Content uploaded by Carlos Rieder
Author content
All content in this area was uploaded by Carlos Rieder on Oct 11, 2015
Content may be subject to copyright.
125 3Pharmacogenomics (2014) 15(9) , 1253–12 71 ISSN 1462-2416
part of
Pharmacogenomics
Review
10.2217/PGS.14.93 © 2014 Future Medicine Ltd
Pharmacogenomics
Review
15
9
2014
Parkinson’s disease (PD) is unique among neurodegenerative disorders because a
highly effective pharmacological symptomatic treatment is available. The marked
variability in drug response and in adverse profiles associated with this treatment
led to the search of genetic markers associated with these features. We present a
review of the literature on PD pharmacogenetics to provide a critical discussion of
the current findings, new approaches, limitations and recommendations for future
research. Pharmacogenetics studies in this field have assessed several outcomes and
genes, with special focus on dopaminergic genes, mainly DRD2, which is the most
important receptor in nigrostriatal pathway. The heterogeneity in methodological
strategies employed by different studies is impressive. The question of whether PD
pharmacogenetics studies will improve clinical management by causing a shift from
a trial-and-error approach to a pharmacological regimen that takes into account the
individual variabilit y remains an open question. Collaborative longitudinal studies with
larger sample sizes, better outcome definitions and replication studies are required.
Keywords: adverse effects • dopamine receptors • dopaminergic agents pharmacogenetics
• levodopa • Parkinson’s disease
Parkinson’s disease (PD) is a neurodegenera-
tive disorder mainly characterized by motor
symptoms, such as bradykinesia, rigidity
and rest tremor. These features could be
explained by nigrostriatal pathway degen-
eration, leading to dopamine deficits in
basal ganglia. Nevertheless, the disease is
not restricted to the nigrostriatal pathway
and there is evidence of typical pathological
alterations in other brain regions [1] . More-
over, patients could experience a myriad of
non-motor symptoms, such as olfactory and
sleep disturbances, neuropsychiatric symp-
toms and autonomic dysfunction. PD is
distributed worldwide, with a prevalence of
1–3% in people older than 65 years [2]. Since
its prevalence increases with aging, the phar-
macological management of these patients is
important, especially in countries in which
the population is getting older.
Despite the marked clinical and pathologi-
cal heterogeneity, no other neurodegenerative
disorder has a pharmacological treatment
with a magnitude of symptomatic response
like PD. The drugs used act chiefly through
mechanisms that enhance dopaminergic neu-
rotransmission, among them levodopa is the
one that provides the best response. In the first
few years of treatment, patients experience
an almost optimal control of motor symp-
toms, although a marked variability in dose
response is observed. Nevertheless, within
the first 5 years of levodopa treatment, about
half of patients will develop motor complica-
tions, such as motor fluctuation (drug effect
finishes earlier than expected) and dyskinesia
(hyperkinetic involuntary movements) [3] .
Visual hallucinations and other psychotic
symptoms are also attributed to dopaminergic
medications, although a contribution of dis-
ease-related factors may occur. This variable
response and the adverse effects of levodopa
and other dopaminergic agents may, at least
in part, be explained by genetic factors.
Parkinson’s disease pharmacogenomics:
new findings and perspectives
Artur F Schumacher-Schuh1,2,
Carlos RM Rieder2,3 &
Mara H Hutz*,1
1Departamento de Genética, Instituto de
Biociências, UFRGS, Caixa Postal 15053,
91501–970, Porto Alegre, RS, Brazil
2Serviço de Neurologia, Hospital de
Clínicas de Por to Alegre, Porto Alegre,
Brazil
3Universidade Federal de Ciências da
Saúde de Por to Alegre, Porto Alegre,
Brazil
*Author for correspondence:
Tel.: +55 51 3308 6720
Fax: +55 51 3308 7311
mara.hutz@ufrgs.br
For reprint orders, please contact: reprints@futuremedicine.com
125 4 Pharmacogenomics (2 014) 15 (9) future science group
Review Schumacher-Schuh, Rieder & Hutz
A review of the literature on PD pharmacogenetics
is presented to provide a critical discussion of the cur-
rent findings, new approaches, limitations and recom-
mendations for future research. A systematic search
in the electronic databases PubMed, Web of Science
and Google Scholar was conducted, with last access on
22 May 2014. The search terms were (pharmacogen*
OR polymorphism) AND ((Parkinson) AND levodopa
OR pramipexole OR bromocriptine OR ropinirole OR
rotigotine OR piribedil OR selegiline OR rasagiline
OR entacapone OR tolcapone). Titles and abstracts
in English were independently reviewed by two of us
(AF Schumacher-Schuh and CRM Rieder). Inclusion
criteria were: cross-sectional or longitudinal, observa-
tional or interventional studies; at least one study group
should have idiopathic PD; study factors could be any
kind of genetic marker; outcomes were any kind of phe-
nomena that could be potentially related to the use of
dopaminergic agents (e.g., dose response, motor fluctu-
ation, dyskinesia, psychosis and sleep attacks); patients
should be in use of dopaminergic agents, namely
levodopa, dopamine agonists (bromocriptine, prami-
pexole, piribedil, rotigotine and ropinirole), MAO-B
inhibitors (selegiline or rasagiline) and COMT inhibi-
tors (tolcapone and entacapone). Reviews were not
included, but their references were checked, as well as
the references of the reviewed articles. The main out-
comes investigated were levodopa adverse effects and
levodopa dose. The systematic search procedures used
are shown in Figure 1. Based on the searched articles,
Figure 2A presents the most studied genes and shows
the most studied outcomes. The pharmacogenetic data
are presented in the following ‘Dopaminergic genes’
and ‘Other genes’ sections.
Dopaminergic genes
Dopamine receptor genes
Dopamine receptors (D1, D2, D3, D4 and D5) medi-
ate all physiological functions of the catecholaminergic
neuro transmitter dopamine, ranging from voluntary
movement and reward to hormonal regulation and
hypertension. These receptors are involved in dopamine
and its antagonist action in presynaptic and postsynap-
tic neurons. These receptors are encoded by five genes
(DRD1, DRD2, DRD3, DRD4 and DRD5) that are the
most studied genes in PD pharmacogenomics ( Tab l e 1 ) .
Among all dopamine receptor genes, DRD2 (chro-
mosome 11q22-q23) was the most investigated
(Figure 1A & Table 1). The protein derived from DRD2
is one of the largest sites of action of dopamine in
the nigrostriatal circuit. TaqIA (rs1800497) was the
most studied polymorphism in this genomic region
in PD. It was previously considered to be in DR D2
but now its exact place was demonstrated to be in the
ANKK1 gene [42] . ANKK1 is closely related to DR D2,
since they share an overlapping segment. This gene is
expressed in astrocytes of human adults and rodents
and alters expression levels of NF-κB-regulated genes
[43] . ANKK1 is linked to DRD2 through an indirect
pathway [4 4] .
Wang et al. found the presence of DRD2/ANKK1
TaqIA polymorphism A1/A1 genotype to be associ-
ated with motor fluctuations in a sample of 140 PD
patients [4 ]. Motor fluctuation was defined based on
clinical judgment and patients with or without this
outcome were matched. Two other studies did not
show association between motor fluctuations and
DRD2 polymorphisms [8,3 1] .
Rieck et al. reported an association between
DRD2/ANKK1 haplotypes, including the TaqIA
polymorphism, and dyskinesia in 199 Brazilian
patients [8] .
Oliveri et al. studied a sample of 136 PD patients
and found that the presence of 13 and 14 repeat alleles
of a DRD2 intronic (CA)n short tandem repeat (STR)
was associated with less levodopa-induced dyskinesia
in a case–control design [5] . Zappia et al. determined
peak of dose dyskinesia after levodopa challenge (a
standardized administration of levodopa followed by
serial clinical examinations) in a cross-sectional study
and observed a similar effect in a sample of 215 PD
patients, but the protective effect on dyskinesia risk
due to the 13 and 14 repeat alleles was restricted
to males [6 ]. In line with those results, Strong et al.
observed that the 14 and 15 repeat alleles of the DRD2
(CA)n STR were associated with earlier onset of dys-
kinesia in 92 PD subjects [7]. Nevertheless this STR is
mapped to a noncoding region and is nonfunctional
and probably is in linkage disequilibrium with other
functional variants.
Makoff et al. conducted a case–control study with
155 PD patients stratified by early- or late-onset hal-
lucinations (development of this symptom before or
after 5 years of disease, respectively). The presence of
the DRD2 TaqIA A2 allele was associated with late
hallucinations [9] . This study was not replicated in lat-
ter studies [1 8,31] . Impulse control disorder is another
psych iatric complication related to dopaminergic
drugs in PD, especially with dopamine agonists. Val-
lelunga et al. studied this outcome but no association
with DRD2 polymorphisms was detected [1 0] .
