Week 1: Introduction to Clinical Pharmacogenomics and Precision Medicine

post-HGP (Human Genome Project)

2013: AMP vs. Myriad

can human genes be patented in the U.S.? why or why not

NO; DNA is a “product of nature”

post-HGP (Human Genome Project)

2013: AMP vs. Myriad

human genes cannot be patented in the U.S. since DNA is a “product of nature”

can manipulated DNA (cDNA) sequences be patented?

YES

post-HGP (Human Genome Project)

2013: AMP vs. Myriad

human genes cannot be patented in the U.S. since DNA is a “product of nature”

_______________ DNA (__DNA) sequences can be patented

manipulated (cDNA)

the _________ __________ _________ in 2003 along with technological advances created a spike in PGx and PGt interest

huma genome project

focus on pharmacogenomics

genetic changes are most relevant to a pharmacist

_________-___________ changes or

changes influencing _________ ________

disease-causing, medication efficacy

Basic Human Genetics: The Genome

human genome constituted of ~3 billion base pairs

~___________ genes

20,000

Basic Human Genetics: The Genome

Chromosome: composed of 2 DNA strands

human have ______ chromosomes (____ pairs total)

46, 23

Basic Human Genetics: The Genome

Chromosome: composed of 2 DNA strands

human have 46 chromosomes (23 pairs total)

_____ pair(s) of autosomes and _____ pair(s) of sex chromosomes

22, 1

Basic Human Genetics: The Genome

Chromosome: composed of 2 DNA strands

human have 46 chromosomes (23 pairs total)

22 pairs of ___________ and 1 pair of _________ chromosomes

autosomes, sex

Basic Human Genetics: The Genome

Chromosome: composed of 2 DNA strands

human have 46 chromosomes (23 pairs total)

22 pairs of autosomes and 1 pair of sex chromosomes (____ in males and ____ in females)

XY, XX

Basic Human Genetics: Transcription

Promoter region

Pre-mRNA coding sequences

_______: coding region of a gene

_______: non-coding region of a gene

exon, intron

Basic Human Genetics: Variation

Polymorphism: variations in _________ that occur in >1% of the populations

Mutation: variation occurring in <1% of the population

DNA (can be disease- or non-disease causing)

Basic Human Genetics: Variation

_____________: variations occurring in >1% of the populations

_____________: variation occurring in <1% of the population

polymorphism, mutation

Basic Human Genetics: Polymorphism

___________________ are the most common and well studied polymorphism

single nucleotide polymorphisms (SNP)

Basic Human Genetics: Polymorphism

_________________= # of copies of a gene can vary from person to person

ex: deletion or duplication

copy number variant

Basic Human Genetics: Polymorphism

Copy Number Variant (CNV)= # of copies of a gene can vary from person to person

example= ________; can have increased or decreased activity

CYP

Basic Human Genetics: Polymorphism

Copy Number Variant (CNV)= # of copies of a gene can vary from person to person

example= CYP2D6; can have _________ activity

__________ codeine metabolism into morphine

increased

Basic Human Genetics: Polymorphism

______________: single base pair to entire region of chromosome

Indel (Insertion/Deletion of genetic material)

Basic Human Genetics: Polymorphism

Indel= Insertion or Deletion of genetic material

could be a _______ _______ _______, or __________ region of chromosome

single base pair, entire

Basic Human Genetics: Polymorphism

Indel= Insertion or Deletion of genetic material

could be a single base pair, or entire region of chromosome

clinical example: _________ which is a serotonin transporter → psychotropic response

SLC6A4

Basic Human Genetics: Polymorphism

Indel= Insertion or Deletion of genetic material

could be a single base pair, or entire region of chromosome

clinical example: SLC6A4 which is a _________ transporter → psychotropic response

serotonin

Basic Human Genetics: Polymorphism

_________________: short stretches of DNA (1-6 base pairs length) over and over

Short Tandem Repeat (STR)

