Page 124 - Cardiac Nursing

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100 PA R T I I / Physiologic and Pathologic Responses
genetic change may no longer perform as expected. For example, it National Institutes of Health (NIH) to develop a plan for a joint
is now known that mutations in the gene that codes for the choles- HGP that officially began in 1990. During the early years of the
terol receptor protein (i.e., the low-density lipoprotein receptor, HGP, the Wellcome Trust in the United Kingdom joined the effort
LDLR) are associated with a disease called familial hypercholes- as a major partner. Important contributions also came from other
terolemia. The cells of most individuals with this disease exhibit re- collaborators around the world, including researchers in Japan,
duced receptor function and, as a result, cannot remove a sufficient France, Germany, and China. The ultimate goal of the HGP was to
amount of low-density lipoprotein (LDL), which carries cholesterol generate a high-quality reference DNA sequence for the human
throughout their bloodstream. Such an affected person may then genome and to identify all human genes. Other important goals in-
have dangerously high levels of cholesterol, a known risk factor for cluded sequencing the genomes of model organisms to complement
development of atherosclerosis, putting him or her at increased risk our exploration of human DNA, enhancing computational re-
for cardiovascular disease culminating in heart attack and/or stroke. sources to support future research and commercial applications, ex-
Genetic variations are differences in DNA sequence among in- ploring gene function through mouse–human comparisons, study-
dividuals that may underlie differences in health. Genetic varia- ing human variation, and training future scientists in genomics.
tions occurring in more than 1% of a population would be con- In June 2000, scientists announced the completion of the first
sidered useful polymorphisms for population genetic analyses. working draft of the entire human genome. 2,3 The high-quality
Polymorphism types include single nucleotide polymorphisms reference sequence was completed 2 years ahead of schedule in
(SNPs), small-scale insertions/deletions, and repetitive elements April 2003, marking the achievement of the initial goal of the
(satellite DNA). Satellite DNA is common throughout the HGP. Available to researchers worldwide, the human genome ref-
genome. These groups of variations are segments of DNA that are erence sequence provides an unprecedented biological resource
repeated in tandem and can be used to differentiate individuals that will accelerate research and discovery, which are expected to
with differing numbers of repeats. The most common variations seed a myriad of practical applications. The draft sequence has al-
found in genes are SNPs, which can change the protein product, ready aided locating genes associated with human disease. Hun-
alter the temporal or spatial expression of a gene, or silence its ex- dreds of other genome sequence projects on microbes, plants, and
pression altogether. A comprehensive and complex system of repair animals have been completed since the initiation of the HGP,
genes encodes for enzymes that correct nearly all DNA errors. As which have enabled detailed comparisons among organisms.
our bodies change in response to age, illness, and other factors, our
DNA repair systems may become less efficient and uncorrected
mutations can accumulate, resulting in diseases such as cancer. PHARMACOGENOMICS
It is estimated that more than 100,000 people die each year from
GENE TESTING adverse responses to medications. Another 2.2 million individuals
experience serious reactions, while others fail to respond at all. Re-
DNA-based tests are among the first commercial medical applica- searchers are beginning to correlate DNA variants with individual
tions of the new genetic discoveries. Gene tests can be used to diag- responses to medical treatments, permitting identification of par-
nose disease, confirm, and more precisely define a clinical diagno- ticular subgroups of patients, and develop drugs customized for
sis, provide prognostic information about the course of a disease, or those populations. The discipline that blends pharmacology with
confirm the existence of a disease in asymptomatic individuals. genomics is called pharmacogenomics.
Currently, several hundred genetic tests are in clinical use, with DNA variants in genes involved in drug metabolism are the fo-
a large expansion in available tests expected as a result of the Hu- cus of much current research in this area. Enzymes encoded by
man Genome Project (HGP). Most current tests detect mutations these genes are responsible for metabolizing most drugs used to-
associated with rare genetic disorders that follow mendelian in- day, including many for treating cardiovascular diseases. Enzyme
heritance patterns. These include cystic fibrosis, sickle cell anemia, function affects patient responses to both the drug and its dose re-
and Huntington disease. Recently, tests have been developed to sponse. Future advances will enable rapid testing to determine the
detect mutations for a few more complex conditions such as patient’s genotype and guide treatment with the most effective
breast, ovarian, and colon cancers. Although they have limita- drugs, in addition to drastically reducing adverse reactions.
tions, these tests sometimes are used to make risk estimates in Genomic data and technologies also are expected to make drug
asymptomatic individuals with a family history of the disorder. development faster, cheaper, and more effective. New drugs aimed
One potential benefit to using such gene tests is that they may at specific sites in the body and at particular biochemical events
provide information to help health care providers and patients leading to disease will cause fewer side effects than many current
and caregivers manage the disease more effectively. medicines. Ideally, the new genomic drugs could be administered
earlier in the disease process. As knowledge becomes available to
select patients most likely to benefit from a potential drug, phar-
THE HUMAN GENOME PROJECT macogenomics will hasten the design of clinical trials to bring
drugs into clinical use sooner.
HGP traces its roots to an initiative in the United States Department
of Energy (DOE), which since 1947 has supported the development
of new energy resources and technologies and acquiring a deeper un- BIOCHEMICAL BASIS OF
derstanding of potential health and environmental risks posed by GENETIC DISEASE
their production and use. In 1986, the DOE announced the Human
Genome Initiative, the result of which would provide a reference hu- Our genetic constitution, the way in which our individual genome
man genome sequence. Soon thereafter, the DOE joined with the interacts with the environment, can impact our health in many