Sleep attacks are adverse events experienced by
some patients caused by the use of dopaminergic ther-
apy, mainly with dopamine agonists. This outcome
was associated with the A2 allele at the TaqIA poly-
morphism at the DRD2/ANKK1 cluster in a case–con-
trol study with 137 PD patients with sleep attacks and
137 PD patients without this symptom. These groups
www.futuremedicine.com 125 5
Figure 1. The methodology used.
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
were paired for type and dose of dopamine agonist use,
levodopa dose and other variables [11] . This previous
association was not replicated in another study using
the same case–control paired design [19 ] . Dopaminer-
gic demand defined by levodopa equivalent dose [1 2] ,
response to dopamine agonist [15 ] , and dopamine ago-
nist discontinuation [13 ] were also studied and found to
be associated with the DRD2/ANKK1 cluster (Tabl e 1) .
DR D1 and DR D5 are genes that encode dopa-
mine receptors that are highly homologous and were
mapped to chromosomes 5q35 and 4q16, respectively.
D1 receptors are expressed in many different brain
regions and are related to dopamine action in the
nigrostriatal pathway [45] . Two studies evaluated DR D1
polymorphisms association with dyskinesia and visual
hallucinations, with negative results [5 ,18] . However,
these SNPs were noncoding or silent third base codon
substitutions. The D5 receptor is expressed mainly in
the limbic region; therefore, few efforts were made to
perform PD pharmacogenetic studies with this gene.
Wang et al. did not find an association with a single
nonfunctional polymorphism in DRD5 and motor
fluctuation in PD patients [1 4] .
DRD3 is mapped at chromosome 3q13 and encodes
dopamine receptor D3. Numerous studies were
reported with this gene, mainly with the functional
polymorphism Ser9Gly. The glycine allele yields D3
autoreceptors that have a higher affinity for DA and
display more robust intracellular signaling.
Liu et al. followed a sample of 30 PD patients that
initiated the use of pramipexole for 2 months and
observed an association of at least 20% improve-
ment in the Unified Parkinson’s Disease Rating Scale
(UPDRS) total score with the DRD3 Ser/Ser genotype
[15] . Lee et al. classified patients with a peak of dose and
diphasic dyskinesia in a longitudinal study with 503
PD patients [16 ] . They observed that DRD3 Ser9Gly
polymorphism was associated with diphasic dyskinesia
[16 ] . However, Paus et al. did not observe these results
in a multicenter cross-sectional study [17] . Visual hallu-
cinations were associated with DRD3 polymorphisms
in one study [18], a result not observed by others [9, 31] .
Dopamine receptor D4 is expressed throughout the
brain and its gene is located at chromosome 11p15. The
most studied polymorphism is a 48 bp variable num-
ber of tandem repeat (VNTR). The protein coded by
Titles identified in electronic
databases (Medline, Web of
Science and Google Scholar)
n = 144
Titles identified in
manual search
n = 15
To tal number of articles
evaluated
n = 159
Reviews, opinion articles,
abstracts in congresses
and articles that clearly
did not meet the inclusion
criteria based on abstract
n = 97
Articles that did not meet
the inclusion criteria based
on entrie text analysis
n = 6
Articles submitted to analysis
of the entire text
n = 62
Articles that met all the
inclusion criteria
n = 56
125 6 Pharmacogenomics (2 014) 15 (9)
Figure 2. Most investigated genes and outcomes in Parkinson’s disease pharmacogenetics. (A) Most investigated genes in Parkinson’s
disease pharmacogenomics. (B) Most investigated outcomes in Parkinson’s disease pharmacogenomics.
future science group
Review Schumacher-Schuh, Rieder & Hutz
the 7R allele has a blunted response for cAMP reduc-
tion, requiring a threefold increase in dopamine con-
centration for reductions comparable to the 4R pro-
tein. Paus et al. observed an association of the DRD4
48 bp VNTR short variants with sleep attacks in a
case–control study with 183 patients [19] . However,
Rissling et al. did not observe this association using a
similar approach [11] . Polymorphisms in this gene were
not associated with motor complications and visual
hallucinations [4,18] .
As reviewed above all dopamine receptors genes
were studied, but results are conflicting and the hetero-
geneity of outcomes and methods is very high. The
most consistent finding was the association of DRD2
with dyskinesia ( Tabl e 1) .
Enzymes involved in dopamine metabolism
COMT
The COMT gene is mapped at chromosome 22q11 and
encodes an enzyme that has an important role in dopa-
mine degradation. COMT Val158Met, a functional
polymorphism, was extensively studied in several dis-
orders including PD. Bialecka et al. investigated 95 PD
patients using a cross-sectiona l design and divided them
into those that required at least 500 mg of levodopa
in the first 5 years of disease and those that required
higher doses. They observed an association between
COMT Val158Met polymorphism Met/Met genotype
in patients that required less than 500 mg of levodopa
in the first 5 years of treatment [20] . The same group
examined a larger sample of 322 PD patients and geno-
types for four different polymorphisms in COMT and
derived haplotypes that seem to better predict enzy-
matic activity than Val158Met alone. They reported an
association between increased levodopa doses in 5 years
of disease and the higher enzymatic activity haplotype
[21] . Cheshire et al. in a longitudinal study with 285
PD patients determined an association between higher
levodopa doses and COMT poly morphisms related to
higher enzyme activity [22] . These results are in line
with the previous assumption that carriers of the Met
allele would require less levodopa. In a recent study
this association was not observed [23].
In a longitudinal study with 219 PD patients,
De Lau et al. determined that the Met allele was associ-
ated with an increased risk of levodopa-induced dyski-
nesia [2 4] , which is consistent with the assumption that
dyskinesia is associated with increased dopaminergic
stimulation. Watanabe et al. also described a trend for
COMT Met/Met genotype association with increased
prevalence of motor fluctuation and dyskinesia in a
sample of 121 PD patients but these results were not
confirmed after statistical corrections [2 5]. These results
were not observed by others [21,2 2 ,38 ,39] .
Frauscher et al. observed that subjects with the Met
allele presented higher scores in the Epworth Sleepiness
Others
14%
Levodopa dose
13%
Halluciantion/
psychosis
22%
Dyskinesia
30%
COMT
25%
DRD2
27%
DRD5 2%
DRD1 3%
MAO-B 3%
DRD4
7%
DAT
9%
DRD3
17%
Other genes
7%
Sleep disturbances
8%
Motor fluctuations
13%
www.futuremedicine.com 125 7
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s
disease.
Study (year) Location Drug studied Study size
(Parkinson’s
disease
sample)
Design Genes and polymorphisms Outcomes Main findings Ref.
Wang et al.
(20 01)
China Levodopa 140 Case–control DRD2: TaqIA (rs1800497)
DRD3: product of BalI and
MspI enzyme digestion
Motor fluctuation DRD2 Ta qIA A1 / A1
genotype associated
with motor
fluctuation
[4]
Oliveri et al.
(1999)
Italy Levodopa 136 Case–control DRD1: product of DdeI,
PvuI and BspI enzyme
digestion
DRD2: (CA) n STR
Dyskinesia Less dyskinesia in
carriers of DRD2
(CA)n STR 13 and
14 repeat alleles of
DRD2: (CA) n STR
[5]
Zappia et al.
(2005)
Italy Levodopa 215 Cross-sectional DRD2: (CA) n STR Dyskinesia DRD2 13 and 14
repeat alleles
associated with less
dyskinesia in men
[6]
Strong et al.
(2006)
USA Levodopa 92 Retrospective DRD2: (C A)n STR Dyskinesia DRD2 (CA) n STR
14/15 repeat
genotype associated
with early-onset
dyskinesia
[7]
Rieck et al.
(2012)
Brazil Levodopa 199 Cross-sectional DRD2 /ANKK1: 141C
Ins/Del, rs2283265,
rs1076560, C957T, TaqIA
and rs2734849
Motor fluctuation
Dyskinesia
TTCTA haplotype
associated with
dyskinesia
[8]
Makoff et al.
(2000)
UK Levodopa and
dopamine
agonists
155 Case–control DRD2: 141C Ins/Del and
TaqIA
DRD3: Ser9Gly
Any kind of
hallucination (early
and late hallucination
defined by the
presence before
or after 5 years of
disease)
No association with
overall hallucination
Late hallucination
associated with
DRD2 TaqIA C allele
[9]
Vallelunga
et al. (2 012 )
Italy Dopaminergic
therapy
89 Cross-sectional DRD2: TaqIA
COMT: Val158Met
DAT1 : 40 bp VNTR
Impulse control
disorder
No association [10]
STR: Short tandem repeat; UPDRS: Unied Parkinson’s Disease Rating Scale; V NTR: Variable number t andem repeat.
125 8 Pharmacogenomics (2 014) 15 (9) future science group
Review Schumacher-Schuh, Rieder & Hutz
Study (year) Location Drug studied Study size
(Parkinson’s
disease
sample)
Design Genes and polymorphisms Outcomes Main findings Ref.
Rissling et al.
