Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
doi:10.1093/hmg/dds341Advance Access published on August 19, 2012
Pharmacogenomics of adverse drug reactions:implementing personalized medicine
Chun-Yu Wei1, Ming-Ta Michael Lee1,2,3 and Yuan-Tsong Chen1,4,∗
1Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan 2School of Chinese Medicine, China MedicalUniversity, Taichung, Taiwan 3Laboratory for international Alliance, Center for Genomic Medicine, RIKEN, Yokohama,Japan 4Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Received August 6, 2012; Revised and Accepted August 11, 2012
Pharmacogenomics aims to investigate the genetic basis of inter-individual differences in drug responses,such as efficacy, dose requirements and adverse events. Research in pharmacogenomics has grown overthe past decade, evolving from a candidate-gene approach to genome-wide association studies (GWASs). Genetic variants in genes coding for drug metabolism, drug transport and more recently human-leukocyteantigens (HLAs) have been linked to inter-individual differences in the risk of adverse drug reactions
(ADRs). The tight association of specific HLA alleles with Stevens – Johnson syndrome, toxic epidermalnecrolysis, drug hypersensitivity syndrome and drug-induced liver injury underscore the importance ofHLA in the pathogenesis of these idiosyncratic drug hypersensitivity reactions. However, as with thesearch for the genetic basis for common diseases, pharmacogenomic research, including GWAS, has sofar been a disappointment in discovering major gene variants responsible for the efficacy of drugs used totreat common diseases. This review focuses on the pharmacogenomics of ADRs, the underlying mechan-isms and the potential use of genomic biomarkers in clinical practice for dose adjustment and the avoidanceof drug toxicity. We also discuss obstacles to the implementation of pharmacogenomics and the direction offuture translational research.
allowed the development of new anti-cancer agents aimedat treating patients whose cancer carries the targeted muta-
Pharmacogenetics is an area of research that addresses the
tions, so-called targeted therapies. The pharmacogenetics of
genetically determined variation in how individuals respond
targeted anti-cancer therapy has been extensively reviewed
to specific drugs, in terms of differences in dose requirement,
efficacy and the risk of adverse drug reactions (ADRs).
Since the completion of the Human Genome Project,
Pharmacogenomics, in addition to addressing variability in
pharmacogenomics has been touted as the field with greatest
DNA, is also concerned with gene expression profiling. In
clinical potential to radically improve patient care through
line with the increasing use of functional genomics, pharmaco-
the implementation of personalized medicine. The terms
genetics and pharmacogenomics have been used interchange-
personalized medicine and pharmacogenomics are often
used together, as both aim to maximize therapeutic benefit
Genetically determined variations affecting inter-individual
and avoid ADRs. In addition to improving patient care,
responses to drugs can be grouped, in a broad sense, into
pharmacogenetics-based personalized approaches have the po-
germ-line genetic variants and somatic mutations as occur
tential to save money by improving the cost-effectiveness of
in tumor tissues. Germ-line genetic variants—mainly in
health care delivery. There are many commonly prescribed
genes encoding drug-metabolizing enzymes, drug transpor-
drugs that fail to work for some patients. For example, many
ters, drug targets and human-leukocyte antigen (HLA)—are
patients with high cholesterol fail to respond to statins, and
reported to be responsible for many of the observed inter-
many hypertensive patients do not respond to beta-blockers
individual differences in drug efficacy, the risk for ADRs,
The ability to prescribe drugs only to individuals identified
or both. The different somatic mutations in cancer have
as responders would significantly reduce wasted medical costs.
∗To whom correspondence should be addressed at: Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Sec. 2, Nankang, Taipei11529, Taiwan. Tel: +886 227899081; Fax: +886 227899085; Email: [email protected]
# The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
Furthermore, by not prescribing drugs to those genetically atrisk for ADRs, the costs associated with caring for patientswith untoward drug toxicities could be eliminated.
