Fundamentals of Bioinformatics - Oogurtsov A.N. 2013

Information Principles in Biotechnology
Bioinformatics in Pharmacy
Medical Genomics and Pharmacogenomics

Medical Genomics encompasses the molecular Diagnosis of hereditary disorders, predictive medicine, Gene Therapy, and pharmacogenomics.

Gene Diagnostics and Gene Therapy. Thanks to the breakthroughs of the Human Genome Project—specifically the mapping of single-nucleotide variations (polymorphisms), or SNPs—new avenues in gene diagnostics and therapy have emerged. Genes implicated in the Etiology of over 6,000 Hereditary diseases have now been identified.

Several disorders (such as Duchenne muscular dystrophy, phenylketonuria, and hemophilia) are monogenic, meaning they are caused by Mutations in terminal differentiation genes. However, even in Monogenic Diseases, the severity of the pathological process, age of onset, clinical course, complications, and outcomes are also heavily influenced by modifier genes. The Role of modifier genes becomes even more prominent in late-onset conditions.

Predicting outcomes is far more complex in polygenic and multifactorial disorders, which involve multiple genes interacting with diverse environmental factors. The majority of common diseases fall into this category—including Cancer, Hypertension, asthma, Epilepsy, diabetes, Schizophrenia, and bipolar disorders.

Hereditary diseases can theoretically be treated via gene therapy, which involves the targeted modification of somatic Cells. Gene delivery into cells is typically carried out using viral vectors that utilize RNA to transport the genetic material. Recombinant DNA research enables scientists to determine the specific function of each gene at various stages of ontogenesis, as well as to study how human and other species' genes are expressed in microorganisms.

Introducing genetic material into a Cell can achieve the following objectives:

✵ compensating for the function of a deficient gene;

✵ eliminating a defective gene;

✵ introducing a new gene that confers a trait favoring cell survival.

Nevertheless, the advancement of this field raises serious concerns: the potential for unintended alterations to the human gene pool resulting from the incorporation of novel gene constructs into Germ Cells, as well as the propagation of hereditary conditions in treated individuals who have descendants.

Biological Models of Genetic Diseases. To generate laboratory animals that serve as biological models for hereditary disorders, targeted mutagenesis of Embryonic Stem Cells is employed. These biological models are widely used both to identify genes responsible for specific pathologies and to study complex gene interactions influenced by myriad Factors affecting the human phenotype (such as Gene Mutations, age, sex, infections, toxins, and other environmental exposures).

Numerous Examples illustrate how comparative genomics between humans and laboratory animals AIDS in investigating the etiology of severe and prevalent diseases. Until recently, the metabolic pathways and genes involved in the Pathogenesis of obesity remained largely unknown. Today, mutations in certain genes homologous to those found in mutated fat, obese, and diabetes mouse strains have been identified in patients with morbid obesity. Researchers discovered a gene in mice whose targeted mutation prevented diet-induced obesity. It turned out that the homologous gene in humans encodes a serum glycoprotein secreted by activated T lymphocytes that modulates immune cell interactions. Similarly, several genes have been traced in hypertensive patients whose homologs are mutated in rat strains characterized by congenital hypertension.

Gene Networks. Investigating gene interactions and identifying "master" and modifier genes are closely linked to the construction of so-called gene networks. A gene network comprises the following components:

✵ a core group of genes forming the network's Nucleus;

✵ the Proteins encoded by these genes;

✵ signal Transduction pathways;

✵ positive and negative feedback interactions ensuring autoregulation;

✵ low-molecular-weight compounds.

The genes forming the network's core (central genes) coordinate the Functions of all other network genes. Each network is characterized by a cassette mechanism that activates large groups of genes via a single METABOLISM/31.html">Transcription factor. Gene networks can be constructed for any congenital defect or disease. Data regarding gene networks are compiled in specialized Databases such as GeneNetWorks (http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/) at the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences (SB RAS).