(2004)
Germany Dopaminergic
therapy
274 Case–control DRD2: TaqIA
DRD3: product of MscI
enzyme digestion
DRD4: 120 bp tandem
duplication
Sleep attacks DRD2 TaqIA A2
allele associated
with sleep attacks
[11]
Paus et al.
(2008)
Germany Dopaminergic
therapy
503 Cross-sectional DRD2: TaqIA Levodopa equivalent
dose
No association [12]
Arbouw et al.
(2009)
The
Netherlands
Ropinirole and
pramipexole
38 Retrospective DRD2: 141C Ins/ Del, TaqIA
and (CA)n STR
DRD3: Ser9Gly and
product of MspI enzyme
digestion
Discontinuation of
agonist use
Absence of DRD2
(CA)n STR 15 repeat
allele associated
with decreased rate
of discontinuation
[13]
Wang et al.
(20 01)
China Levodopa 120 Cross-sectional DRD5: T978C Motor fluctuation No association [14]
Liu et al. (2009) China Pramipexole 30 Longitudinal DRD2: TaqIA
DRD3: Ser9Gly
Response to
pramipexole (20%
of improvement in
UPDRS)
DRD3 Ser/
Ser genotype
associated with
better response to
pramipexole
[15]
Lee et al. ( 2 011 ) South Korea Levodopa 503 Longitudinal DRD2: TaqIA
DRD3: Ser9Gly
SLC6A4 : promoter region
Dyskinesia: diphasic
and peak of dose
DRD3 Ser9Gly AA
genotype associated
with diphasic
dyskinesia
[16 ]
Paus et al.
(2009)
Germany Dopaminergic
therapy
690 Cross-sectional DRD3 : Ser9Gly Choreic dyskinesia
Dystonic dyskinesia
Motor fluctuation
No association [17]
Goetz et al.
(20 01)
USA Dopaminergic
therapy
88 Cross-sectional DRD1: 48A>G
DRD2: S e r311C y s
DRD3: Ser9Gly
DRD4: 48 bp VNTR
Visual hallucination DRD3 Ser9Gly
polymorphism
associated with
visual hallucination
[18]
Paus et al.
(2004)
Germany Dopaminergic
therapy
204 Case –control DRD2: 142C Ins /Del, TaqIA
DRD3: Ser9Gly
DRD4: 48 bp VNTR
5HTT: 44 bp Ins/Del
Sleep attacks Short allele of
DRD4 48 bp VNTR
associated with
sleep attacks
[19]
STR: Short tandem repeat; UPDRS: Unied Parkinson’s Disease Rating Scale; V NTR: Variable number t andem repeat.
Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s
disease (cont.).
www.futuremedicine.com 125 9
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
Study (year) Location Drug studied Study size
(Parkinson’s
disease
sample)
Design Genes and polymorphisms Outcomes Main findings Ref.
Bialecka et al.
(2004)
Poland Levodopa 95 Cross-sectional COMT: Val158Me t
MAO- B: A>G íntron 13
Levodopa dose (use
of at least 500 mg of
levodopa after 5 years
of disease)
COMT Met/Met
genotype associated
with the use of less
than 500 mg of
levodopa after 5
years
[20]
Bialecka et al.
(2008)
Poland Levodopa 322 Cross-sectional COMT: rs6269, rs4633,
rs4818 and rs4680
Levodopa dose
Chronic complications
of levodopa use
Haplotype that
encodes higher
enzymatic activity
form of COMT
associated with
higher dose of
levodopa
[21]
Cheshire et al.
(2014)
UK Levodopa 285 Longitudinal COMT
MAO-A
Dyskinesia
Levodopa dose
Polymorphisms that
determined higher
COMT enzymatic
activity and higher
mRNA MAO -A levels
associated with
higher doses of
levodopa
[22]
Yin et al. (2013) China Levodopa 97 Cross-sectional COMT: rs74745580, rs4633,
rs6267 and rs3838146
Motor response
(defined by UPDRS)
Levodopa dose
No association [23]
De Lau et al.
(2012)
The
Netherlands
Levodopa 219 Longitudinal COMT: Val158M et Dyskinesia COMT Met allele
associated with
increased risk of
dyskinesia
[24]
Watanabe
et al. (2003)
Japan Levodopa 121 Cross-sectional COMT: Val158Me t Motor fluctuation
Dyskinesia
No association with
motor fluctuation or
dyskinesia
[25]
Frauscher et al.
(2004)
Austria Dopaminergic
therapy
46 Cross-sectional COMT: Val158Me t Excessive daytime
sleepiness
COMT Met allele
associated with
excessive daytime
sleepiness
[26]
STR: Short tandem repeat; UPDRS: Unied Parkinson’s Disease Rating Scale; V NTR: Variable number t andem repeat.
Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s
disease (cont.).
126 0 Pharmacogenomics (2 014) 15 (9) future science group
Review Schumacher-Schuh, Rieder & Hutz
Study (year) Location Drug studied Study size
(Parkinson’s
disease
sample)
Design Genes and polymorphisms Outcomes Main findings Ref.
Rissling et al.
(2006)
Germany Dopaminergic
therapy
240 Cross-sectional COMT: Val158Met Excessive daytime
sleepiness
No association [2 7]
Camicioli et al.
(2005)
Canada Dopaminergic
therapy
47 Retrospective COMT: Val158 Me t Hallucination No association [28]
Chong et al.
(2000)
Canada Tol c apo ne 24 Longitudinal
(data derived
from a clinical
trial)
COMT: Val158Met Clinical effectiveness
of tolcapone (UPDRS
III scores change from
baseline to 1–2 weeks
and 6 months af ter
treatment)
No association [2 9]
Corvol et al.
(20 11)
France Entacapone 33 Clinical trial COMT: Val158 Met Primary: increased in
‘on’ medication state
Secondar y: levodopa
pharmacokinetic
and COMT activity in
erythrocytes
COMT Val/Val
genotype associated
with increased
gain in ‘on’ period
with the use of
entacapone
COMT Val/
Val genotype
associated with
increased influence
of entacapone
on levodopa
pharmacokinetics
[30]
Kaiser et al.
(2003)
Germany Levodopa 183 Retrospective DRD2: TaqIA, TaqIB,
Taq ID, Pro310Ser and
Ser 311 Cys
DRD3: Ser9Gly and
product of MspI enzyme
digestion
DRD4: 48 bp, 12 bp and
13 bp VNTR
DAT1 : 40 bp VNTR
Time to develop
motor fluctuation,
dyskinesia and
psychosis
DAT1 40 bp VNTR
9 repeats allele
associated with
dyskinesia or
psychosis
[31]
Contin et al.
(2004)
Italy Levodopa 36 Cross-sectional DAT1: 40 bp VNTR [123I]-FP-CIT SPECT
Dyskinesia
No association [3 2]
STR: Short tandem repeat; UPDRS: Unied Parkinson’s Disease Rating Scale; V NTR: Variable number t andem repeat.
Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s
disease (cont.).
www.futuremedicine.com 1261
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
Study (year) Location Drug studied Study size
(Parkinson’s
disease
sample)
Design Genes and polymorphisms Outcomes Main findings Ref.
Schumacher-
Schuh et al.
(2 013 )
Brazil Dopaminergic
therapy
196 Cross-sectional DAT1: 40 bp VNTR and
839C>T
Visual hallucination
Levodopa equivalent
dose
DAT1 839C>T
C allele associated
with visual
hallucination
DAT1 40 bp VNTR
9 repeats allele
associated with
lower levodopa
equivalent doses
[33]
Kaplan et al.
(2014)
Israel Levodopa 352 Retrospective DRD2: 12 polymorphisms
DAT1 : 15 polymorphisms
Dyskinesia DAT1 rs393795
C allele associated
with longer time to
develop dyskinesia
[34 ]
Torkaman-
Boutorabi et al.
(2012)
Tur ke y Levodopa 103 Cross-sectional COMT: G19 47A
MAO- B: A644G
Levodopa dose (use
of at least 500 mg of
levodopa after 5 years
of disease)
No association [35]
Becker et al.
(20 11)
The
Netherlands
Anti-
parkinsonian
drugs
99 Longitudinal
(community
based)
SLC 2 2A1/OCT1: rs622342 Levodopa dose SLC 2 2A1 rs622342
C allele associated
with increased doses
of antiparkinsonian
drugs
[36]
Devos et al.
(2014)
France Levodopa 33 Cross-sectional DDC: rs921451 and
rs3 837091
Motor response
(UPDRS III response
after a levodopa
challenge)
Levodopa
pharmacokinetic
Both polymorphisms
influenced the
motor response
[37]
Lee et al.
(20 01)
South Korea Levodopa 73 Cross-sectional COMT: Val15 8Met Motor response after
a levodopa challenge
No association [3 8]
Contin et al.
