1
Q
What are the genetic factors?
A
- Pharmacodynamics
- Pharmacokinetics
2
Q
What is Pharmacodynamics?
A
- What the drug does to the body
3
Q
What are the aspects for Pharmacodynamics?
A
- Enzymes
- Receptor
- Target
- Signaling
4
Q
What is Pharmacokinetics?
A
- What the body does to the drug
5
Q
What are the aspects of Pharmacokinetics?
A
- ADME
- Absorption, Distribution, Metabolism, Execretion
6
Q
What is the pharmacist role?
A
- Recommended, Designing, Educating, Communication
7
Q
What are some of the competences that we’ll need to establish?
A
- Pharmasict specific knowledge, Genetics & Diseases, Pharmacogentics & Pharmacodynmaics, Ethical & legal implications
8
Q
What is DNA?
A
- A thin, linear polymer fiber that is double stranded
9
Q
What are the four nucleobases in the DNA?
A
- Adenine (A)
- Thymine (T)
- Guanine (G)
- Cytosine (C)
10
Q
What is genome?
A
- Complete set of DNA
- 3 billion bases pairs
- 20,000 genes
11
Q
What is a gene?
A
- Sequence of DNA or RNA which codes for a molecule that has a function
12
Q
What is the main classification of genes?
A
- Proteins Coding Genes [Genes that are expressed to be proteins
- Noncoding Genes [mircoRNA: regulate protein-coding genes expression]
13
Q
What is the structure of a Protein Coding Gene?
A
- 5 prime to 3 prime
- Exon: where the decoding takes place
- Intron: ?
14
Q
What is Transcriptions?
A
- It is the DNA into RNA
- ATGC = AUGC [T become U]
15
Q
What is Translation?
A
- It is RNA into Proteins
- AUG starts it and UGA/UAG/UAA stops it
16
Q
How many codons and amino acids are within Genetic Coding Systems?
A
- 64 Codons [UAG, UGA, UAA = Stop; AUG = Start]
- 20 amino acids
17
Q
Where can polymorphism occur?
A
- Occur at the same position of homologous chromosomes [diploid]
- NO polymorphism on single germ cells [haploid]
18
Q
What is an Allele?
A
- DNA sequence at a locus of ONE of the two HOMOLOGOUS CHROMOSOMES
19
Q
What is a Genotype?
A
- COMBINATION of alleles at the SAME locus of the homologous chromosomes
20
Q
What is a Homozygote?
A
- IDENTICAL alleles at the locus
21
Q
What is the Heterozygote?
A
- TWO DIFFERENT alleles
22
Q
Explain briefly what Mendel’s Law is?
A
- Each of the parents pass a randomly selected allele to the offspring
23
Q
What is a Single Nucleotide Polymorphism [SNP]?
A
- A single nucleotide is changed to another
- CAT to CCT = HIS to PRO
24
Q
What is a Missense SNP?
A
- Amino Acid Substitution [Causing a gain- or loss-of-function
25
What is a Nonsense SNP?
- Amino acid changes to a stop codon [causes loss-of-function]
- HIS to STOP
26
What is Insertion/deletion toward polymorphisms?
- An addition or removal of 1 or 2 [never 3] of nucleotides often causing a framshift
- Loss-of-function
27
What is the difference between CNV, Gene Expression, Missense, Nonsense?
- CNV: Gain-of-Function
- Gene Expression: Loss-of-Function
- Missense: Gain- or Loss-of-Function
- Nonsense: Loss-of-Function
28
How does "QRS" related to genotype data?
- Q = T/T
- R = T/C
- S = C/C
29
How do we calculate the Number of Alleles and the Percent of Allele?
- T allele = 2Q+R
- S allele = 2S+R
- T allele % = [2Q+R]/2N
- S allele % = [2S+R]/2N
30
If the frequencies are known, how do find out MAF?
- Homozygous + 1/2 Heterozygous
31
What is Linkage Disequilibrium [LD]?
- How often two SNPs are inherited together
- Non Random association of alleles at different loci on the same chromosome
- NO LD: infinite recombination
- COMPLETE/PERFECT LD: no recombination
- INCOMPLETE LD: partial recombination
32
How do we measure LD?
- R2 = 0: no LD
- R2 = 1: complete LD/Perfect LD
- R2 > 0.8: Strong LD
33
What does R2 mean within measuring LD?
- How strong the correlation between two variables
34
What is the 1000 Genome Project?
- To find most of the genetic variants with frequencies of 1% in the population
- Major Finding: Different Profiles, Geographic differences , 250-300 loss-of-function
34
What is the 1000 Genome Project?
- To find most of the genetic variants with frequencies of 1% in the population
- Major Finding: Different Profiles, Geographic differences , 250-300 loss-of-function
35
What is the major website used in PGx infomation?
- PHARMGKB
36
Who are able to perform a PGx test?
- CLIA certified labs that offer the testing
37
What are some Important factors to be considered when testing?
- Family history, Race & Ethnicity, Vulnerable Population, Consent/assent
38
What is the target for samples during PGx testing?
- DNA
- Its easy to collect, avoids contamination, less invasive, standard procedure
39
What is important to know about Peripheral Blood?
- White Blood Cells have the DNA
- Need about 2-6ml
40
Are we able to get DNA from red blood cells?
- NO, we can not
41
What is important to know about Cheek Swabs?