Basic Human Genetics: Polymorphism

Short Tandem Repeat: short stretches of DNA (1-6 base pairs length) repeated over and over

more commonly found in ___________ regions

non-coding (intron)

Basic Human Genetics: Polymorphism

Short Tandem Repeat: short stretches of DNA (1-6 base pairs length) repeated over and over

clinical example: _________ with Atazanavir

UGT1A1

Basic Human Genetics: Mutations

_________ mutation: insertion or deletion of a nucleotide that completely changes the amino acid sequence and coding

frameshift

Basic Human Genetics: Mutations

Frameshift Mutation: insertion or deletion of __________ that completely changes the amino acid sequence and coding

nucleotide

Basic Human Genetics: Mutations

Frameshift Mutation: insertion or deletion of nucleotide that completely changes the amino acid ____________ and _________

sequence and coding

Basic Human Genetics: Mutations

Chromosomal ___________: deletion or addition of a chromosome

Aberration

Basic Human Genetics: Mutations

Chromosomal Aberration

Monosomy: __________ of a chromosome (ex: Turner syndrome)

Trisomy: _________ of a chromosome (ex: Down syndrome)

deletion, addition

Basic Human Genetics: Mutations

Chromosomal Aberration

Monosomy: deletion of a chromosome (ex: _________ syndrome)

Trisomy: addition of a chromosome (ex: _________ syndrome)

turner, down

Basic Human Genetics: Mutations

____________: a portion of a chromosome reattaches to a different chromosome

translocation

Polymorphism and Mutation Impact

Silent (synonymous) Polymorphism: SNP codes for _______ amino acid

same (no change)

Polymorphism and Mutation Impact

___________ Polymorphism: SNP still codes for the same amino acid → no change

silent

Polymorphism and Mutation Impact

___________ Mutation: SNP results in a different amino acid being coded → change OR no change

Missense

Polymorphism and Mutation Impact

Missense Mutation: SNP results in _________ amino acid being coded → change OR no change

different

Polymorphism and Mutation Impact

Missense Mutation: SNP results in a different amino acid being coded → _________

change or no change

Polymorphism and Mutation Impact

___________ Mutation: SNP results in a STOP codon → most likely a bad change

Nonsense

Polymorphism and Mutation Impact

Nonsense Mutation: SNP results in __________ codon → most likely a bad change

stop

Basic Human Genetics: Definitions

Genotype: an individual’s collection of genes

Phenotype: observable expression of the genotype

________: a version/form of a gene

allele

Haplotype: set of DNA variations inherited together ________ a __________ (ABC and abc)

along a chromosome

_____________: set of DNA variations inherited together along a chromosome (ABC and abc)

haplotype

Diplotype: a ________ of _____________ (ABC/abc)

pair of haplotypes

___________: a pair of haplotypes (ABC/abc)

diplotype

Genomics vs. Genetics

Pharmacogenomics studies how _______ genes can influence responses to drugs

Pharmacogenetics study how a ________ gene’s function/composition affects drug response (PD) and ADME (PK)

all, single

Pharmaco___________: studies how all genes can influence responses to drugs

Pharmaco_________: study how a single gene’s function/composition affects drug response (PD) and ADME (PK)

genomics, genetics

Precision Health/Medicine= Lifestyle, Environment, and _________

PGx: one component/approach of precision medicine

impact of __________ on drug response (PK, PD, other aspects)

genome

Utility of Pharmacogenomics

Improve Drug Development Process: reduce ______, _______, and ________ rate of clinical trials

“_______” drugs that failed clinical trails or were withdrawn from the market

time, cost, failure, revive

Utility of Pharmacogenomics

shift emphasis from __________ → _________= preempt progression

reaction, prevention

Utility of Pharmacogenomics

shift emphasis from reaction → prevention= preempt progression

predict _________ to disease

improve disease ___________

customize __________ strategies

susceptibility, detection, prevention

Limitation of Precision Medicine

medication response is multifactorial: ____________ factors, epigenetics, interactions with other genes, etc.

non-genetic