(2005)
Italy Levodopa 104 Cross-sec tional COMT: Val15 8M et Levodopa
pharmacokinetic
Dyskinesia
No association [3 9]
STR: Short tandem repeat; UPDRS: Unied Parkinson’s Disease Rating Scale; V NTR: Variable number t andem repeat.
Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s
disease (cont.).
126 2 Pharmacogenomics (2 014) 15(9) future science group
Review Schumacher-Schuh, Rieder & Hutz
Scale in 46 PD patients [26 ]. However, when the same
group investigated a larger sample, which included
240 PD patients, they could not replicate their previ-
ous findings [27] . Visual hallucinations associated with
COMT polymorphisms was investigated in only one
study that included 47 autopsy proven PD patients
without significant associations [28] .
Chong et al. were the first to assess the effect of
COMT polymorphisms in response to COMT inhibi-
tors, a type of drug available to treat PD [29] . They
studied a sample of 24 PD patients derived from a clin-
ical trial. These patients were using tolcapone and the
outcome was defined as the change in UPDRS part III
from baseline to 1–2 weeks and 6 months of treatment.
No difference was observed regarding the outcome or
in adverse effect profile. A clinical trial oriented by
genetic information was conducted by Corvol et al.
[30] . In that study two groups of PD patients homo-
zygous for COMT Val158Met alleles (Val/Val = 17;
Met/Met = 16) were randomly assigned to receive a
challenge dose of levodopa associated with entacapone
or placebo in a double-blind crossover trial. The pri-
mary end point was gain in ‘on time’ (period with drug
response) and the secondary end point was related to
pharmacokinetics parameters. The authors observed
that Val/Val homozygous patients presented a higher
gain of on time and higher increase in levodopa con-
centration with the use of entacapone. This result
suggested that patients homozygous for the Val allele
would have more benefit from entacapone use. Never-
theless, the benefit of entacapone in this acute levodopa
challenge may not represent the effect of chronic use
of this medication. Two studies followed patients and
did not find a significant effect of COMT Val158Met
genotype on response to entacapone [4 0,41] .
MAOB
MAOB degrades dopamine and has an important
role in PD pharmacological treatment. This enzyme
is encoded by the MOAB gene mapped at chromo-
some Xp11. Despite its importance in dopamine
metabolism and levodopa action, few efforts were
made to study this gene in PD pharmacogenetics.
Bialecka et al. did not observe a significant association
between levodopa doses used for 5 years and a SNP
(rs1799836) in MAOB intron 13 that creates a splicing
enhancer [2 0] . Negative results were also reported by
Torkaman-Boutorali et al. [35] .
DDC
DDC converts levodopa to dopamine. The DDC gene
is mapped at chromosome 7p12. Recently, Devos
et al. observed that two polymorphisms in this gene
(rs921451 and rs3837091) influenced individual motor
Study (year) Location Drug studied Study size
(Parkinson’s
disease
sample)
Design Genes and polymorphisms Outcomes Main findings Ref.
Lee et al.
(2002)
Korea Entacapone 65 Longitudinal COMT Val158 Met Levodopa diar y (time
spent in ‘on’ and ‘off’
state)
UPDRS
No association [40]
Kim et al.
(20 11)
Korea Entacapone 16 8 Longitudinal COMT Val15 8Met Levodopa diary (time
spent in ‘on’ and ‘off’
state)
Adverse effect
No association [41]
STR: Short tandem repeat; UPDRS: Unied Parkinson’s Disease Rating Scale; V NTR: Variable number t andem repeat.
Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s
disease (cont.).
www.futuremedicine.com 126 3
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
Table 2. Studies assessing the effect of genes not associated with dopamine on response to dopaminergic treatment variability in Parkinson’s disease.
Study (year) Location Drug studied Study
size (PD
sample)
Design Genes and
polymorphisms
Outcomes Main findings Ref.
De la Fuente-
Fernández
et al. (1999)
Spain Dopaminergic
therapy
105 Cross-sectional APOE: E*4 allele Hallucination APOE E*4 allele associated
with hallucination
[54 ]
Feldman et al.
(2006)
Israel Dopaminergic
therapy
87 Retrospective APOE: E*2, E*3 and E4
alleles
Psychosis APOE E*4 associated with
psychosis
[55]
Molchadski
et al. (2011 )
Israel Levodopa 155 Cross-sectional APOE: E*2, E*3 and
E*4 alleles
Dyskinesia No association [56]
Fujii et al.
(1999)
Japan Dopaminergic
therapy
116 Cross-sectional CCK: 196G>A, 45C>T,
1270C>G and 6662C>T
Hallucination CCK 45C>T associated
with hallucination
[57]
Wang et al.
(2003)
China Dopaminergic
therapy
166 Cross-sectional CCK: 45C>T
CCKAR: 779T> C
CCKBR : 1550G>A
Visual hallucination CCK C allele and CCK AR
C allele associated with
visual hallucination
[58]
Rissling et al.
(2005)
Germany Dopaminergic
therapy
264 Cross-sectional HCRT: 909T>C, 22C>T
and 20C>A
Sleep attack HCRT 909T>C T allele
associated with sleep
attack
[59]
Strong et al.
(2006)
USA Levodopa 92 Retrospective OPRM1: A118G Dyskinesia OPRM1 A118G G allele
associated with early
onset dyskinesia
[7]
Lin et al. (2007) China Levodopa 251 Cross-sectional ACE: intron 16 Ins /Del Motor fluctuation
Dyskinesia
Psychosis
ACE Ins /Ins genotype
associated with psychosis
[60]
Pascale et al.
(2009)
Italy Levodopa 120 Cross-sectional ACE: intron 16 Ins/Del Motor fluctuation
Dyskinesia
Psychosis
No association [61]
Foltynie et al.
(2009)
UK Levodopa 315 Longitudinal BDNF: Val66Met Dyskinesia BDNF Val66Met Met allele
associated with dyskinesia
[62]
De Luca et al.
(2009)
Italy Dopaminergic
therapy
131 Cross-sectional HOMER1: rs4704559,
rs10942891 and
rs470 4560
Hallucination HOMER1 rs4704559
A allele associated with
hallucination
[63]
Schumacher-
Schuh et al.
(2 013 )
Brazil Dopaminergic
therapy
205 Cross-sectional HOMER1: rs470 4559,
rs10942891 and
rs470 4560
Motor fluctuation
Dyskinesia
Visual hallucination
HOMER1 rs4704559
G allele associated with
decreased prevalence of
visual hallucination
[64]
PD: Pharmacodynamics.
126 4 Pharmacogenomics (2 014) 15 (9) future science group
Review Schumacher-Schuh, Rieder & Hutz
Study (year) Location Drug studied Study
size (PD
sample)
Design Genes and
polymorphisms
Outcomes Main findings Ref.
Ivanova et al.
(2012)
Russia Dopaminergic
therapy
101 Cross-sectional GRIN2A: 15
polymorphisms
GRIN2B: 9
polymorphisms
Dyskinesia GRIN2A rs7192557 and
rs8057394 associated with
dyskinesia
[65]
Yahalom et al.
(2012)
Israel Dopaminergic
therapy
349 Retrospective LRRK2 G2019S Dyskinesia No association [66]
Goldman et al.
(2004)
USA Dopaminergic
therapy
86 Cross-sectional CCK: 45C >T
CCKAR: 779T> C
CCKBR : 1550G>A
Hallucination No association [67]
Camicioli et al.
(2005)
Canada Dopaminergic
therapy
47 Retrospective APOE: E*2, E*3 and
E*4
Hallucination No association [2 8]
Goetz et al.
(20 01)
USA Dopaminergic
therapy
88 Cross-sectional APOE: E*4 allele Visual hallucination No association [18]
Lee et al. ( 2 011 ) South
Korea
Levodopa 503 Longitudinal GRIN2B : 266C>T,
366C>G and 200T>G
Dyskinesia: diphasic
and peak of dose
No association [16]
Kaplan et al.
(2014)
Israel Levodopa 352 Retrospective BDNF: seven
polymorphisms
Dyskinesia No association [3 4]
Cheshire et al.
(2014)
UK Levodopa 285 Longitudinal BDNF Dyskinesia
Levodopa dose
No association [2 2]
PD: Pharmacodynamics.
Table 2. Studies assessing the effect of genes not associated with dopamine on response to dopaminergic treatment variability in Parkinson’s disease
(cont.).
www.futuremedicine.com 126 5
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
response, with no effect on levodopa pharmaco kinetics
in a cross-sectional study of 33 PD patients [37 ]. The
function of these polymorphisms in gene product
expression is unknown.
As summarized in Figure 2A, the COMT Val158Met
polymorphism is the most frequently investigated
dopamine enzyme. The most important results are the
association of Val158Met with levodopa dose.
Transporter genes
DAT1
The cessation of dopamine neurotransmission, apart
from the enzymatic degradation, is also determined
by presynaptic dopamine transporter (DAT) reuptake.