ADRs are a major clinical problem that accounts for 6.7%
of all hospitalizations and ranks between the fourth and sixthmost common cause of inpatient death in western countries,posing challenges to the healthcare system in terms of bothpatient wellbeing and medical costs (,). ADRs are also amajor burden for the pharmaceutical industry. From 1990 to2012, there have been 43 drugs withdraw from the marketdue to severe ADRs (). ADRs are often classified into twogroups. Type A reactions are predictable by the mode of
Figure 1. Metabolic enzymes identified in drug labels of FDA-approved
pharmacological mechanisms and are often dose-dependent.
drugs. The percentage of drugs with genetic information on responding meta-
In contrast, type B reactions, which account for
bolic enzymes in their drug labels related to dosage adjustment or risk for
dose-independent, idiosyncratic reactions ).
Recent pharmacogenomic studies that have evolved from a
million individuals are ultra-rapid metabolizers who experi-
candidate-gene approach to the genome-wide association
ence no response to standard treatment (For example,
study (GWAS) have greatly advanced the discovery of genes
one meta-analysis demonstrated a reduction in
associated with inter-individual differences in drug response,
average dose for most tricyclic antidepressants in patients
especially genes that predispose individuals to ADRs and, to
who are CYP2D6 poor metabolizers (CYP2D6∗3/∗3) In
a lesser extent, genes responsible for drug efficacy. These
the case of codeine, which requires CYP2D6 for bioactivation
studies also have advanced our understanding of the under-
and conversion to morphine, poor metabolizers experience
lying mechanisms of ADRs and drug efficacy. Based on
little therapeutic effect, whereas morphine conversion is
these discoveries, the Food and Drug Administration (FDA)
increased in ultra-rapid metabolizers (CYP2D6∗1/∗1 and ∗1/
has relabeled over 100 approved drugs to include genetic in-
∗2), which results in severe or life threatening toxic side
formation. A list of valid genomic biomarkers for clinical
guidance can be found on the FDA website ‘Table of Phar-
Clopidogrel is a thienopyridine antiplatelet drug used to
macogenomic Biomarkers in Drug labels’ (http://www.fda.
prevent recurrent thrombosis in patients with myocardial in-
farction and percutaneous coronary intervention with stent im-
ucm083378.htm). Here, we summarize recent important find-
plantation. However, responses to clopidogrel vary widely,
ings that advance our knowledge of the genetic contribution
both inter-individually and inter-ethnically. Several genes
to inter-individual variability in drug efficacy and ADRs.
have been investigated, but variations in the CYP2C19 gene
We focus on the pharmacogenomics of ADRs, especially on
appear to be the most consistent genetic determinants for dif-
genes coding for drug metabolizing enzymes, drug transpor-
ferences in response to clopidogrel treatment. Patients who
ters and HLAs, as well as the potential use of these genomic
carry the reduced function alleles CYP2C19∗2 are at higher
biomarkers in clinical practice for dose adjustment and for
risk for major cardiovascular events compared with non-
preventing drug toxicity. We also discuss key challenges for
the implementation of pharmacogenomics and the direction
Another important drug-metabolizing enzyme is thiopurine
TPMT∗3A and TPMT∗3C are at high risk of severe hemato-
logic toxicity, and homozygous-TPMT-deficient patients
Before genome-wide technologies were available, early phar-
require substantial dose reductions. Reliable TPMT genotyp-
macogenomic studies relied on candidate-gene approaches;
ing tests with high sensitivity (90%) and specificity (99%)
thus, genes affecting drug metabolism and detoxification
are commercially available and allow proper dose adjustment
were obvious candidates. As a result, numerous metabolic bio-
(). Similarly, patients with a polymorphism that results in
markers have been identified (Fig. ). As of July 2012, 67
decreased expression of uridine diphospho glucuronosyltrans-
drugs with valid metabolic biomarkers for dosage adjustment
ferase 1A1 (UGT1A1) are at a risk for neutropenia following
have been listed in the Table of Pharmacogenomic Biomarkers
the initiation of irinotecan treatment (The homozygous
in Drug Labels; of these, 87% have genetic tests approved or
and heterozygous genotypes of UGT1A1∗28 present the most
cleared by the FDA. However, for most there are no guidelines
significant risk, and a reduced initial dose of irinotecan is sug-
to direct the clinical use of this genetic information ).
In addition to the metabolizing enzymes that affect drug
P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and
pharmacokinetics, there are genetic variants that influence
their rates of metabolism can vary .100-fold depending on
drug pharmacodynamics. One successful example of a drug
allelic variability in different ethnic groups ). Seven
percent of Western Europeans are CYP2D6 poor metabolizers
biomarkers are used for individualized dose prediction is war-
who require lower prescribing doses, whereas an estimated 20
farin. Warfarin is the most commonly prescribed anticoagulant.