Pharmacogenomics. It has long been observed that for the exact same disease, identical medications can exhibit varying efficacy and trigger diverse adverse side effects. These variations are driven by numerous factors (such as the pathogenesis and severity of the disease, the patient's AGE AND SEX, Liver and Kidney function, and co-occurring conditions), all of which must be accounted for during clinical drug trials. As early as the 1950s, documented reports emerged indicating that drug efficacy and toxicity depend heavily on the Organism's hereditary traits. Among the earliest publications were clinical observations noting that:

✵ the excessively prolonged effect of suxamethonium, a Muscle relaxant used during surgical Procedures, is associated with an inherited deficiency of plasma cholinesterase;

✵ the onset of hemolysis during antimalarial therapy correlates with the inherited activity level of erythrocyte glucose-6-phosphate dehydrogenase;

✵ adverse reactions to isoniazid, manifesting as peripheral neuropathy, occur due to a genetically determined reduction in Acetylation rate.

This marked the birth of a new discipline—Pharmacogenetics—focused primarily on pharmacological phenotypes.

The explosive growth of bioinformatics beginning in the 1980s, combined with novel molecular biology techniques for sequencing and cloning genome coding sequences, transformed pharmacogenetics into pharmacogenomics. This modern field identifies hereditary traits at the molecular-genetic level and aims to develop drugs tailored to specific genotypes.

Pharmacogenetics and pharmacogenomics essentially study the same object, but at the phenotypic and genotypic levels, respectively. Consequently, these two terms are often used interchangeably.

The therapeutic and Adverse effects of a drug (pharmacodynamics) are primarily determined by its interaction with so-called pharmacological targets—neurotransmitter and Hormone Receptors, Enzymes, signaling proteins, and numerous other proteins that regulate cellular functions. In addition, the balance between a drug's efficacy and toxicity heavily depends on pharmacokinetics, which governs the time course of the drug's distribution, metabolism, and excretion within the body.

The goal of functional Genomics and Proteomics is to study the Functions of Proteins synthesized by the organism As a result of Gene Expression. Functional genomics has revealed that individual differences in therapeutic efficacy and the severity of adverse drug reactions are associated with polymorphisms in genes encoding (1) target proteins and (2) metabolic enzymes. While gene polymorphisms are most commonly associated with reduced activity of the encoded protein, they occasionally result in a protein with enhanced activity.

Pharmacogenomics investigates gene constellations (combinations) that determine the efficacy and toxicity of specific drugs.

Gene polymorphisms of pharmacological targets. Polymorphisms have been identified for nearly all genes encoding pharmacological targets, contributing to individual Variability in drug response.

The pharmacological role of a single nucleotide polymorphism (SNP) is illustrated schematically in Figure 84.

As molecular studies have shown, gene polymorphisms frequently correlate with altered sensitivity to the therapeutic effects of certain drugs, for example:

✵ ß-adrenoceptor polymorphisms correspond to sensitivity to ß-agonists in asthma patients;

✵ angiotensin-II type 1 receptor polymorphisms correspond to vascular sensitivity to phenylephrine;

✵ sulfonylurea receptor polymorphisms correlate with sensitivity to hypoglycemic sulfonylurea derivatives;

✵ serotonin receptor polymorphisms correspond to variations in response to antipsychotics, particularly clozapine.

Furthermore, altered drug sensitivity can be observed in polymorphisms of genes encoding proteins involved in disease pathogenesis. For instance, mutations in the gene determining apolipoprotein E reduce the efficacy of tacrine in Alzheimer's disease.

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Figure 84 - Patient genotypes determined by SNPs

Individual predisposition to adverse drug reactions can also depend on gene polymorphisms of pharmacological targets:

✵ dopamine D3 receptor polymorphism and the risk of tardive dyskinesia;

✵ potassium channel mutations and the risk of arrhythmic events;

✵ ryanodine receptor polymorphism and the risk of malignant hyperthermia during anesthesia.

Another cause of variable drug sensitivity is polymorphisms in the target proteins of pathogens and Viruses (e.g., HUMAN IMMUNODEFICIENCY VIRUS, Mycobacterium tuberculosis).

