2. INTRODUCTION
Pharmacogenetics involves the search for genetic variations that lead to
interindividual differences in drug response. The term pharmacogenetics
often is used interchangeably with the term pharmacogenomics.
However, pharmacogenetics generally refers to monogenetic variants that
affect drug response, whereas pharmacogenomics refers to the entire
spectrum of genes that interact to determine drug efficacy and safety.
3. NEED FOR PHARMACOGENETICS
The goals of pharmacogenetics are to optimize drug therapy and limit
drug toxicity based on an individual’s genetic profile.
Thus, pharmacogenetics aims to use genetic information to choose a drug,
drug dose, and treatment duration that will have the greatest likelihood of
achieving therapeutic outcomes with the least potential for harm in a
given patient.
5. A gene is a series of codons that specifies a particular protein.
Genes contain several regions: exons that encode for the final protein,
introns that consist of intervening noncoding regions, and regulatory
regions that control gene transcription. In most cases, an individual
carries two alleles, one from each parent, at each gene locus.
An allele is defined as the sequence of nucleic acid bases at a given gene
chromosomal locus. Two identical alleles make up a homozygous
genotype. Two different alleles make up a heterozygous genotype. The
phenotype refers to the outward expression of the genotype.
6. Polymorphisms are defined as variations that occur at a frequency of at
least 1% in the human population.
Single nucleotide polymorphisms (SNPs; pronounced “snips”) are the
most common genetic variations in human DNA, occurring
approximately once in every 100 to 300 base pairs.
To date more than four million SNPs have been mapped in the human
genome.
SNPs are single-base differences that exist between individuals.
Nucleotide substitution results in two possible alleles.
7.
8. A SNP may change the codon resulting in amino acid substitution, which may
or may not alter the amount or function of the encoded protein.
SNPs such as this that result in amino acid substitution are referred to as
nonsynonymous. Nonsynonymous SNPs usually are designated by the amino
acids and codon involved. For example, Arg16Gly or Arg16→Gly indicates
that glycine is substituted for arginine at codon 16.
SNPs that do not result in amino acid substitution are called synonymous.
Synonymous SNPs usually are abbreviated based on the nucleotides involved
and the nucleotide base position. For example, A1166C or A1166→C
indicates that cytosine is substituted for adenine at nucleotide position 1166 of
a given gene region.
9. Insertion–deletion polymorphisms, in which a nucleotide or nucleotide sequence either is
added to or deleted from a DNA sequence
Tandem repeats, in which a nucleotide sequence repeats in tandem (e.g., if “AG” is the
nucleotide repeat unit, “AGAGAGAGAG” is a five-tandem repeat)
Frameshift mutation, in which there is an insertion/deletion polymorphism and the number
of nucleotides added or lost is not a multiple of three, resulting in disruption of the gene’s
reading frame
Defective splicing, in which an internal polypeptide segment is abnormally removed, and the
ends of the remaining polypeptide chain are joined
Aberrant splice site, in which processing of the protein occurs at an alternate site
Premature stop codon polymorphisms, in which there is premature termination of the
polypeptide chain by a stop codon (specific sequence of three nucleotides that do not code for
an amino acid but rather specify polypeptide chain termination)
10. SNPs may occur in exon, intron, or regulatory regions of a gene.
Those occurring in exon regions may alter the function of a protein, whereas
those in regulatory regions may alter the amount of protein that is produced.
Variations in the intron region often are silent unless they affect intron
splicing. Multiple SNPs may be in linkage disequilibrium with each other,
meaning that two or more SNPs are inherited together more frequently than
expected based on chance alone.
For example, if two SNPs, A46T and G72C, are possible in a given gene and
if a T at position 46 always occurs with a C at position 72, the two SNPs are
said to be in complete linkage disequilibrium. A set of SNPs that are inherited
together is called a haplotype.
