Klinisk Biokemi i Norden Nr 1, vol. 20, 2008 - page 23

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| 1 | 2008
Klinisk Biokemi i Norden
(Fortsætter side 24)
Determining the genetic bases of the common
“multi factorial” diseases, however, represents a major
challenge. The genetics of these diseases are compli-
cated by the interplay by many genes in combination
with the environment. Because SNPs are densely
distributed across the whole genome, they are ideal
markers for large scale genome-wide association stud-
ies to discover common complex diseases, such as
cancer, hypertension, diabetes, obesity, and psychiatric
disorders.
Since cancer is a DNA disease characterized by
uncontrolled cell proliferation due to accumulation
of genetic alterations, genetic instability has also been
recognized as a central biomarker in many forms of
cancer. Most colorectal cancers are identified through
chromosomal instability, either allelic losses of chro-
mosomes or instability of microsatellites. These altera-
tions may contribute to inactivation of tumor suppres-
sor genes and accumulation of mutations in important
genes regulating the cell cycle and apoptosis, respec-
tively (12). Aberrant methylation can be used as a
marker to detect cancer cells (13). A number of stud-
ies have provided evidence that specific methylation
changes can alter the response to different therapeutic
agents in cancer, and therefore be useful as biomarker
(14)
The focus of SNP analysis is now changing from the
identification of new SNPs to their typing in popula-
tions. For SNPs to be potentially biomarkers, the
polymorphisms have to be mapped accurately, their
frequency in various populations determined, and
automated high-throughput assay techniques devel-
oped. One problem researchers face when designing
human genetic studies with SNPs, is the difficult task
of selecting the most suitable set of DNA variants for
the goal at hand and in a cost-effective manner.
Pharmacogenomics
It is commonly accepted that no drug works well for
all patients. Some of the differences in how patients
respond to a drug are due to personal characteristics
such as age, size and gender, the nature of their dis-
ease and what other drugs are being used. Despite all
these factors, it is claimed that half of all variation in
drug response is attributable to the genetic differences
among patients.
Some of the specific genetic factors involved in
drug response have been known for a long time and
belong to a class of proteins called “drug metaboliz-
ing enzymes”. The Cytochrom P-450 system (CYP)
is the most important and characterized enzyme sys-
tem involved in drug metabolism (15), but other
classes of enzymes and several drug receptors are
contributing to pharmacokinetic variations as well
(16;17). Variations in the genes that encode these CYP-
molecules (CYP1A2, CYP2C9, CYP2C19, CYP2D6
and CYP3A4) influence how quickly these enzymes
process and eliminate the drug and their metabo-
lites from the blood. Drugs metabolized too quickly,
may not reach a high enough concentration to cure
the targeted disease or relieve the symptoms. Drugs
metabolized too slowly, may accumulate and reach a
toxic level in the body. The availability of the human
DNA sequence, its variation between individuals and
the functional understanding of genetic determinants
between individuals may enable a safer dosage towards
a more effective and personalized drugs.
The ease of using DNA from circulating white blood
cells for hunting biomarkers is obvious. DNA is the
ultimate stable molecule upon storage and no preana-
lytical precautions need to be fulfilled. A few microliter
of EDTA whole blood is sufficient for up to a hundred
genotypings. The challenge for tomorrow will be to
exploit and quality control all the reported information
from the databases.
Cellular RNA
General considerations
Understanding the function of genes and other parts
of the genome is known as functional genomics. The
Human Genome Project was just the first step in
understanding humans at the molecular level. Though
the project is complete, many questions still remain
unanswered, including the function of most of the
estimated 33,000 human genes. Most genes and vari-
ous regulatory regions surrounding the genes, contain
information for making specific proteins. mRNAs the
intermediate molecules between DNA and proteins,
are the target molecules for gene expression analysis,
the process by which proteins are made from the
instructions encoded in the DNA molecule.
Cellular RNA in disease.
Recent reports have revealed that peripheral leuko-
cytes that communicate with every tissue and organ in
the body, have the potential to be used diagnostically
as surrogates for direct sampling of sites of different
disease processes. Detection of disease-specific prog-
nostic markers from blood cells in leukemia patients
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