This transporter is encoded by DAT1. The most studied
polymorphism in this gene is a VNTR (rs28363170) in
the 3´-UTR. Alleles with 9 and 10 repeats are the most
common. This polymorphism has been found to act as
a modulator of gene transcription: the 10-repeat allele
being associated with higher levels of DAT expression.
In young people, DAT1 expression was reported to be
higher in 9 repeat allele carriers [4 6] . However, DAT1
expression decreases with aging and this could be more
intense in 9 repeat homozygous individuals [47– 49] .
Kaiser et al. studied 183 PD patients in a cross-
sectional design and retrospectively determined time to
develop dyskinesia, motor fluctuation and psychosis in
association with DAT1 VNTR polymorphism [31] . They
found that the presence of a 9 repeat allele was associ-
ated with lower prevalence of dyskinesia or psychosis.
Contin et al. assessed the potential association between
DAT genotype, single-photon emission computed
tomography (SPECT) measures using [123I]-FP-CIT
of striatal dopaminergic function, and oral levodopa
response pattern in 36 patients with PD, but they did
not identify clinically relevant in vivo DAT neuro-
chemical function phenotypes or levodopa response
patterns associated with DAT1 polymorphisms [32] .
Schumacher-Schuh et al. studied visual hallucina-
tions and two polymorphisms in the DAT1 gene [33] .
One was the VNTR and the other was DAT1 - 839C>T
(rs2652511) in the 5´ region of the gene, which has been
shown to be potentially related to transcriptional rec-
ognition sites [5 0] . In a cross-sectional design with 196
PD patients they observed that carriers of the DAT1
-839C allele presented an increased prevalence of
visual hallucinations. The 9 repeat allele of the DAT1
VNTR was associated with lower levodopa equivalent
dose use in this sample.
Kaplan et al. evaluated 353 PD patients retro-
spectively in order to determine the time to levodopa-
induced dyskinesia development [34 ] . A total of 34 poly-
morphisms in three genomic regions (DAT1/ SLC6 A 3,
DRD2 and BDNF ) were determined. DAT1 rs393795
polymorphism C allele was associated with a n increased
time to develop dyskinesia.
Other transporter genes associated with
dopamine
Serotonergic neurons were recognized as being involved
in the nigrostriatal synapses, particularly in PD. Some
evidence showed that these neurons sprout and potenti-
ate dopamine release and are also related to levodopa-
induced dyskinesia [51, 52] . In the absence of nigral cells,
these neurons could be involved in levodopa uptake,
convert it to dopamine, a nd release this neuro tran smitter
into the synaptic cleft. The serotonin transporter gene
(SLC6A4, SERT ) is mapped at chromosome 17q11. The
most investigated variant is a 44 bp insertion/deletion
functional polymorphism in the 5-HTT gene promoter
region (HTTLPR) that led to changes in expression of
this transporter in humans. This gene was investigated
in association with sleep attacks [19] and with diphasic
and peak of dose dyskinesia [16 ] , both studies reported
negative results.
OCT1 is a polyspecific organic cation transporter
that is associated with dopamine transport. The gene
encoding this protein is located at chromosome 6q25
(SLC22A1/OCT1) [53 ] . Becker et al. used data from a
community based cohort of 7983 subjects in Rotterdam
with 99 incident cases of PD patients and studied the
association between antiparkinsonian drug doses and
SLC22A1/OCT1 rs622342 polymorphism [3 6] . Patients
with the C allele used higher antiparkinsonian drug
doses. This polymorphism was also related to a higher
mortality rate. This SNP is most likely nonfunctional
although specific studies have not been performed
DAT1 is the most investigated gene transporter but
no consistent findings have been pointed out because
different polymorphisms and different outcomes were
screened in the studies, as shown in Tab l e 1.
Other genes
Tab le 2 lists other genes nonrelated to dopamine that
were investigated in PD pharmacogenetic studies, as
with dopaminergic genes the main outcome investigated
was levodopa adverse effects.
APOE is widely known to be associated with an
increased risk of Alzheimer’s disease. This gene has
two variants encoding three different isoforms. The
E*4 allele determines an up to seven-times increase in
disease risk [68]. This polymorphism was also associ-
ated with dementia in PD [69] . De la Fuente-Fernández
et al. described an association between the APOE E*4
allele and hallucinations in 105 PD patients in a cross-
sectional study [5 4] . Feldman et al. showed that this
same allele was associated with an increased incidence
of psychosis in PD in a retrospective study with 87 PD
126 6 Pharmacogenomics (2 014) 15 (9) future science group
Review Schumacher-Schuh, Rieder & Hutz
patients [55] . However, two other studies did not repli-
cate these findings [1 8, 28] . One study reported absence
of association between APOE and dyskinesia [5 6] .
CCK modulates dopaminergic neurotransmission [70] .
Polymorphisms in the promoter region of the CCK gene
that may affect CCK transcription based on its Sp1 cis-
binding element location and in genes encoding CCK
receptors (CCKAR and CCKBR) were studied in PD
pharmacogenetics by three groups [57, 5 8, 6 7]. Fujii et al.
and Wang et al. reported an association of CCK poly-
morphisms and hallucinations in cross-sectional design
studies in Asian PD patients [57, 58] . This association was
not observed in European PD patients [6 7,7 1] .
ACE is a molecule with a widely known function
of converting angiotensin I to angiotensin II. The
gene encoding ACE is located on the long arm of
chromosome 17 (17q23). An insertion/deletion (I/D)
polymorphism in intron 16 of the ACE gene has been
extensively investigated as a marker for functional
polymorphisms. A high concentration of this molecule
was found in basal ganglia and there is evidence sup-
porting a relationship with dopaminergic transmis-
sion and PD [72] . Lin et al. reported that psychosis was
associated with ACE in a cross-sectional study with
251 PD patients [60]. However, psychosis was not asso-
ciated with ACE polymorphisms in a latter study with
120 European PD patients [ 61] .
Association between a polymorphism in the HCRT
gene and sleep attacks was described in a cross-sectional
study comprising 264 PD patients [59] . Strong et al., in
a cross-sectional study with 92 PD patients, observed
that the G allele of OPRM1 A118G polymorphism was
associated with early-onset dyskinesia [7]. Nevertheless
the precise function of this SNP has yet to be clarified.
Opioid neurotransmission occurs in basal ganglia and
evidence suggests that alterations in this system could
be associated with dyskinesia.
An increasing body of evidence points towards
neural and synaptic plasticity involvement in levodopa-
induced complications, mainly dyskinesia [7 3,74] .
Foltynie et al. followed 315 PD patients free of dys-
kinesia at baseline and observed that the BNDF Va l-
66Met Met allele was associated with an increased risk
for developing dyskinesia [62] . De Luca et al. reported
an association between hallucinations and HOMER1
rs4704559 polymorphism in a cross-sectional study
with 131 PD patients [63]. Similarly, Schumacher-
Schuh et al. reported that the HOMER1 rs 4704559
G allele has a protective effect for visual hallucinations
[64] . There are no reports about the potential function
of the rs4704559 polymorphism but considering this
lack of information and also considering that this poly-
morphism is in the 5´-UTR, close to the gene promoter,
a role in transcription regulation would be plausible.
Ivanova et al. studied hyperkinetic involuntary move-
ments in tardive dyskinesia in schizophrenia, Hunting-
ton’s disease and PD [65] . In 101 PD patients, an associ-
ation between dyskinesia and GRIN2A polymorphisms
was observed.
HTR2A 102C>T (rs6313), a presumed functional
variant, was reported to be associated with impulse
control and repetitive behavior symptoms usually asso-
ciated with chronic use of dopaminergic drugs, mainly
dopamine agonists [75] .
The most important enzyme involved in COMT
inhibitor (tolcapone and entacapone) biotransforma-
tion is UGT1A. Ferrari et al. reported that UGT1A9
genotypes that determine low enzymatic levels were
associated with COMT inhibitor adverse reactions
leading to treatment withdrawal [76] .
Approximately 10% of PD patients have a mono-
genic form of disease and almost 20 loci were identified
as being causative of the disorder [77] . The role of vari-
ants in these loci and their relation to pharmacological
response was poorly investigated. PARK8 is mapped
at chromosome 12q12 and encodes LRRK2. Muta-
tions in this locus represent the most common form
of monogenic PD and polymorphisms in this gene are
associated with sporadic PD. However, no association
between the G2019S LRRK2 polymorphism and dys-
kinesia was observed in the single pharmacogenetic
study of this gene [66] .
The results reported for these few genes associated
with PD pharmacogenetics by different mechanisms
other than dopamine were far from consistent. Dyski-
nesia was the outcome with more significant findings
(Tab le 2 ) . Clearly more reserach is needed to identify
new mechanisms of action of dopaminergic therapy.
Conclusion & future perspective
PD is a condition that determines significant disability.