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
Despite its clinical effectiveness, warfarin has a narrow thera-
cassette (ABC) and the influx transporter solute carrier
peutic index and shows large inter-individual variability ().
(SLC) transporters (). For instance, genetic variants of
Warfarin overdose is often associated with major bleeding com-
ABCB1, encoding p-glycoprotein (Pgp) associated with mul-
plications Both candidate-gene and GWA studies have
tiple drug resistance, may account for a difference of 25% in
confirmed that dose requirement of warfarin is primarily deter-
the renal clearance of cyclosporine (In fact, the functional
mined by CYP2C9, coding for the enzyme that metabolizes the
polymorphism ABCB1 34355TT is strongly associated with
potent S-isomer of warfarin, and vitamin K epoxide reductase
cyclosporine-induced nephrotoxicity ). Similarly, subjects
enzyme complex subunit 1 (VKORC1), encoding the warfarin
with Q141K variant of ABCG2, which codes for breast
target protein –It is now recognized that compared
cancer resistance protein, are at risk of gefitinib-induced diar-
with wild-type CYP2C9∗1, the non-synonymous polymorph-
isms CYP2C9∗2 and ∗3 coding variants with reduced enzymatic
Statins, or HMG-CoA reductase inhibitors, are one of the
activity and prolonged warfarin half-life have a significant clin-
most commonly prescribed classes of drug for reducing chol-
ical influence on warfarin sensitivity and severe bleeding
esterol levels and preventing cardiovascular events ).
events. On the other hand, the non-coding polymorphism of
However, patients treated with a statin are at risk for muscle
VKORC1 at the promoter region, a guanine to adenine substitu-
complications, including myopathy or fatal rhabdomyolysis.
A) at position 21639, decreases expression of the
A recent GWAS study identified a strong association
gene and the availability of vitamin K. Recently, a large collab-
between simvastatin-induced myopathy and the SLC organic
orative study with multi-ethnic groups, the International War-
anion transporter family member 1B1 (SLCO1B1), which
farin Pharmacogenetics Consortium, established a warfarin
dosing algorithm that incorporates the clinical factors and gen-
(OATP1B1). Homozygous CC of the SNP rs4363657 accounts
otypes of CYP2C9 and VKORC1 to more accurately predict
for an 18% cumulative risk of myopathy (In addition,
warfarin doses ,). A large prospective randomized multi-
clinical studies have shown that the C allele of rs4149056
center double-blinded study comparing the genotype guided
SLCO1B1 is also associated with higher blood statin concen-
dosing of warfarin with other approaches is ongoing (http://
trations and increased risk of myopathy (However, the as-
sociation of rs4149056 in SLCO1B1 with simvastatin-inducedmyopathy is not highly predictive for other statins, suggestingthat this association may not be a class effect ). Conse-
quently, genotyping of SLCO1B1 may be a clinically usefultool
Enzymes affecting drug metabolism can also be found in two
classical inborn errors of metabolism, dihydropyrimidine de-
hydrogenase (DPD) deficiency and glucose-6-phosphate de-hydrogenase (G6PD) deficiency. DPD is the rate-limitingenzyme involved in the catabolism of thymidine and uracil.
It is also the main enzyme involved in the degradation of
The HLA system has been a major focus for Type B ADRs,
structurally related compounds like 5-fluorouracil (5-FU) or
i.e. those associated with drug hypersensitivity reactions, in-
its prodrug capecitabine, two widely used anticancer drugs.
