Exam 1 - Pharmacogenomics Flashcards by Zach Bell

study of how an individual’s genes influence effects of drugs on that individual’s health

pharmacogenomics

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entire genetic information of an organism

genome

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study of structure and function of genomes

genomics

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reduces adverse drug events (ADEs, something related to patient that gets reported), reduces health care costs, improves health care outcomes, stakeholders demand use of PGx

applications of PGx to health care

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anticoagulants, antidiabetics, antiepileptics, opioids, aspirin

most common ADR culprits

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lead to increased length of hospital stays, readmission rates, total hospitalization costs, inpatient mortality

ORADEs (opioid related ADEs)

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pharmaceutical companies received this saying that they must use genomic information as part of med guides

FDA issued guidance

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President Bush signs this into law in 2008

Genetic Information Nondiscrimination Act (GINA)

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how many nucleotides in human genome?

3.2 billion

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what percentage of the human genome constitutes genes?

less than 2%, many repeated sequences, many movable/jumping elements

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gene or element that moves from place to place in genome

movable/jumping elements

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our genomes are ____ not ____, ______% same only _____% different, these differences are what cause us to respond differently to _____

similar, same, 99.9, 0.1, drugs

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chromosomes number variations, gene copy number variations,insertion/deletion nucleotides, SNPs

types of DNA sequence variations

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differences in one nucleotide, good because it is better than, for example, a whole chromosome being added/deleted, predominate variations (98%)

single nucleotide polymorphisms (SNPs)

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study of biological variation and principles governing the inheritance and maintenance of that variation

definition of genetics

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variation is essential for survival, some variation may be disadvantageous (the ones that get discarded), or may be advantageous (the ones that stay)

central assumptions of genetics

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threadlike structures in which an organism’s genetic material is organized, composed of DNA RNA proteins (eukaroytic), composed of two chromatids joined at centromere, normally present in pairs, different species have different numbers of these, specific to each organism

chromosomes

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somatic cells, double chromosome number (2N/2n)

diploid cells

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reproductive cells/gametes have half the number of chromosomes (N/n) as that of somatic cells

haploid cells

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technique to display chromosomes

karyotyping

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chromosome pairs 1-22 are called _____ while pair 23 is called ____ and is designated ____ or ____

autosomes, sex chromosomes, XX, XY

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Down syndrome

trisomy 21, extra copy of chromosome 21

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severe retardation, death

trisomy 13, extra copy of chromosome 13

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microcephaly (smaller brain size)

trisomy 18, extra copy of chromosome 18

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behavioral defects

trisomy X, extra copy of chromosome X in females

sterility, gynecomastia (breasts developed)

XXY, extra copy of X in males

hyperactivity

XYY, extra copy of Y in males

physical transfer of part of one chromosome to another, often cause schizophrenia or bipolar disorders and some cancers

translocations

why does DNA folding happen?

DNA is a very large structure and needs to fit inside nucleus of cells, also needs to be able to unfold at will

coiling and compaction is an intrinsic property of cellular DNA, all cellular DNA is reversibly supercoiled to various degrees, cellular proteins affect degree of coiling and compaction

DNA supercoiling

enzyme that bind to DNA/"rides" DNA, enzyme opens DNA strand but remains attached to 3' end of DNA, once enzyme releases itself of DNA a phosphodiester bond is formed to close DNA strand (anytime there is a strand that is broken and remain unfixed the cell will die), relieve supercoiling of DNA

mechanism of action of topoisomerases

cut only one strand of DNA and unwind supercoils

Type I topoisomerases

cut both DNA strands and unwind supercoils

Type II topoisomerases

make it so that topoisomerases must remain bound to DNA, in case of antibiotics, the drug remains bound to bacterial DNA to cause cells to die because broken strands that remain unfixed die

topoisomerase inhibitors

gastric, colon, lung, ovarian cancers, leukemias

camptothecin

testicular, lung, gastric cancers, leukemias, sarcomas

etoposide (VP-16)

breast cancer, osteogenic sarcomas, lymphomas

doxorubicin

leukemia

daunorubicin

acute lymphoblastic leukemia

teniposide (VM-26)

