Textbook of Personalized Medicine - Second Edition [2015]

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drug treatment, the magnitude of plasma lipid responses to drug therapies varies
considerably among individuals modifi ed by a number of factors such as age, gen-
der, concomitant disease and genetic determination. Pharmacogenetics provides 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 hypolipidemic drug treatment.

Polymorphisms in Genes Involved in Cholesterol Metabolism

Polymorphisms in genes involved in cholesterol synthesis, absorption, and trans-
port may affect statin effi cacy. 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 10 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 signifi cantly
associated with reduced effi cacy of pravastatin therapy. Both of these SNPs were in
the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reduc-
tase, 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 par-
ticipants. Thus, individuals heterozygous for a genetic variant in the HMG-CoA

Pharmacokinetics

Select delivery

method of anti-

hypertensives

Initial clinical

examination/

Measure BP

Consider risk

factors of heart

disease & HPN

Correlation of

stage of HPN

with risk factors

Genotyping: SNPs,

mutations of genes

for susceptibility

Sequencing

Integration of information

Genomics of HPN & risk factor

Pharmacogenetics/genomics

of antihypertensive drugs

Prescription of :

personalized

medicine and life

style modification

Molecular

diagnostic

Drug resistance severe hypertension:

vagal stimulation, renal denervation

Abbr: HPN= hypertension; BP=blood pressure © Jain PharmaBiotech

Fig. 14.1 A scheme of personalized approach to management of hypertension

Role of Diagnostics in Personalized Management of Cardiovascular Disease