11. DRUG TARGETS
Genetic polymorphisms occur commonly for drug target proteins,
including receptors, enzymes, ion channels, and intracellular
signaling proteins.
Drug target genes may work in concert with genes that affect
pharmacokinetic properties to contribute to overall drug response.
12.
13. RECEPTOR GENOTYPES AND
DRUG RESPONSE
β1-Receptors are located in the heart and kidney, where they are
involved in the regulation of heart rate, cardiac contractility, and
blood pressure. Two common nonsynonymous SNPs in the β1-
receptor gene are located at codons 49 (Ser→Gly) and 389
(Arg→Gly).
The influence of the β1-receptor gene on blood pressure response to
β1-receptor blockade with metoprolol.
Hypertensive patients who were homozygous for both the Ser49 and
Arg389 alleles had greater reductions in diastolic blood pressure
with metoprolol monotherapy compared with carriers of the Gly49
and/or Gly389 alleles.
14. β2-Receptors are located on bronchial smooth muscle cells, where they
mediate bronchodilation upon exposure to the β2-receptor agonists.
Inhaled β2-agonists are the most effective agents for acute reversal of
bronchospasm; however, the magnitude of their effects varies substantially
among asthmatic patients.
More than 11 SNPs have been identified in the β2-receptor gene, three of
which occur frequently and result in amino acid changes.
Two common nonsynonymous SNPs are found in the gene’s coding block
region, at codons 16 and 27, and a third occurs upstream from the coding
block in the gene’s promoter region.
15.
16. ENZYME GENES AND DRUG
RESPONSE
Vitamin K epoxide reductase (VKOR) is an example of an
enzyme with genetic contributions to drug response.
Warfarin exerts its anticoagulant effects by inhibiting VKOR, thus
preventing carboxylation of clotting factors II, VII, IX, and X.
The vitamin K epoxide reductase complex subunit-1 gene
(VKORC1) encodes for VKOR.
Mutations in the VKORC1 coding region cause rare cases of
warfarin resistance.
Carriers of these mutations either require exceptionally high
warfarin doses (>100 mg/wk) to achieve effective anticoagulation
or fail to respond to any dose of warfarin.
17. Haplotype
Name
Type Ethnic groups
1. VKORC1*1 Wild Reference sequence
AY587020
High frequencies
in populations of
African origin
2. VKORC1*2
(H1 & H2)
Variant A allele at position
3673 and a T allele at
position 6484 of
AY587020
Europeans 42%,
Chinese 95%,
African
Americans 14%
3. VKORC1*3
(H7,H8 & H9)
Variant A allele at position
9041 (homozygous)
heterozygous or
homozygous for the G
allele
African
population=
Caucasians
4. VKORC1*4
(H7,H8 & H9)
Variant position 9041
18. GENES FOR INTRACELLULAR SIGNALING
PROTEINS, ION CHANNELS, AND DRUG RESPONSE
Cellular responses to many drugs are mediated through GTPbinding proteins,
also called G proteins.
19. Disturbances in G-protein–mediated signal transduction have been implicated
in the response to antidepressant drugs.
A common SNP (C825T) occurs in the gene for the inhibitory G (Gi) protein
β3-subunit and has been associated with enhanced intracellular signal
transduction.
The TT genotype has been correlated with greater improvement in depression
symptoms among patients treated with either a tricyclic antidepressant or
serotonin reuptake inhibitor, implying that the Gi protein β3-subunit gene may
have a role in therapeutic decisions for depression management.
20. The epithelial sodium channel (ENaC) is an example of an ion channel with
genetic contributions to drug response.
The ENaC is located in the distal renal tubule and collecting duct of the
nephron, where it serves as the final site for sodium reabsorption.
The channel is composed of α-, β-, and γ-subunits. Mutations in the β- or γ-
subunit cause excessive sodium reabsorption and an inherited form of
hypertension called Liddle syndrome.
The more common variant Thr594Met occurs exclusively in blacks and is
associated with high blood pressure in this population.