- There is a less DNA yield than blood
- Possible contamination from food
42
What are the PGx Testing methods?
- Genotyping: DNA Chip [test known variants]
- Sequencing: Sanger Sequencing & High-Throughput sequencing [both known and unknown
43
What is a Polymerase Chain Reaction [PCR]?
- The most useful technique for DNA amplification
44
What are some of the substates used in PCR?
- DNA template, dNTPs, Primers [2 short regions], Buffer [pH, Mg2+], Enzymes
45
What is Denaturation in PCR?
- Temperature in increased to separate DNA strands
46
What is Annealing in PCR?
- Temperature is decreased to allow primers to base pair to complementary DNA template
47
What is Extension in PCR?
- Polymerase extends primer to form nascent DNA strand
48
What is the Exponential Amplification of PCR?
- Process is repeated and the region of interest is amplified exponentially
49
What is important point to know about PCR?
- They amplify DNA from both DNA molecules of Homologous chromosomes
50
What does the DNA chip do?
- Detects KNOWN SNPs or targeted SNPs
- High Throughput [a lot of results]
- Low Cost
51
What is the Chip-based PGx Testing Platform?
- Amplichip CYP450 Array
52
What is used in DNA [Sanger] Sequencing?
- Conventional Sequencing [Sanger]: Low throughput & Targeted Sequencing
- Next Generation Sequencing: High Throughput, Parallel Sequencing, & Massive Sequencing
53
What does the Sanger Sequencing do?
- Can detect BOTH KNOWN and UNKNOWN alleles: SNPs, Indel, Small CNV
- Low Throughout
54
What is important to know about Next Generation Sequencing [NGS]?
- Can sequnce DNA of Mulitple indiviuals
- Higher cost
- Very low cost per SNP
- Detects ALL KNOWN or UNKNOWN alleles
55
What is sequencing depth and coverage?
- The average number of reads that align to known reference bases
- 10x to 30x depth and coverage is recommended
- Need multiple oberservation to come to a reliable base call
56
What is the difference between Germline and Somatic?
- Germline: sequence of germ cells that may be passed to a child [exists since the individual was born]
- Somatic: Sequence of nongermline cells that is not passed to a child [acquired]
57
What is the interpretation of P Value?
- P>0.1: No significant association
- 0.05
58
What is the way that we measure the strength of the P value?
- Odds Ratio: increased risk for a phenotype by carrying a specific genotype/allele compared to the patients without carrying
59
How do we calculated Odds Ratio?
- OR= (odds of phenotype with genotype/allele)/(odds of phenotype without genotype/allele)
- OR=1: no association
- OR>1: Increased risk [high risk to phenotype]
- OR<1: Decreased risk [low risk to phenotype]
60
What is the 95% Confidence Interval?
- CI>1: Significant Risk
- CI=1: No Statistical Significance
- CI<1: Significant Protective
61
How do we test our hypothesis during experiments?
- Control is key [Positive and Negative Control]
- No negative control in human trials
- Reliable results NEED a large sample size
- Clinical Studies use median and NOT the mean
62
Why do we not use the mean to test a hypothesis?
- The median is FASTER and the patient data is not NORMALLY DISTRIBUTED
63
What is the desirable value for LDL?
- <130 mg/dl [patients with hypercholesterolemia carry the gain-of-function]
- 12.1 mmol/L ~ 465 mg/dl?
64
What is the key function of PCSK9?
- Helps regulate LDL-C
- A fully human monoclonal antibody against PCSK9 blocks PCSK9/LDL-c interaction [decrease LDL]
65
What does Antisense Oligonucleotide [ASO] do?
- Blocks the mRNA directly to reduce the protein being made from that particular mRNA [no disease causing protein made]
66
Explain mRNA medicine?
- Spike protein is removed from the virus
- mRNA sequence is generated
- mRNA sequence is coated with lipids
- Once injected, the mRNA sequence makes millions of copies of proteins
- the protein produces antibodies that protect the body
67
What is monoclonal antibodies and ADC?
- An antibody is a type of protein that very specifically binds to its target and often blocks the function of its target
68
What does Gene Therapy with adeno-associated virus [AAV] do?
- Packages the transgene into AAV vectors
- There is a one time infusion
- Goes in the liver to enable production of therapeutic proteins
69
What does CRISPR/Cas9 do within the genome?
- A DNA editing technique that will find a segment of DNA, use an enzyme and cut it off, then replace it with a healthy copy
70
What about stem cells?
- Still in early stage
71
What are the first line drugs that are used in the treatment of Pancreatic Cancers?
- Folfirinox, Gemcitabine, Nabpaclitaxel, Cisplatin
72
What are the PD-1 Blockers?
- Perbrolizumab, Nivolumab, Cemiplimab
73
What are the PD-L1 Blockers?
- Atezolizumab, Avelumab, Durvalumab
74
What is Synthetic Lethality?
- A mutation in two genes that results in cell death [BRAC-1 is already mutated] but a mutation in just one of the two genes does not
75
What are the two pathways that KRAS can activate?
- RAF-MEK pathway: Inhibited by Vemurafenib & Trametinib
- PI3K pathway: Inhibtied by GDC0941
76
What is important to know about AMG 510?
- First in class KRAS G12c inhibition ONLY
77
What is the drug combo for Melanoma Patients with NRAS mutation
- Ribociclib + Binimetinib
PHRM 847: Genomics
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