used against pathogens resistant to other antibiotics

moxifloxacin

used against pathogens resistant to other antibiotics and anthrax

ciprofloxacin

mass of nucleic acids (mostly DNA, some RNA) and proteins in the nucleus of eukaryotic cells, undergoes physiochemical changes depending on cell physiology

chromatin

diffused open structure that represents active genes

euchromatin

compact dense structure that is inactive

heterochromatin

fundamental organizational unit of chromatin, formed by DNA and tightly bound proteins (histones), DNA wraps around histones which is important for cancer treatment

nucleosomes

small proteins with high basic amino acid content, five major classes

histones

dynamic nature of chromatin structure governs its function, structure regulates DNA replication, expression, amplification, silencing of genes

therapeutic applications of chromatin structure

chromatin structure application, cancer treatment

histone deacetylase

chromatin structure application, cancer treatment, heart disease

Poly-ADP-Ribose polymerase

chromatin structure application, viral diseases including HIV

DNA polymerase, reverse transcriptase, integrase

most eukaryotic non-gene DNA is ______, about half of which is derived from _______

repetitive, transposable elements (TEs), so of the 98% of DNA that aren't genes about half of that is movable throughout the genome, may cause mutations

ends of a chromosome, unique function during DNA replication

telomere

highly repetitive DNA, critical in cell division, middle of chromsome

centromere

basic unit of inheritance responsible for determining a trait of an organism, contains all genetic information necessary and sufficient for producing a functional polypeptide or RNA molecule

gene

regulate expression of genes

promoters

sequences that do not code for proteins

introns

code for part or all of a specific protein or RNA product

exons

removes intronic RNA, joins exonic RNA, makes mature message

splicing

amyotrophic lateral sclerosis (ALS), calcium-activated K+ channel in inner ear hair, muscular dystrophy, dementia

alternative splicing defects

skeletal muscle atrophy, X-linked, defects in dystrophin, different forms or subtypes, DMD most common

muscular dystrophy

largest gene in humans, encodes largest human protein dystrophin, multiple isoforms produced by alternative splicing, mutations known to affect splicing

DMD (Duchenne MD) genetics

____ can be in any place on the gene

deletions

during transcription, transcription factors skip certain exons

exon skipping

single stranded oligonucleotides, complementary to target pre-RNA or mRNA, modulate translation and increase/decrease protein level

antisense oligonucleotides (AONs) as drugs

drug used for age related macular degeneration

Macugen / AON: Pegaptanib

drug used for muscular atrophy

Spinraza / AON: Nusinersen

drug used for HF Hypercholesterolemia

Kynamro / AON: Mipomersen

drug used for DMD

Exondys 51 / AON: Eteplirsen

basic unit of hereditary final product may be protein or RNA

gene

different form of a gene, in a population there may be more than one of these per gene

allele

only one copy essential to exhibit a trait

dominant

two copies of allele required to exhibit a trait

recessive

indicates presence of two alleles that are exact copies of each in the same individual organism

homozygous

two different alleles of a gene in the same individual organism

heterozygous

description of the genetic composition of a specific trait

genotype

description of a physical, physiological, biochemical, pharmacological, clinical presentation of a trait, some are visible and others are not

phenotype

any physical or chemical change in the genetic material of an organism, may occur anywhere in the genome of an organism, anytime in the life cycle of an organism, may be disadvantageous/advantageous to organism, heritable these transmitted to offspring

mutations

study of inheritance of a trait in several generations of genetically related individuals, provides valuable information, help understand inheritance patterns of traits within families (many generations), important method of studying inheritance of a known disease or defect, requires precise reliable set of clinical features associated with the conditions, 3-4 generations used, management and counseling

pedigree charts

manifests even if only one copy of the allele is present, males and females are affected in same ratio, condition does not skip generations, whether or not offspring will inherit a dominant trait is 50%, more common in structural protein genes (brittle bone disease), may also result in gain-of function (additional function may be advantageous or deleterious)

autosomal dominant genes/inheritance

Huntington disease, color blindness, polycystic kidney disease, familial hypercholesterolemia

examples of dominant gene disorders