Given that aging is the most important risk factor and
considering that modern societies are getting older, the
study of better treatment options should be seen as a
priority. Symptomatic pharmacological management
has great efficacy in PD, but treatment shows large
variability in drug response and could be a challenge
in clinical practice, mainly in advanced disease. The
identification of factors associated with this variability
could lead to a more personalized treatment approach,
increase efficacy and limit costs. Pharmacogenetic
studies in PD are scarce. The present review gives
an overview of the published data on PD pharmaco-
genetics, shows their limitations and gives insights that
may be useful to future studies.
As expected, most studies assessed the role of genes
encoding proteins directly related to dopaminergic
treatment (Figure 2A), most of them are expressed in
www.futuremedicine.com 1267
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
the CNS. DRD2 was the most investigated gene as the
main action of dopamine on motor control is mediated
through this receptor. COMT Val158Met polymor-
phism was also widely studied; this gene has a role in
dopamine degradation. More recently, complications
of chronic use of dopaminergic therapy, especially dys-
kinesia, were associated in two studies with abnormal
neuronal plasticity and glutamate transmission.
The papers published presented conflicting results
for all genes investigated, which could be explained,
at least in part, by the high heterogeneity of outcome
definitions. This phenotypic heterogeneity is a con-
sequence of the lack of precise and widely accepted
definitions and clinical instruments to adequately mea-
sure the main adverse effects and/or drug efficacy and
safety. Efforts in order to improve these instruments
will improve reproducibility and external validity. The
UPDRS is a complete inventory on PD symptoms and
contains questions that could be used to assess outcomes
in a more systematic way [78] . The new Movement Dis-
order Society (MDS)-UPDRS was revised to improve
previous questions and included others [79]. This new
version includes questions about impulse control disor-
der, an important adverse drug effect, especially seen
with dopamine agonists. This outcome would be an
interesting focus for future studies. In order to better
define levodopa-induced dyskinesia and quantify this
adverse effect, the use of a detailed assessment would be
preferable. The Unified Dyskinesia Rating Scale, which
is a complete assessment constructed by renowned spe-
cialists [80] should be preferred. Recommendations on
scales for psychotic symptoms in PD have recently been
published [81] and could be employed for pharmaco-
genetic studies. Motor fluctuation, a heterogeneous side
effect of levodopa, lacks clear definitions and classifica-
tions. The preferable way to assess it would be the use of
patient diaries, in which the subject records his/her state
every hour. However, this method required patients to
be educated regarding the method in order for high
compliance to be achieved.
Genetic heterogeneity is another source of variability
between studies because different markers in the same
genes were employed for these associations; moreover,
patients with different genetic backgrounds may not be
strictly comparable. The lack of a clear statement about
how genotype groups were pooled as well as how rare
alleles were included in the statistical analyses make
replications difficult.
Most studies reviewed here have fragile designs
(e.g., cross-sectional and retrospective). PD is a pro-
gressive and dynamic disorder and longitudinal stud-
ies evaluating pharmacological response would be pre-
ferred to better define the precise onset of adverse events
and define them temporally in the context of other
clinical variables. However, cross-sectional studies are
important for hypothesis generation.
In order to overcome these pitfalls, some actions are
suggested. First, replications of previous findings with
Executive summary
Pharmacological response in Parkinson’s disease
• Parkinson’s disease is a neurodegenerative disorder in which a pharmacological treatment with great
symptomatic effect is available, mainly for motor symptoms, such as bradykinesia, rigidity and rest tremor.
• There are a high number of dif ferent drugs to treat Parkinson’s disease patients; most of them improve
dopaminergic neurotransmission.
• Pharmacological response is highly variable among patients. Chronic complications in dopaminergic agent use
are common, such as motor fluctuation, dyskinesia, visual hallucinations and sleep disturbances.
• The variabilit y in drug response and in chronic complication occurrence might be explained by genetic factors.
Dopaminergic genes
• Most pharmacogenetic studies have focused on dopaminergic genes, such as dopamine receptors, dopamine
transpor ters and enzymes associated with dopamine transformation and degradation.
• DRD2 and DAT1 were associated, in most studies, with dyskinesia whereas COMT was more frequently related
to levodopa dose.
Other genes
• The most investigated nondopaminergic genes were APOE and CCK.
• More recently, evidence has pointed to neuroplastic phenomena and glutamatergic transmission being
potentially implicated in dopaminergic therapy chronic complications, mainly dyskinesia. Consequently, genes
encoding neurotrophic factors and molecules associated with glutamate metabolism are new interesting
targets for Parkinson’s disease pharmacogenetic studies.
Limitations & future perspective
• At present, most studies reported conflicting results, therefore no clinical recommendations could be made.
• Small sample sizes, heterogeneity in outcome definitions and in genetic marker selection are important
limitations of the published results. Clearly, collaborative studies with larger samples, standardized outcome
definitions, better scales assessments, longitudinal designs and replication samples are required.
126 8 Pharmacogenomics (2 014) 15 (9) future science group
Review Schumacher-Schuh, Rieder & Hutz
a similar methodology, with the same polymorphisms
and in different populations are urgently needed. Sec-
ond, collaborative studies with larger sample sizes are
important to corroborate previous works, to detect
small gene effects and to perform high-throughput
DNA analyses. Third, the functional effect of the poly-
morphisms studied should also be explored to better
determine biological plausibility and to give insights
for future works. Fourth, assessment of gene–gene and
gene–environment interactions and haplotypes are
preferred to single SNP analyses. At a later stage, cost-
effective studies should be performed to complete the
translation to clinical practice.
Our knowledge on the pharmacogenomics of PD is
growing at a very slow pace and the results presented here
should be interpreted in light of previously discussed
limitations. A lthough no clinical recommendation could
be made at present it is expected that clear guidelines will
be developed. With the cost of geno typing getting lower,
its use in clinical practice is becoming more common,
and therefore, the use of personalized medicine in PD
therapy is expected in the future.
Financial & competing interests disclosure
The authors research is supported by Conselho Nacional de
Desenvolvimento Cientíco e Tecnológico (CNPq, Brazil). The
authors have no other relevant afliations or nancial involve-
ment with any organization or entity with a nancial interest
in or nancial conic t with the subject mat ter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
References
Papers of special note have been highlighted as:
• of interest ; •• of consider able interest
1 Braak H, Del Tredici K, Rüb U, de Vos RA , Jansen Steur
EN, Braak E. Staging of bra in pathology related to sporadic
Parkinson’s disease. Neurobiol. Aging 24(2), 197–211 (2003).
2 De Lau LM, Breteler MM. Epidemiology of Parkinson’s
disease. Lancet Neurol. 5(6), 525–535 (2006).
3 Fox SH, Lang AE. Levodopa-related motor
complications–phenomenology. Mov. Disord. 23(Suppl. 3),
S509 –S514 (2008).
4 Wang J, Liu ZL, Chen B. Association study of dopamine D2,
D3 receptor gene polymorphisms with motor fluctuations in
PD. Neurology 56(12 ), 1757–1759 (2001).
5 Oliveri RL, Annesi G, Zappia M et al. Dopamine D2
receptor gene polymorphism and the risk of levodopa-
induced dyskinesias in PD. Neurology 53(7), 1425–1430
(1999).
• Firststudytoinvestigatepharmacogenetics
oflevodopa-induceddyskinesia.
6 Zappia M, Annesi G, Nicoletti G et al . Sex differences in
clinical and genetic determinants of levodopa peak-dose
dyskinesias in Parkinson disease: an exploratory study. Arch.
Neurol. 62(4), 601–605 (2005).
7 Strong JA, Dalvi A, Revilla FJ et al. Genotype and smoking
history affect risk of levodopa-induced dyskinesias in
Parkinson’s disease. Mov. Disord. 21(5), 654–659 (2006).
8 R ieck M, Schumacher-Schuh AF, Altmann V et al. DR D2
haplotype is associated with dysk inesia induced by levodopa
therapy in Parkinson’s disease patients. Pharmacogenomics
13 (15), 1701–1710 (2 012) .
9 Ma koff AJ, Graham JM, Arranz MJ et al. Association
study of dopamine receptor gene polymorphisms with
drug-induced hallucinations in patients with idiopathic
Parkinson’s disease. Pharmacogenetics 10(1), 43– 48 (2000).
10 Vallelunga A, Flaibani R, Formento-Dojot P, Biundo R,
Facchini S, Antonini A. Role of genetic polymorphisms of
the dopaminergic system in Parkinson’s disease patients
with impulse control disorders. Parkinsonism Relat. Disord.
18(4), 397–399 (2012).
11 Rissling I, Geller F, Bandmann O et al. Dopa mine receptor
gene polymorphisms in Parkinson’s disease patients
reporting “sleep attacks.” Mov. Disord. 19(11), 1279 –1284
(2004).
12 Paus S, Grünewald A, K lein C et al . The DRD2 TaqI A
polymorphism and demand of dopaminergic medication in
Parkinson’s disease. Mov. Disord. 23(4), 599–602 (2008).
13 Arbouw ME , Movig KL, Egberts TC et al. Clinical and
pharmacogenetic determinants for the discontinuation of
non-ergoline dopamine agonists in Parkinson’s disea se. Eur.
