501Prediction of Response to Statins
Statins are the most frequently prescribed drugs for lowering LDL-cholesterol
(LDLC) levels and risk of cardiovascular disease. Statins reduce LDLC levels by
inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the
enzyme that catalyzes the rate-limiting step of cholesterol biosynthesis. Although
numerous clinical trials have demonstrated effi cacy of statins, there is substantial
inter-individual variation in the magnitude of statin-induced LDLC reduction. To
date, analysis of individual DNA sequence variants has explained only a small pro-
portion of this variability.
Marked lowering of LDLC levels (< or = 50 %) with intensive statin therapy is
associated with major reduction in cardiovascular risk, but it is limited by a poten-
tial increase in adverse effects, thereby justifying optimization of LDL-C reduction
with minimal risk. The organic anion transporting polypeptide-1B1 encoded by the
SLCO1B1 gene is implicated as a major transporter in cellular uptake of statins, and
notably fl uvastatin. Results of a pharmacogenomics study on elderly subjects with
hypercholesterolemia reveal that OATP1B1 gene is implicated in the pharmacologi-
cal action and effi cacy of fl uvastatin (Couvert et al. 2008 ). The common *14 allele
of SLCO1B1, which is distinguished by the presence of the c.463C > A polymor-
phism, was associated with enhanced lipid-lowering effi cacy in this study.
Transcriptomic analyses have been used to identify additional genetic contribu-
tions to inter-individual differences in statin effi cacy. Using expression array
data from immortalized lymphoblastoid cell lines derived from participants in
the Cholesterol and Pharmacogenetics clinical trial, investigators identifi ed 100 sig-
nature genes differentiating high versus low statin responders (Kim et al. 2014 ).
Two of the signature genes, CYP51A1 and NFYC, have been previously impli-
cated in cholesterol metabolism. The enzyme encoded by CYP51A1, lanosterol
14-α-demethylase, catalyzes the conversion of lanosterol to 24,25- dihydrolanosterol
in one of the later steps of the cholesterol biosynthesis pathway. A radial-basis sup-
port vector machine prediction model of these signature genes with addition of
SNPs previously reported to be associated with statin response in GWAS results in
a combined model that predicts 15 % of the most extreme 15 % of high and low
responders with high accuracy. These results demonstrate that transcriptomic infor-
mation, combined with genetic information, is a substantial contribution to variance
of LDLC response to statin treatment. This may provide a framework for identify-
ing novel pathways that infl uence cholesterol metabolism.
Personalized Management of Women with Hyperlipidemia
Several studies have shown that C-reactive protein (CRP) levels may be more
important than cholesterol levels for predicting cardiovascular events such as heart
attacks. In particular, these studies have shown that elevated CRP is a risk factor that
is independent of cholesterol levels. It had previously been shown that HRT caused
elevated levels of CRP and of heart attacks and strokes (Women’s Health Initiative).
Role of Diagnostics in Personalized Management of Cardiovascular Disease