cluding Stevens – Johnson syndrome (SJS), toxic epidermal
A decrease in DPD activity can result in toxicity to 5-FU
necrolysis (TEN), hypersensitivity syndrome (HSS) and
and capecitabine; therefore, these drugs should not be used
drug-induced liver injury. Ample evidence supports the view
in DPD-deficient patients (G6PD deficiency is charac-
that drug hypersensitivity is mediated by adaptive immunity,
terized by abnormally low levels of G6PD, a metabolic
which involves MHC-restricted drug presentation, activation
enzyme involved in the pentose phosphate pathway. The
and clonal expansion of T cells. The specific MHC molecules
most notable symptom of G6PD deficiency is hemolytic
involved have been identified, for example, HLA-B∗5701 in
anemia caused by ingestion of drugs, food and other trigger
abacavir-induced drug hypersensitivity and HLA-B∗1502 in
substances that cause oxidative stress. Of the many drugs
carbamazepine (CBZ)-induced SJS (see Table for the list
known to cause hemolytic anemia in patients with G6PD defi-
ciency, chloroquine, dapsone and rasburicase are the three for
The HLA/ADR association is known to be phenotype spe-
which the FDA recommends screening for G6PD deficiency
cific. In the case of CBZ-induced cutaneous ADRs, studies
before beginning treatment. Rasburicase is a recombinant
in Han Chinese demonstrate that CBZ-SJS/TEN is highly
uricase recently approved for the management of high uric
associated with HLA-B∗1502, whereas CBZ-induced maculo-
acid levels associated with chemotherapy for certain type of
papular eruption and HSS are not. Instead, induced maculo-
cancer. Patients deficient in G6PD have an impaired ability
papular eruption is associated with SNPs in the HLA-E
to reduce hydrogen peroxide formed as a major byproduct of
region and HLA-A∗3101, and HSS is associated with the
the rasburicase-catalyzed oxidation of uric acid to allantoin.
MHC class II genes ). Likewise, HLA-DPB1∗0301 isrelated to aspirin-induced asthma, while HLA-DRB1∗1302and HLA-DQB1∗0609 are associated with aspirin-induced ur-
ticaria/angioedema and asthma (The discrepancy of
Drug transporters represent another class of genes affecting
HLA association in hypersensitivities induced by the same
drug pharmacokinetics. These are mainly classified into two
drug may contribute to distinct pathogenesis of particular
major superfamilies: the efflux transporter ATP-binding
disease phenotypes. It should be noted that the HLA
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
Table 1. Serious adverse drug reactions with HLA association
cADR, cutaneous adverse drug reaction; DHS, delayed-type hypersensitivity reaction; DILI, drug-induced liver injury; HSS, hypersensitivity syndrome; SCAR,severe cutaneous adverse drug reaction; SJS, Stevens – Johnson syndrome; TEN, toxic epidermal necrolysis; NA, not available; OR, odds ratio. aWithdrawn from the markets.
association in CBZ-induced cutaneous ADRs seen in Japanese
drug with immune receptors) (Fig. ). According to the
and Caucasian patients does not show phenotypic specificity
hapten concept, chemically reactive drugs or metabolites co-
valently bind a protein or peptide to become neo-epitopes
It is also widely recognized that the genetic association can
(). An example is the covalent binding of penicillin to
also be ethnicity specific, which could be due to difference in
lysine residue of serum albumin and its presentation by
allele frequency. In populations such as Japanese and Cauca-
HLA through the classical processing-required pathway to
sians, where the HLA-B∗1502 allele is very low to absent,
trigger T cell activation, eliciting penicillin allergy (Con-
the susceptibility to CBZ-SJS is not associated with
versely, the p – i concept proposes a direct interaction between
HLA-B∗1502. It is instead associated with HLA-A∗3101,
drugs and immune receptors, such as the T-cell receptor or
which is present at a higher allelic frequency in Japanese
HLA (For example, CBZ interacts directly with
(9.1%) and Caucasians (5%), but is found in only 1.8% of
Han-Chinese (http://www.allelefrequencies.net/). Similarly,
which is sufficient to elicit cytotoxic T lymphocyte activation
there is also an ethnic difference in the genetic association
(,Key interacting chemical moieties on CBZ and resi-
dues in the HLA-B∗1502 antigen-binding cleft have also
HLA-B∗5701, which is prevalent in Caucasians, but not in His-
been identified to explain the specificity of HLA/drug by
panics or Africans (These studies illustrate that ancestry
steric complementarity and non-covalent interacting forces
plays an important role in the biomarker assessment of drug
The tight HLA association in certain drug-induced hyper-
The physiological role of HLA is to present an antigen to
sensitivity reactions (odds ratio .100, Table provides a
the T cell receptor, thereby initiating the T cell-mediated
