in RYR1 account for only approximately half of cases of malignant hyperthermia. At least five other loci have now been identified, one of which is the CACNA1S gene, which encodes the α1 subunit of a dihydropyridine- sensitive calcium channel. Precisely why the abnormalities in calcium handling in muscle found with RYR1 or CACNA1S variants make the muscle sensitive to inhalation anesthetics and muscle relaxants and precipitate malignant hyperthermia is unknown.

The need for special precautions when at- risk persons require anesthesia is obvious. Cooling blankets, muscle relaxants, and cardiac antiarrhythmics may all be used to prevent or reduce the severity of the response if an unsuspected attack occurs, and alternative anesthetics can be given to patients at risk. Pharmacogenomics guidelines are available to help guide clinical decision making.

Adverse Drug Reactions

 The majority (75– 80%) of adverse drug events result from predictable, nonimmunologic drug toxicities such as overdoses caused by medication errors, renal or hepatic disease, or drug- drug interactions. Most non predictable adverse drug events are thought to have a genetic component related to drug- gene interactions that contribute to about one- third of potential major or substantial drug interactions that occur in patients.

Of these, ~25 to 50% are true IgE- mediated drug hypersensitivity reactions (HSRs), including life- threatening anaphylaxis characterized by sudden onset of laryngeal edema, leading to occlusion of the airway, marked hypotension, and cardiac arrhythmias.

The remaining 50 to 75% of adverse drug reactions are genetically determined nonallergic immune reactions (i.e., HSR). These manifest as widespread damage to skin and mucous membranes, referred to as Stevens- Johnson syndrome (SJS) and (in its more serious extreme form), toxic epidermal necrolysis (TEN) (Case 1). Although rare, TEN is a very serious adverse drug reaction that causes denuding of large areas of skin and carries a mortality rate of 30 to 40%. There is a strong correlation between particular drugs and certain human leukocyte antigen (HLA) alleles in the major histocompatibility complex (see Chapter 9) that result in SJS and TEN. For example, individuals who take the retroviral drug abacavir and carry the HLA- B*5701 allele have a 50% risk for SJS or TEN, leading to the introduction of HLA- B*5701 typing as a standard of care screening tool prior to prescribing abacavir. Because ~5 to 8% of Europeans carry the HLA- B*5701 allele, the risk for a severe drug reaction in abacavir- treated patients from this population is especially significant. HLA- B*5701 screening has a negative predictive value of 100% and a positive predictive value of 47.9% for immunologically confirmed HSR (i.e., positive result on epicutaneous patch testing 6 to 10 weeks after clinical diagnosis), as demonstrated by one study. A similar situation exists with the use of the antiseizure medication carbamazepine and HLA- B*1502, which is present in (see Table 2).

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية يقيم مهرجان الماء المعين السنوي الثالث في بغداد

على هامش المؤتمر التمهيدي لألفية الحوزة العلمية.. الهيأة العليا تقيم جلسة حوارية عن تراث الشيخ الطوسي

العتبة العباسية المقدسة تستعد لإقامة حفل التكليف الشرعي لتلميذات مدارس كربلاء

لليوم الثاني.. قسم التطوير يواصل تقديم دورة إعداد المدربين (TOT) لملاكات مديرية تربية كربلاء

المزيد

الآخبار الصحية

اللحظات الأخيرة قبل الموت.. هذا هو تسلسل "فقدان الحواس"

وخز الأطراف وضعف الذاكرة.. علامات على نقص فيتامين هام

عادة صباحية بسيطة.. تأثيرها قد يحسن ضغط الدم

عادات يومية تدمر قلبك بصمت.. خبراء يطلقون التحذير

المزيد

الآخبار التكنلوجية

الذكاء الاصطناعي يفك لغز آثار أقدام الديناصورات

القمر أولا.."سبيس إكس" تؤجل خططها الخاصة بالرحلات إلى المريخ

الذكور أم الإناث؟ دراسة "تنسف الشائع" بشأن التوحد

خبير يكشف عن اقتراب العلماء من فك شفرات "لغات الحيوانات" !

المزيد

مواضيع ذات صلة

Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes

Genetic Basis of Cancer

Conditional Mutations Can Be Used to Study Essential Genes in Yeast

Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity

Recessive and Dominant Mutant Alleles Generally Have Opposite Effects on Gene Function

Genes and Environment in Development

Gene Therapy

The Genetics of mtDNA Disease

The APOE Gene Is an Alzheimer Disease Susceptibility Locus

The Genetics of Alzheimer Disease