Parkinson's disease pharmacogenomics: new findings and perspectives.

Review For reprint orders, please contact: [email protected]

Pharmacogenomics

Parkinson’s disease pharmacogenomics: new findings and perspectives

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 variability remains an open question. Collaborative longitudinal studies with larger sample sizes, better outcome definitions and replication studies are required.

Artur F Schumacher-Schuh1,2, Carlos RM Rieder2,3 & Mara H Hutz*,1 Departamento de Genética, Instituto de Biociências, UFRGS, Caixa Postal 15053, 91501–970, Porto Alegre, RS, Brazil 2 Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil 3 Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil *Author for correspondence: Tel.: +55 51 3308 6720 Fax: +55 51 3308 7311 mara.hutz@ ufrgs.br 1

Keywords: adverse effects • dopamine receptors • dopaminergic agents pharmacogenetics • levodopa • Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder mainly characterized by motor symptoms, such as bradykinesia, rigidity and rest tremor. These features could be explained by nigrostriatal pathway degeneration, 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] . Moreover, patients could experience a myriad of non-motor symptoms, such as olfactory and sleep disturbances, neuropsychiatric symptoms 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 pharmacological management of these patients is important, especially in countries in which the population is getting older. Despite the marked clinical and pathological heterogeneity, no other neurodegenerative

10.2217/PGS.14.93 © 2014 Future Medicine Ltd

disorder has a pharmacological treatment with a magnitude of symptomatic response like PD. The drugs used act chiefly through mechanisms that enhance dopaminergic neurotransmission, 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 symptoms, 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 complications, 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 disease-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.

Pharmacogenomics (2014) 15(9), 1253–1271

part of

ISSN 1462-2416

1253

Review Schumacher-Schuh, Rieder & Hutz A review of the literature on PD pharmacogenetics is presented to provide a critical discussion of the current findings, new approaches, limitations and recommendations 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, observational 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 phenomena that could be potentially related to the use of dopaminergic agents (e.g., dose response, motor fluctuation, dyskinesia, psychosis and sleep attacks); patients should be in use of dopaminergic agents, namely levodopa, dopamine agonists (bromocriptine, pramipexole, piribedil, rotigotine and ropinirole), MAO-B inhibitors (selegiline or rasagiline) and COMT inhibitors (tolcapone and entacapone). Reviews were not included, but their references were checked, as well as the references of the reviewed articles. The main outcomes 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) mediate 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 postsynaptic neurons. These receptors are encoded by five genes (DRD1, DRD2, DRD3, DRD4 and DRD5) that are the most studied genes in PD pharmacogenomics (Table 1). Among all dopamine receptor genes, DRD2 (chromosome 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 DRD2 but now its exact place was demonstrated to be in the

1254

Pharmacogenomics (2014) 15(9)

ANKK1 gene [42] . ANKK1 is closely related to DRD2, 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 [44] . Wang et al. found the presence of DRD2/ANKK1 TaqIA polymorphism A1/A1 genotype to be associated 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 [8,31] . 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 dyskinesia 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 hallucinations (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 latter studies [18,31] . Impulse control disorder is another psych iatric complication related to dopaminergic drugs in PD, especially with dopamine agonists. Vallelunga et al. studied this outcome but no association with DRD2 polymorphisms was detected [10] . Sleep attacks are adverse events experienced by some patients caused by the use of dopaminergic therapy, 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–control study with 137 PD patients with sleep attacks and 137 PD patients without this symptom. These groups

future science group

Parkinson’s disease pharmacogenomics: new findings & perspectives

Titles identified in electronic databases (Medline, Web of Science and Google Scholar) n = 144

Titles identified in manual search n = 15

Total 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 submitted to analysis of the entire text n = 62

Articles that did not meet the inclusion criteria based on entrie text analysis n=6

Review

Articles that met all the inclusion criteria n = 56

Figure 1. The methodology used.

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] . Dopaminergic demand defined by levodopa equivalent dose [12] , response to dopamine agonist [15] , and dopamine agonist discontinuation [13] were also studied and found to be associated with the DRD2/ANKK1 cluster (Table 1) . DRD1 and DRD5 are genes that encode dopamine 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 DRD1 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 [14] .


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% improvement 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 hallucinations 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 number of tandem repeat (VNTR). The protein coded by

www.futuremedicine.com

1255

Review Schumacher-Schuh, Rieder & Hutz

3%

-B 3%

D1

DRD5 2%

MAO

DR

es en rg he Ot 7%

DRD4 7%

DRD2 27%

DAT 9%

Sl 8% eep

Others 14% dis

tu

rb

an

Dyskinesia 30% ce

s

Levodopa dose 13%

DRD3 17%

COMT 25%

ns

tio

a ctu

lu rf oto M % 13

Halluciantion/ psychosis 22%

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.

the 7R allele has a blunted response for cAMP reduction, requiring a threefold increase in dopamine concentration for reductions comparable to the 4R protein. 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 (Table 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 dopamine degradation. COMT Val158Met, a functional polymorphism, was extensively studied in several disorders including PD. Bialecka et al. investigated 95 PD patients using a cross-sectional 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