J. Clin. Pharmacol . 65(12), 1245–1251 (2009).
14 Wang J, Liu ZL, Chen B. Dopamine D5 receptor gene
polymorphism and the risk of levodopa-induced motor
fluctuations in patients with Parkinson’s disease. Neurosci.
Lett. 308 (1), 21–24 (20 01).
15 Liu Y-Z, Tang B-S, Yan X-X et al. Association of the DRD2
and DRD3 polymorphisms with response to pramipexole in
Parkinson’s disease patients. Eur. J. Clin. Pharmacol. 65(7),
679– 683 (20 09).
16 Lee J-Y, Cho J, Lee E-K, Park S-S, Jeon BS. Differential
genetic susceptibility in diphasic and peak-dose dyskinesias
in Parkinson’s disease. Mov. Disord. 26(1), 73 –79 (2011).
• Showsthegeneticdifferencesbet weenpeakofdose
dyskinesiaanddiphasicdyskinesia.
17 Paus S, Gadow F, Knapp M, Klein C, K lockgether T,
Wüllner U. Motor complications in patients form the
German Competence Network on Parkinson’s disease and
the DRD3 Ser9Gly polymorphism. Mov. Disord. 24(7),
1080–1084 (2009).
18 Goetz CG, Burke PF, Leurgans S et al. Genetic variation
analysis in Parkinson disease patients with and without
hallucinations: case–control study. Arch. Neurol. 58(2),
209–213 (2001).
19 Paus S, Seeger G, Brecht HM et al. Association study of
dopamine D2, D3, D4 receptor and serotonin transporter
www.futuremedicine.com 126 9
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
gene polymorphisms with sleep attacks in Parkinson’s
disease. Mov. Disord. 19(6), 705–707 (2004).
20 Białecka M, Droździk M, Kłodowska-Duda G et al. The
effect of monoamine oxidase B (MAOB) a nd catechol-O-
methyltransferase (COMT) polymorphisms on levodopa
therapy in patients with sporadic Parkinson’s disease. Acta
Neurol. Scand. 110(4), 260–266 (2004).
21 Bialecka M, Kurzawski M, Klodowska-Duda G, Opa la
G, Tan E-K, Drozdzik M. The association of functional
catechol-O-methyltransferase haplot ypes with risk of
Parkinson’s disease, levodopa treatment response, and
complications. Pharmacogenet. Genomics 18(9), 815–821
(2008).
22 Cheshire P, Bertram K, Ling H et al. Influence of single
nucleotide polymorphisms in COMT, MAO-A and BDNF
genes on dyskinesias and levodopa use in Parkinson’s disease.
Neurodegener. Dis. 13(1), 24 –28 (2014).
• Animpor tantstudywith285pathological lyconrmed
Parkinson’sdiseasepatientsusingalongitudinaldesign.
23 Yin B, Chen Y, Zhang L. Association between catechol-
O-methyltransferase (COMT) gene polymorphisms,
Parkinson’s disease, and levodopa efficacy. Mol. Diagn. Ther.
doi:10.1007/s40291-013-0066-z (2013) (Epub ahead of
print).
24 De Lau LM, Verbaan D, Marinus J, Heutink P, van Hilten
JJ. Catechol-O-methyltransferase Val158Met and the risk
of dyskinesias in Parkinson’s disease. Mov. Disord. 27(1),
132–135 (2012).
25 Watanabe M, Ha rada S, Nakamura T et al. Association
between catechol-O-methyltransferase gene polymorphisms
and wearing-off and dyskinesia in Parkinson’s disease.
Neuropsychobiolog y 48(4 ), 19 0 –193 ( 200 3).
26 Frauscher B, Högl B, Maret S et al. Association of daytime
sleepiness with COMT polymorphism in patients with
Parkinson disease: a pilot study. Sleep 27(4), 733–736 (2004).
27 Rissling I, Frauscher B, Kronenberg F et al. Daytime
sleepiness and the COMT val158met polymorphism in
patients with Parkinson disease. Sleep 29(1), 108–111 (20 06).
28 Camicioli R, Rajput A, R ajput M et al. Apolipoprotein E
epsilon4 and catechol-O-methyltransferase alleles in autopsy-
proven Parkinson’s disease: relationship to dementia and
hallucinations. Mov. Disord. 20(8 ), 989–994 (2005).
29 Chong DJ, Suchowersky O, Szumlanski C , Weinshilboum
RM, Brant R, Campbell NR. The relationship between
COMT genotype and the clinical effectiveness of tolcapone, a
COMT inhibitor, in patients with Parkinson’s disease. Clin.
Neuropharmacol . 23 (3) , 14 3 –148 (20 00) .
30 Corvol J-C, Bonnet C, Charbonnier-Beaupel F et al. The
COMT Val158Met polymorphism affects the response to
entacapone in Parkinson’s disease: a randomized crossover
clinical trial. Ann. Neurol. 69 (1), 111–118 ( 2011) .
•• Firstclinica ltria lorientedbypharmacogeneticinformation.
31 Kaiser R, Hofer A, Grapengiesser A et al. l-dopa-induced
adverse ef fects in PD and dopamine tra nsporter gene
polymorphism. Neurology 60(11), 1750–1755 (2003).
32 Contin M, Martinelli P, Mochi M et al. Dopamine
transporter gene polymorphism, spect imaging, and
levodopa response in patients with Parkinson disease. Clin.
Neuropharmacol . 27 (3), 111–115 ( 200 4).
33 Schumacher-Schuh AF, Francisconi C, Altmann V
et al. Polymorphisms in the dopamine transporter gene
are associated with visual hallucinations and levodopa
equivalent dose in Bra zilians with Parkinson’s disease. Int.
J. Neuropsychopharmacol. doi:http ://d x.doi.org/10.1017/
S1461145712001666 (2013) (Epub ahead of print).
34 Kaplan N, Vituri A, Korczyn AD et al. Sequence variants
in SLC6A3, DR D2, and BDNF genes a nd time to levodopa-
induced dyskinesias in Parkinson’s disease. J. Mol . Neurosci.
53(2), 183–188 (2014).
35 Torkaman-Boutorabi A, Shahidi GA, Choopani S et al. The
catechol-O-methyltransferase and monoamine oxidase B
polymorphisms and levodopa therapy in the Iranian patients
with sporadic Parkinson’s disease. Acta Neurobiol. Exp.
(Warsz. ) 72(3), 272–282 (2012).
36 Becker ML, Visser LE, va n Schaik RHN, Hofman A,
Uitterlinden AG, Stricker BHC. OCT1 polymorphism
is associated with response and sur vival time in anti-
Parkinsonian drug users. Neurogenetics 12(1), 79– 82 (2011).
37 Devos D, Lejeune S, Cormier-Dequaire F et al. Dopa-
decarboxylase gene polymorphisms affect the motor response
to L-dopa in Parkinson’s disease. Parkinsonism Relat. Disord.
20(2), 170–175 (2014).
38 Lee MS, Lyoo CH, Ulmanen I, Syvänen AC, Rinne JO.
Genotypes of catechol-O-methyltransferase and response
to levodopa treatment in patients with Parkinson’s disease.
Neurosci. Lett. 298(2), 131–134 (2001).
39 Contin M, Martinelli P, Mochi M, Riva R, Albani F, Baruzzi
A. Genetic polymorphism of catechol-O-methyltransferase
and levodopa pharmacokinetic –pharmacodynamic pattern
in patients with Parkinson’s disea se. Mov. Disord. 20 (6),
734–739 (2005).
40 Lee MS, Kim HS, Cho EK, Lim JH, Rinne JO. COMT
genotype and effectiveness of entacapone in patients with
fluctuating Parkinson’s disea se. Neurology 58(4), 564–567
(2002).
41 Kim JS, K im J-Y, Kim J-M et al. No correlation between
COMT genotype and entacapone benefits in Parkinson’s
disease. Neurol. Asia 16 (3 ), 211 –216 ( 2011) .
42 Neville MJ, Johnstone EC, Walton RT. Identification and
characterization of ANKK1: a novel kinase gene closely
linked to DRD2 on chromosome band 11q23.1. Hum.
Mutat. 23(6), 540–545 (2004).
43 Hoenicka J, Quiñones-Lombraña A, España-Serra no L et al.
The ANKK1 gene associated with addictions is expressed
in astroglial cells and upregulated by apomorphine. Biol.
Psychiatry 67(1), 3–11 (2010).
44 Bontempi S, Fiorentini C, Busi C, Guerra N, Spano P,
Missale C. Identification and characterization of two nuclear
factor-kappaB sites in the regulatory region of the dopamine
D2 receptor. Endocrinology 148(5), 2563–2570 (20 07).
45 Dearry A, Gingrich JA, Falardeau P, Fremeau RT Jr, Bates
MD, Caron MG. Molecular cloning and expression of the
gene for a human D1 dopamine receptor. Nature 347(6288),
72 –76 (19 90) .
