Biomedical Engineering Reference
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in systolic blood pressure alone. The results open up the possibility of improved
patient stratification, as they allow predictions to be made about the effectiveness
of rostafuroxin (but not that of any other antihypertensive drugs) in patients carry-
ing key gene variants.
Pharmacogenetics of Lipid-Lowering Therapies
Cardiovascular disease is associated with nonmodifiable risk factors such as age,
gender, and genetic background, and with modifiable risk factors such as lipid
concentrations. Lowering serum lipid levels has been demonstrated to slow the
progression of, or even induce regression in, atherosclerosis. However, like any
other drug treatment, the magnitude of plasma lipid responses to drug therapies
varies considerably among individuals modified by a number of factors such as age,
gender, concomitant disease, and genetic determination. Pharmacogenetics pro-
vides the experimental basis to understand the variability in response to drugs as a
function of the individual genetic makeup. Information from small clinical trials
reveals that several candidate genes may hold some promise in our quest to predict
individual success to hypolipemic drug treatment.
Polymorphisms in Genes Involved in Cholesterol Metabolism
Polymorphisms in genes involved in cholesterol synthesis, absorption, and trans-
port may affect statin efficacy. Genetic variation at the LDL receptor locus can
affect baseline lipids, response to pravastatin, and cardiovascular disease risk in
subjects placed on statin treatment (Polisecki et al.
2008
). The DNA of 1,536 indi-
viduals treated with pravastatin, was analyzed for 148 SNPs within ten candidate
genes related to lipid metabolism (Chasman et al.
2004
). Variation within these
genes was then examined for associations with changes in lipid levels observed
with pravastatin therapy. Two common and tightly linked SNPs were significantly
associated with reduced efficacy of pravastatin therapy. Both of these SNPs were in
the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the target enzyme that is inhibited by pravastatin. The association for
total cholesterol reduction persisted even after adjusting for multiple tests on all
33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs
evaluated was similar in magnitude and direction among men and women and was
present in the ethnically diverse total cohort as well as in the majority subgroup of
white participants. Thus, individuals heterozygous for a genetic variant in the
HMG-CoA reductase gene may experience significantly smaller reductions in choles-
terol when treated with pravastatin. The absolute difference in total cholesterol
reduction associated with HMG-CoA reductase was significant enough to affect
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