Gene polymorphisms of metabolic enzymes. Enzyme-catalyzed degradation of exogenous compounds leads to their detoxification and elimination from the body. Conversely, the therapeutic effect often requires The formation of an active product through the metabolism of a precursor molecule. A wide variety of enzymes are involved in xenobiotic metabolism, and the genes encoding these enzymes are frequently polymorphic.

Hereditary variations in Metabolic pathways are often monogenic. Their impact on a drug's pharmacokinetics and pharmacodynamics depends on whether the encoded protein is involved in the activation or inactivation of the substance.

If the protein encoded by an allelic gene is required for drug inactivation, the consequence may be increased toxicity (e.g., potentially fatal hematopoietic disorders at standard doses of mercaptopurine or azathioprine in patients with thiopurine S-methyltransferase deficiency).

Conversely, if the therapeutic effect requires drug activation by the encoded protein, gene polymorphism results in decreased efficacy (embodying, for example, significant individual variations in the analgesic effect of codeine).

However, the net effect of drugs is typically polygenic in nature, meaning it is determined by the interaction of multiple genes. For instance, one gene may determine the inactivation of a substance and, consequently, its plasma concentration in a given individual, while another gene determines target sensitivity and, therefore, the magnitude of the response at that concentration. The therapeutic efficacy-to-toxicity ratio will thus differ between patients who are heterozygous or homozygous for each of the two alleles.

Such gene interactions are extremely difficult to track solely through phenotypic observations (i.e., clinical signs), but bioinformatics methodologies have made this achievable.

It should be noted that alterations in genes encoding metabolic enzymes are not always critical for the normal metabolism of endogenous compounds. In such cases, pronounced pharmacological phenotypes manifest only upon provocation by specific exogenous substances.

However, certain metabolic genotypes affect the phenotype regardless of exogenous provocation. For instance, some forms of dihydropyrimidine dehydrogenase deficiency are associated with mental retardation.

Furthermore, polymorphisms in genes determining xenobiotic-metabolizing enzymes are associated with increased risks—such as The Development of certain types of cancer—due to impaired inactivation of exogenous or endogenous mutagenic molecules.

Numerous enzymes are involved in xenobiotic metabolism, and each individual represents a unique combination of metabolizing enzyme phenotypes. The concurrence of several metabolic gene defects, particularly when polymorphisms of pharmacological targets are simultaneously present, plays a significant role in idiosyncratic reactions to certain drugs.

Opportunities for a personalized approach to pharmacotherapy. Gene polymorphisms can be one of the reasons for Discrepancies in Data regarding the effects of medications. Therefore, clinical trial designs must account for such critical factors as the racial, ethnic, and population COMPOSITION OF THE compared test groups.

Genetic screening makes it possible to identify mutations in genes whose expression products play a key role in the pathogenesis of certain diseases. Developing drugs targeted at these specific sites can prevent the onset of disease in genetically predisposed individuals, thereby opening new horizons for preventive medicine.

Pharmacogenomics opens up possibilities for personalized drug therapy. The traditional strategy of the pharmaceutical industry is to develop drugs that are effective and safe for the majority of the population (although, of course, contraindications such as comorbidities and potential drug-drug interactions are always noted).

The development, manufacturing, and distribution of medications intended for small patient groups are commercially unviable. Nevertheless, the integration of automated personalized molecular genetic diagnostic systems (using gene chips) will enable the targeted Selection of drugs and their dosages.

A prime example is the molecular genetic approach to prescribing Chemotherapy for patients with acute lymphoblastic leukemia. The genotype of acute lymphoblastic leukemia is considered a crucial prognostic factor determining Treatment intensity. Additionally, certain polymorphisms in metabolic enzyme genes are known to significantly affect the efficacy and toxicity of chemotherapeutic agents used in this form of leukemia.

Gene polymorphisms of cytokines and other determinants of host susceptibility to pathogens have been identified, along with polymorphisms of cellular receptors in the cardiovascular, endocrine, and other systems that influence individual toxicity from chemotherapy. Ultimately, this makes it possible to develop an acute lymphoblastic leukemia microarray to help objectively and rapidly tailor therapy for each patient.