1270 Pharmacogenomics ( 2014) 15(9)
46 Van de Giessen E, de Win MM, Tanck MW, van den Brink
W, Baas F, Booij J. Striata l dopamine transporter availability
associated with polymorphisms in the dopamine transporter
gene SLC6A3. J. Nucl. Med . 50(1), 45–52 (20 09).
47 Volkow ND, Ding YS, Fowler JS et al. Dopamine
transporters decrease with age. J. Nucl. Med. 37 (4 ), 554 –559
(1996 ).
48 Bannon MJ, Whitty CJ. Age-related and regional differences
in dopamine transporter mRNA expression in human
midbrain. Neurology 48(4), 969–977 (1997).
49 Shumay E, Chen J, Fowler JS, Volkow ND. Genotype
and ancestry modulate brain’s DAT availability in healthy
humans. PLoS ONE 6(8), e22754 (2011).
50 Rubie C, Schmidt F, Knapp M et al . The huma n dopamine
transporter gene: the 5´-flanking region reveals five diallelic
polymorphic sites in a Caucasian population sample.
Neurosci. Lett. 297(2), 125–128 (2001).
51 Carta M, Carlsson T, Kirik D, Björklund A. Dopamine
released from 5-HT termina ls is the cause of l- DOPA-
induced dyskinesia in parkinsonian rats. Brain J. Neurol.
130(7), 1819–1833 (2007).
52 Rylander D, Parent M, O’Sullivan SS et al. Maladaptive
plasticity of serotonin axon terminals in levodopa-induced
dyskinesia. Ann. Neurol. 68(5), 619–628 (2010).
53 Koepsell H, Lips K, Volk C. Polyspecific organic cation
transporters : structure, function, physiological roles,
and biopharmaceutical implications. Pharm. Res. 24(7),
1227–1251 (2007).
54 De la Fuente-Fernández R, Núñez MA, López E. The
apolipoprotein E epsilon 4 allele increases the risk of
drug-induced hallucinations in Parkinson’s disea se. Clin.
Neuropharmacol . 22(4), 226–230 (1999).
55 Feldman B, Chapma n J, Korczyn AD. Apolipoprotein
epsilon4 advances appearance of psychosis in patients with
Parkinson’s disease. Acta Neurol. Scand . 113(1), 14–17
(2006).
56 Molchadski I, Korczyn AD, Cohen OS et al. The role of
apolipoprotein E polymorphisms in levodopa-induced
dyskinesia. Acta Neurol . Scand . 123(2), 117–121 (2011).
57 Fujii C, Harada S, Ohkoshi N et al. Association between
polymorphism of the cholecystok inin gene and idiopathic
Parkinson’s disease. Clin. Genet. 56(5), 394–399 (1999).
58 Wang J, Si Y-M, Liu Z-L, Yu L. Cholecystokinin,
cholecystokinin-A receptor and cholecystokinin-B receptor
gene polymorphisms in Parkinson’s disease. Pharmacogenetics
13(6), 365–369 (20 03).
59 Rissling I, Körner Y, Geller F, Stiasny-Kolster K, Oertel WH,
Möller JC. Preprohypocretin polymorphisms in Parkinson
disease patients reporting “sleep attacks.” Sleep 28(7),
871–875 (2005).
60 Lin J-J, Yueh K-C, Lin S-Z, Harn H-J, Liu J-T. Genetic
polymorphism of the angiotensin converting enzyme and
L-dopa-induced adverse effects in Parkinson’s disease.
J. Neurol. Sci. 252(2), 130–134 (2007).
61 Pascale E, Purcaro C, Passa relli E et al. Genetic
polymorphism of angiotensin-converting enzyme is not
associated with the development of Parkinson’s disease and
of l-dopa-induced adverse effects. J. Neurol. Sci. 276(1–2) ,
18– 21 ( 20 09) .
62 Foltynie T, Cheeran B, Williams- Gray CH et al. BDNF
val66met influences time to onset of levodopa induced
dyskinesia in Parkinson’s disease. J. Neurol. Neurosurg.
Psychiatry. 80(2), 141–144 (2009).
63 De Luca V, Annesi G, De Marco EV et al. HOMER1
promoter ana lysis in Parkinson’s disease : association study
with psychotic symptoms. Neuropsychobiology 59(4), 239–245
(2009).
64 Schumacher-Schuh AF, Altmann V, Rieck M et al.
Association of common genetic va riants of HOMER1 gene
with levodopa adverse effects in Parkinson’s disease patients.
Pharmacogenomics J. 14(3), 289–294 (2013).
65 Ivanova SA, Loonen AJM, Pechlivanoglou P et al. NM DA
receptor genotypes associated with the vulnerability to
develop dyskinesia. Transl. Psychiatry 2, e67 (2012).
66 Yahalom G, Kaplan N, Vituri A et al. Dysk inesia s in patients
with Park inson’s disease: effect of the leucine-rich repeat
kinase 2 (LRRK2) G2019S mutation. Parkinsonism Relat.
Disord. 18(9), 1039 –1041 (2 012).
67 Goldman JG, Goetz CG, Berry-Kravis E, Leurgans S, Zhou
L. Genetic polymorphisms in Parkinson disease subjects with
and without hallucinations : an analysis of the cholecystokinin
system. Arch. Neurol. 61(8), 1280–1284 (2004).
68 Corder EH, Saunders AM, Strittmatter WJ et al. Gene dose
of apolipoprotein E type 4 allele and the risk of Alzheimer’s
disease in late onset families. Science 261(5123), 921–923
(1993 ).
69 Huang X, Chen P, Kaufer DI, Tröster AI, Poole C.
Apolipoprotein E and dementia in Parkinson disease : a meta-
analysis. Arch. Neurol. 63(2), 189–193 (2006).
70 Rotzinger S, Bush DE, Vaccarino FJ. Cholecystokinin
modulation of mesolimbic dopamine function: regulation
of motivated behaviour. Pharmacol. Toxicol. 91(6), 404–413
(2002).
71 Goldman JG, Marr D, Zhou L et al. Racial differences
may influence the role of cholecystokinin polymorphisms
in Parkinson’s disease hallucinations. Mov. Disord. 26(9),
1781–1782 (2011).
72 Labandeira-Garcia JL, Rodriguez-Pallares J, Dominguez-
Meijide A, Valenzuela R, Villar-Cheda B, Rodríguez-Perez
AI. Dopa mine-angiotensin interactions in the basa l ganglia
and their relevance for Parkinson’s disease. Mov. Disord.
28(10), 1337–13 42 (2013).
73 Linazasoro G. New ideas on the origin of l-dopa-induced
dyskinesias : age, genes and neural pla sticity. Trends
Pharmacol. Sci. 26(8), 391–397 (2005).
•• Aninterestingreviewthatproposesthatneuralplasticity
andlevodopachroniccomplicationscouldberelated.
74 Cenci MA, Konradi C. Maladaptive striatal plasticity in
l-DOPA-induced dyskinesia. Prog. Brain Res. 183, 209–233
(2010) .
75 Lee J-Y, Jeon BS, Kim H-J, Park S-S. Genetic variant of
HTR2A associates with risk of impulse control and repetitive
behaviors in Parkinson’s disease. Parkinsonism Relat. Disord.
18(1), 76 –78 (2012).
future science group
Review Schumacher-Schuh, Rieder & Hutz
www.futuremedicine.com 1271
76 Ferrari M, Martignoni E, Blandini F et al. Association of
UDP-glucuronosyltra nsfera se 1A9 polymorphisms with
adverse reactions to catechol-O-methyltransferase inhibitors
in Parkinson’s disease patients. Eur. J. Clin. Pharmacol.
68(11), 1493–1499 (2012).
77 Singleton AB, Farrer MJ, Bonifati V. The genetics of
Parkinson’s disease : progress and therapeutic implications.
Mov. Disord. 28(1), 14–23 (2013).
78 Fahn S, Elton R L, UPDRS Development Committee.
The Unified Parkinson’s Disease Rating Scale. In: Recent
Developments in Parkinson’s Disease. Macmillan Healthcare
Information, Florham Park, NJ, USA (1987).
79 Goetz CG, Tilley BC, Shaftman SR et al. Movement
Disorder Society-sponsored revision of the Unified
Parkinson’s Disease Rating Sc ale (MDS-UPDRS): scale
presentation and clinimetric testing results. Mov. Disord.
23(15), 2129–2170 (2008).
80 Goetz CG, Nutt JG, Stebbins GT. The Unified Dyskinesia
Rating Scale: presentation and clinimetric profile. Mov.
Disord. 23(16), 2398–2403 (2008).
81 Fernandez HH, Aarsland D, Fénelon G et al. Scales
to assess psychosis in Parkinson’s disease: critique and
recommendations. Mov. Disord. 23(4), 484–500 (2008).
future science group
Parkinson’s disease pharmacogenomics: new findings & perspectives Review
