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C H A P T E R 8

PHARMACOGENOMICS AND HEMATOLOGIC DISEASES

Leo Kager and William E. Evans

A fundamental hypothesis pursued in genetics is that heritable genetic rearrangements that affect >50 bp of sequence). Comparisons among
variation (i.e., genotypes or haplotypes) translates into inherited human genomes showed that they differ more as a consequence of
phenotypes (e.g., disease risk, drug response). On the basis of this structural variation than as a result of single-nucleotide variation. For
hypothesis, one aim of medical genetics and pharmacogenomics is to practical purposes, the term sequence variation is mainly used herein.
understand the myriad associations between inherited genotypes and Polymorphisms are defined as common inherited variations in DNA
specific phenotypes of disease or drug response, with the ultimate goal sequence that are typically, although somewhat arbitrarily, defined as
of better defining the risk for, or outcome of, diseases and the response the least common allele having a frequency of 1% or more in the
to specific medications. In cancer, disease prognosis and treatment population.
response can be affected by both inherited (germline) and acquired
(somatic) genome variation, and both types of genome variation
have been shown to alter the effects of certain medications. Many SINGLE-NUCLEOTIDE POLYMORPHISMS
seminal discoveries in medical genetics were made in the course of
investigating hematologic disorders, as exemplified by the fact that the The most common and important inherited sequence variations are
most prevalent monogenic disorders, the hemoglobinopathies, affect SNPs, positions in the genome where individuals have inherited
approximately 7% of the world’s population. Pharmacogenomics also a nucleotide that differs from the most common sequence (“wild-
has a long tradition in hematology; one of the first documented type”) at the position in the genome. Many efforts are underway to
clinical observations of inherited differences in drug effects was the catalogue these variants, because a comprehensive SNP catalog offers
relationship between hemolysis after antimalarial therapy and the the possibility to pinpoint important variants in which nucleotide
inherited glucose-6-phosphate dehydrogenase (G6PD) activity in changes alter the function or expression of a gene that influences
erythrocytes. 1 diseases or response to medications. The main public database is
In the pregenomic era, efforts concentrated on mapping highly the “Database of Short Genetic Variations” (dbSNP; a repository of
penetrant monogenic (Mendelian) loci for both specific diseases and genetic variations less than 50 bp in length) and a growing number of
drug-metabolizing pathways that influence the effects of medications. SNPs (currently about 88 million validated) has recently been driven
Completion of the Human Genome Project and the development largely by the International HapMap Project and the 1000 Genomes
of arrays for genome-wide single-nucleotide polymorphism (SNP) Project (see Table 8.1).
and DNA methylation analyses, “next-generation” DNA sequencing
technologies (whole-exome sequencing [coding regions only] and
whole-genome sequencing [coding and noncoding regions]) have SINGLE-NUCLEOTIDE POLYMORPHISMS
enabled relatively inexpensive and essentially agnostic genome-wide AND PHENOTYPES
approaches to identify genomic variants that predispose to diseases
and/or modify drug responses and/or contribute to heterogeneity of SNPs are present in exons, introns, promoters, enhancers, and
monogenetic disorders and complex diseases that are polygenetic in intergenic regions. To elucidate the relationship between SNPs and
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nature. In addition to genome sequence variation, epigenetic differ- phenotypes of interest, initial efforts have concentrated mainly on
ences are increasingly recognized as important for the development of SNPs that are likely to alter the function or expression of a gene.
diseases and contribute to differences in the pharmacologic effects of However, only a small portion of the identified SNPs lie within
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many medications, referred to as pharmacoepigenomics. This chapter coding regions; only about half of those SNPs cause amino acid
provides a brief overview of pharmacogenomics and pharmacoepig- changes in expressed proteins, and only a subset of those alter the
enomics, using selected examples to illustrate its current and potential function of the encoded protein (“damaging SNPs”). SNPs that cause
impact on the treatment of hematologic diseases. amino acid changes are referred to as nonsynonymous SNPs (nsSNPs),
and are the main sequence variants underlying most of the highly
penetrant inherited monogenic diseases currently known, such as
VARIATION IN THE HUMAN GENOME hemoglobinopathies. The likelihood that nsSNPs will result in disease
or functional changes in drug metabolism or transport depends on the
The genome-wide systematic identification of heritable (i.e., germ- localization and nature of the amino acid change within the encoded
line) and acquired (i.e., somatic) variants, and the functional analysis protein; software algorithms have been developed to “predict” whether
of genes, their variants, their expression, and their related products a certain amino acid change is likely to have a major or minor effect
(i.e., proteins) have revolutionized the study of many diseases, the on protein function (i.e., “damaging” versus “non-damaging”).
development of new medications, and the optimization of drug Although it is intuitively obvious that amino acid substitutions
therapy. Genomics increasingly enable clinicians to make intelligent have the potential to change the function of a protein, gene expres-
and reliable assessments of a person’s risk for acquiring a particular sion also can be affected by SNPs positioned in regulatory sequences
disease, to identify drug targets, and to explain interindividual differ- or intronic regions. For example, a “silent” or synonymous SNP
ences in the effectiveness and toxicity of medications. 2 has been identified that affects protein folding and function of an
The Human Genome Project and subsequent projects such as the important drug transporter, namely ATP-binding cassette transporter
International HapMap Project, the 1000 Genomes Project, and the ABCB1, and this variant has the potential to influence the intra-
ENCODE Project have unveiled many types of variations within cellular accumulation of drugs that are substrates for ABCB1 (a
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the 3 billion base pairs (bp) of the human haploid genome (Table transporter out of cells). Moreover, SNPs in the promoter region
8.1); the spectrum ranges from single-base-pair differences to large can alter the regulatory promoter function and the gene’s expression,
chromosome events. Variations encompass SNPs, insertions or dele- thereby influencing drug effects. Using a genome-wide association
tions of chromosomal DNA, and structural variants (SVs; genomic study (GWAS), the rs924607 TT polymorphism in the promoter

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