plausible basis for further development of such a test to iden-
immune response (The strong association between HLA
tify individuals at risk of developing these life-threatening
alleles and ADRs implies a causal relationship of HLA in
conditions. In fact, the FDA has recommended HLA-B∗1502
the development of drug hypersensitivity, with the offending
genetic screening before prescribing CBZ to reduce the risk
drug in the role of antigen. In support of this view, drug-
of SJS and TEN and HLA-B∗5701 testing to avoid abacavir-
specific CD8+ cytotoxic T cells activated in a HLA class I-
induced hypersensitivity, in patients with ancestry from
restricted pathway were found in the blister fluid of
areas in which those HLA-B alleles are prevalent. Recent pro-
drug-induced SJS/TEN patients ). Currently, there are
spective studies using HLA genotyping as a screening tool
two drug-presentation hypotheses, the hapten concept and
before abacavir or CBZ treatment have illustrated the remark-
p – i concept (the direct pharmacological interaction of a
able capability of HLA screening to prevent these severe
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
Figure 2. Working model of severe drug hypersensitivity reactions. (Upper panel) A schematic diagram of the hapten concept. Most drugs are small moleculesand are unlikely to trigger an immune reaction on their own, so the specific drugs or metabolites act as haptens that bind covalently to endogenous proteins andform distinct antigenic epitopes. The haptenized peptides present on MHC after cellular processing and are recognized by T cells for HLA-restricted T cellactivation. (Lower panel) A schematic diagram of p – i concept (pharmacologic interaction with immune receptors). The chemically inert drug can bind directlyto peptide/HLA complexes without cellular processing to activate drug-specific T cells.
ADRs, indicating that personalized medicine and pharmaco-
Amplichip CYP450 Test). However, the implementation of
genomics are extremely useful in the right clinical setting.
the vast information generated from the chip is still problem-
These studies have made genetic testing to prevent drug tox-
atic. CYP2D6 metabolizes more than 100 commercially avail-
able drugs; with the exception of codeine and doxepin, theneed for dose adjustment for these drugs is unclear. Thus,further research is required on how to best use the information
Table lists some pharmacogenomic tests for drugs currently
in use that have practical value in predicting ADRs and/ordrug efficacy. These are based on well-defined genetic variants
It is well recognized that genetics can affect clinical outcomes
that are known to have reproducible and significant conse-
of drug therapy. The greatest obstacle to the clinical imple-
quences for drug therapy. These tests have high predictive
mentation of genetic biomarker tests is that, with the exception
values (either high negative predictive value, high positive
of those listed in Table , few of them have sufficient sensitiv-
predictive value or both), and a causal relationship between
ity, specificity and predictive value to be clinically useful as
genetic variations and drug response and clinical utility have
screening tools to predict drug efficacy and prevent ADRs.
been established. Many of the tests also have clinical guide-
This is especially true for the genes responsible for drug effi-
lines for dose adjustment and alternative medications
cacy, as thus far pharmacogenomic studies on the efficacy of
assembled by The Clinical Pharmacogenomics Implementa-
drugs used to treat common diseases have been disappointing.
tion Consortium (Table The biomarkers include the
Taking statins again as an example, there is large variability in
genetic variants in the above-mentioned drug metabolizing
the clinical response to statin treatment. Genetic variants in
enzymes, inborn errors of metabolism, drug transporters and
HMGCR and APOE have been reported to influence the
HLA alleles. The tests are available commercially as well as
lipid-lowering response after stain therapy ). However,
in academic settings. In addition, the costs of the tests may
conflicting results have also been reported for both APOE
be reimbursed by third-party payers, for example, Taiwan Na-
and for HMGCR ,). GWAS so far have identified mul-
tional Health Insurance pays for the HLA-B∗1502 test for all
tiple loci; however, each locus plays only a small role and
new CBZ users, some private insurance companies in the
none of the loci, alone or in combination, has shown clinical
USA and Australia pay for the HLA-B∗5701 test for abacavir
users, and more recently, US Medicare pays for the CYP2C19
There are several reasons for the slow progress of the phar-
test for clopidogrel treatment. The tests are also available as an
macogenomic study of drug efficacy for common diseases.
