Quality by design Flashcards
Describe the composition of the human genome
The human genome is the complete set of genetic instructions that encode the biological characteristics of a human being. It is composed of DNA, which is made up of four nucleotide bases: adenine (A), guanine (G), cytosine (C), and thymine (T). These nucleotide bases pair up in specific combinations, with A always pairing with T, and C always pairing with G, forming a double helix structure.
The human genome consists of approximately 3 billion base pairs, which are organized into 23 pairs of chromosomes. These chromosomes are divided into two categories: autosomes and sex chromosomes. The first 22 pairs of chromosomes are autosomes, while the 23rd pair is the sex chromosomes, which determine an individual’s biological sex. Females have two X chromosomes, while males have one X and one Y chromosome.
Only a small fraction of the human genome actually codes for proteins, which are the building blocks of cells. This protein-coding DNA makes up about 1.5% of the genome. The remaining 98.5% of the genome is non-coding DNA, which is involved in regulating gene expression, controlling chromosome structure, and other important biological processes.
The human genome also contains many repetitive sequences, which are sequences of DNA that are repeated multiple times throughout the genome. These repetitive sequences can vary in length and can be found in different regions of the genome. Some repetitive sequences are important for regulating gene expression, while others have no known function.
Explain how a knowledge of the human genome
can benefit patient treatment
Personalized Medicine: The genetic information in a patient’s genome can help doctors to tailor treatments to the individual, based on their unique genetic makeup. For example, genetic testing can identify patients who are at increased risk of developing certain diseases, allowing for earlier interventions or preventative measures. Additionally, genomic data can inform the selection of medications that are most likely to be effective for an individual patient and minimize the risk of side effects.
Disease Diagnosis: Genetic testing can also be used to diagnose certain diseases, particularly those that have a genetic component. For example, genetic testing can identify mutations in the BRCA1 and BRCA2 genes that increase a person’s risk of developing breast and ovarian cancer, allowing for earlier and more targeted interventions.
Disease Prevention: A knowledge of the human genome can inform preventative measures for diseases that have a genetic component. For example, individuals with a family history of colon cancer can undergo regular colonoscopies starting at an earlier age than recommended for the general population. Genetic testing can also identify carriers of genetic mutations that increase the risk of passing on certain diseases to their children, allowing for informed family planning decisions.
Drug Development: Understanding the genetic basis of diseases can inform the development of new drugs and therapies. For example, drugs that target specific genetic mutations that drive cancer growth can be developed, leading to more effective and targeted cancer treatments.
Define the terms pharmacogenetic and
pharmacogenomic`
Pharmacogenetics is the study of how genetic variations can affect an individual’s response to drugs. It focuses on identifying genetic differences that can impact drug metabolism, drug efficacy, and drug toxicity. Pharmacogenetic testing can help to identify genetic variants that can affect how an individual metabolizes a drug, allowing doctors to personalize treatment and select medications that are most likely to be effective for the patient.
Pharmacogenomics, on the other hand, is the broader study of how genetic variations can affect drug response on a larger scale, using high-throughput technologies to analyze large sets of genetic data. It involves studying the entire genome, rather than specific genes, to identify genetic variations that can impact drug response. Pharmacogenomics aims to identify genetic variants that are associated with drug response across populations, allowing for the development of more effective and targeted drug therapies.
Describe, using examples, how pharmacogenetic
variation influences drug efficacy and toxicity
Codeine metabolism: Codeine is a commonly used pain medication that is metabolized by the liver enzyme CYP2D6. However, individuals with genetic variations that result in reduced CYP2D6 activity may not be able to effectively metabolize codeine into its active form, leading to reduced pain relief. On the other hand, individuals with increased CYP2D6 activity may rapidly metabolize codeine into its active form, leading to increased risk of toxicity.
Warfarin dosing: Warfarin is a blood-thinning medication that is commonly used to prevent blood clots. However, the optimal dose of warfarin can vary widely between individuals, and is influenced by genetic variations in the CYP2C9 and VKORC1 genes. Individuals with reduced CYP2C9 activity or increased VKORC1 activity may require lower doses of warfarin to achieve the desired anticoagulant effect, while individuals with increased CYP2C9 activity or reduced VKORC1 activity may require higher doses.
6-MP toxicity: 6-Mercaptopurine (6-MP) is a medication used to treat leukemia and other cancers. However, individuals with genetic variations in the TPMT gene may have reduced TPMT activity, which can lead to increased toxicity from 6-MP. In these individuals, lower doses of 6-MP may be necessary to avoid toxicity.
Abacavir hypersensitivity: Abacavir is an antiretroviral medication used to treat HIV. However, approximately 5-8% of individuals who take abacavir experience a hypersensitivity reaction, which can be severe and potentially life-threatening. This hypersensitivity reaction is strongly associated with genetic variations in the HLA-B gene. Genetic testing for the HLA-B*5701 variant can help identify individuals who are at increased risk of abacavir hypersensitivity and avoid this medication.
– Describe, using examples, how pharmacogenomic
variation is responsible for patient response to
therapy
HER2-positive breast cancer: HER2-positive breast cancer is a subtype of breast cancer that is characterized by overexpression of the HER2 protein. Treatment with the drug trastuzumab (Herceptin) has been shown to be highly effective in patients with HER2-positive breast cancer. However, not all patients with HER2-positive breast cancer respond to trastuzumab. This may be due in part to genetic variations in the HER2 gene itself or in other genes involved in the HER2 signaling pathway.
EGFR-mutant lung cancer: Epidermal growth factor receptor (EGFR) mutations are commonly found in patients with non-small cell lung cancer. Treatment with EGFR inhibitors such as gefitinib and erlotinib can be highly effective in these patients. However, not all patients with EGFR-mutant lung cancer respond to these drugs. This may be due in part to genetic variations in the EGFR gene or in other genes involved in the EGFR signaling pathway.
Thiopurine therapy for inflammatory bowel disease: Thiopurine drugs such as azathioprine and 6-mercaptopurine are commonly used to treat inflammatory bowel disease (IBD). However, not all patients with IBD respond to thiopurine therapy, and some experience significant side effects. This may be due in part to genetic variations in the genes involved in thiopurine metabolism, such as TPMT and NUDT15.
Statin therapy for high cholesterol: Statins are a class of drugs commonly used to lower cholesterol levels. However, not all patients respond to statin therapy, and some experience significant side effects. This may be due in part to genetic variations in the genes involved in statin metabolism, such as SLCO1B1 and CYP3A4.