FDA-approved panel, including a pharmacogenetic test that
First, the causes of common diseases are multifactorial, in-
covers all gene variants of CYP2D6 and CYP2C19 (Roche
volving both genetic and environmental factors, and in most
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1
Table 2. Clinical useful pharmacogenomics tests in predicting drug efficacy and adverse drug reactions
Consider starting treatment at half the lowest recommended dose in poor metabolizers (CYP2C9∗3/∗3) to avoid
adverse cardiovascular and gastrointestinal events
Poor metabolizers (CYP2C9∗3/∗3) should administrated with caution to avoid adverse cardiovascular and
Dose adjustment based on CYP2C9 and VKORC1 genotypes to achieve efficacy and avoid bleeding complications
Poor metabolizers (CYP2C19∗2/∗2) should take alternative therapy to avoid bleeding complications
Ultra-rapid metabolizers (CYP2D6∗1/∗1 and ∗1/∗2) should avoid usage due to potential for toxicity
Poor metabolizers (CYP2D6∗3/∗3) should reduce dose by 60% to avoid arrhythmia and myelosuppression
Avoid usage in DPD deficient patients to prevent severe ADRs
Avoid usage in G6PD deficient patients to prevent hemolysis
Avoid usage in HLA-B∗1502 carriers to prevent SJS/TEN
Avoid usage in HLA-B∗5701 carriers to prevent hepatotoxicity
Avoid usage in HLA-B∗5801 carriers to prevent severe cutaneous ADRs
Dose adjustment based on SLCO1B1 genotype (C allele of rs4149056 SLCO1B1) to avoid myopathy
Dose adjustment based on TPMT genotype to achieve efficacy and avoid bone-marrow suppression (non-functional
alleles TPMT∗2, TPMT∗3A, and TPMT∗3C)
Dose adjustment based on UGT1A1 genotype (UGT1A1∗28) to achieve efficacy and avoid neutropenia
ADR, adverse drug reaction; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; G6PD, glucose-6-phosphate dehydrogenase; HLA,human-leukocyte antigen; SJS, Stevens – Johnson syndrome; SLCO1B1, solute carrier organic anion transporter family, member 1B1; TEN, toxic epidermalnecrolysis; TPMT, thiopurine S-methyltransferase; UGT, UDP-glucuronosyltransferase. aGuidelines provided.
cases genetic determinants underlying the disease pathogen-
medications, avoiding ADRs, and optimizing drug dosing,
esis are unknown. Thus, drugs used to treat these common dis-
thus allowing for personalized therapy. Pharmacogenomics
eases, such as statins, may target only one of the factors/
can also help reveal pathogenic mechanisms of disease. The
pathways. If the cause of elevated blood lipid levels for an in-
clinically useful pharmacogenomic tests currently available
dividual is not targeted by a statin, a statin would be ineffect-
are directed more at predicting drug toxicities and dose adjust-
ive. To better understand the mechanisms of drug efficacy and
ment. More research will be needed to identifying genetic
identify clinically useful biomarkers requires a better under-
determinants of responders and non-responders, especially
standing of the diseases. Secondly, the effects of many drugs
for drugs used to treat common complex diseases.
are influenced by drug – drug or drug – diet interactions. Drugefficacy may be modulated by concomitant drugs or diet,
Conflict of Interest statement. Y.-T.C. is an inventor of ‘Risk
making it difficult to control pharmacogenomic studies. Simi-
Assessment for Adverse Drug Reactions’ which has been
larly, common diseases are also largely influenced by both en-
licensed to PharmiGene, Inc. Y.-T.C. Chairs the Scientific Ad-
vironment and diet. If life style and diet are not modified
during statin treatment, the treatment may be of limitedbenefit for the patient ). Obviously, more basic researchis needed. It is hoped that a comprehensive study and analyses
of combined data from GWAS, next generation sequencing,epigenetics, proteomics and metabolomics, and a detailed de-
This research was supported by grants from Academia Sinica,
scription of clinical phenotypes/endophenotypes as well as en-
Taiwan (40-05-GMM) and National Science Council, Taiwan
vironmental factors will reveal functional variants not only for
(NSC 101-2319-B-001-001, NSC 101-2325-B-001-006 and
common diseases, but also for drug responses.
Even with the well-defined genetic variants (Table that
have been validated and shown to have high predictivevalue with robust clinical evidence of utility, broad acceptance
by the medical community can be slow. Objective practice
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