1256


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 genotypes for four different polymorphisms in COMT and derived haplotypes that seem to better predict enzymatic 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 polymorphisms 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 associated with an increased risk of levodopa-induced dyskinesia [24] , 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 [25] . These results were not observed by others [21,22,38,39] . Frauscher et al. observed that subjects with the Met allele presented higher scores in the Epworth Sleepiness




China

Italy

Italy

USA

Brazil

UK

Italy

Wang et al. (2001)

Oliveri et al. (1999)

Zappia et al. (2005)

Strong et al. (2006)

Rieck et al. (2012)

Makoff et al. (2000)

Vallelunga et al. (2012)

199

92

215

136

140

Dopaminergic 89 therapy

DRD1: product of DdeI, PvuI and BspI enzyme digestion DRD2: (CA)n STR

DRD2: TaqIA (rs1800497) DRD3: product of BalI and MspI enzyme digestion

DRD2: (CA)n STR

DRD2: 141C Ins/Del and TaqIA DRD3: Ser9Gly

Cross-sectional DRD2: TaqIA COMT: Val158Met DAT1: 40 bp VNTR

Case–control

Cross-sectional DRD2/ANKK1: 141C Ins/Del, rs2283265, rs1076560, C957T, TaqIA and rs2734849

Retrospective

Impulse control disorder

Any kind of hallucination (early and late hallucination defined by the presence before or after 5 years of disease)

Motor fluctuation Dyskinesia

Dyskinesia

Dyskinesia

Dyskinesia

Motor fluctuation

Genes and polymorphisms Outcomes

Cross-sectional DRD2: (CA)n STR

Case–control

Case–control

Study size Design (Parkinson’s disease sample)

Levodopa and 155 dopamine agonists

Levodopa

Levodopa

Levodopa

Levodopa

Levodopa

Drug studied

STR: Short tandem repeat; UPDRS: Unified Parkinson’s Disease Rating Scale; VNTR: Variable number tandem repeat.

Location

Study (year)

No association

No association with overall hallucination Late hallucination associated with DRD2 TaqIA C allele

TTCTA haplotype associated with dyskinesia

DRD2 (CA)n STR 14/15 repeat genotype associated with early-onset dyskinesia

DRD2 13 and 14 repeat alleles associated with less dyskinesia in men

Less dyskinesia in carriers of DRD2 (CA)n STR 13 and 14 repeat alleles of DRD2: (CA)n STR

DRD2 TaqIA A1/A1 genotype associated with motor fluctuation

Main findings

[10]

[9]

[8]

[7]

[6]

[5]

[4]

Ref.

Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s disease.


Review

1257

1258


China

Wang et al. (2001)

Pramipexole

Levodopa




503

30

120

DRD2: 141C Ins/Del, TaqIA and (CA)n STR DRD3: Ser9Gly and product of MspI enzyme digestion

DRD2: TaqIA DRD3: Ser9Gly SLC6A4: promoter region

DRD2: TaqIA DRD3: Ser9Gly

Case–control

DRD2: 142C Ins/Del, TaqIA DRD3: Ser9Gly DRD4: 48 bp VNTR 5HTT: 44 bp Ins/Del

Cross-sectional DRD1: 48A>G DRD2: Ser311Cys DRD3: Ser9Gly DRD4: 48 bp VNTR

Cross-sectional DRD3: Ser9Gly

Longitudinal

Longitudinal

Cross-sectional DRD5: T978C

Retrospective

Cross-sectional DRD2: TaqIA

DRD2: TaqIA DRD3: product of MscI enzyme digestion DRD4: 120 bp tandem duplication

Sleep attacks

Visual hallucination

Choreic dyskinesia Dystonic dyskinesia Motor fluctuation

Dyskinesia: diphasic and peak of dose

Response to pramipexole (20% of improvement in UPDRS)

Motor fluctuation

Discontinuation of agonist use

Levodopa equivalent dose

Sleep attacks



Germany

USA

Goetz et al. (2001)

Paus et al. (2004)

Germany

Paus et al. (2009)

Lee et al. (2011) South Korea Levodopa

Liu et al. (2009) China

The Ropinirole and 38 Netherlands pramipexole

Arbouw et al. (2009)


Germany

Paus et al. (2008)

Case–control



Drug studied

Germany

Location

Rissling et al. (2004)

Study (year)

Short allele of DRD4 48 bp VNTR associated with sleep attacks

DRD3 Ser9Gly polymorphism associated with visual hallucination

No association

DRD3 Ser9Gly AA genotype associated with diphasic dyskinesia

DRD3 Ser/ Ser genotype associated with better response to pramipexole

No association

Absence of DRD2 (CA)n STR 15 repeat allele associated with decreased rate of discontinuation

No association

DRD2 TaqIA A2 allele associated with sleep attacks

Main findings

[19]

[18]

[17]

[16]

[15]

[14]

[13]

[12]

[11]

Ref.

Table 1. Studies assessing the effect of genes associated with dopaminergic genes on response to dopaminergic treatment variability in Parkinson’s disease (cont.).




Poland

Poland

UK

Bialecka et al. (2004)

Bialecka et al. (2008)

Cheshire et al. (2014)



121

219

97

285

322

95

COMT MAO-A

Dyskinesia Levodopa dose

Levodopa dose Chronic complications of levodopa use

COMT: Val158Met

Cross-sectional COMT: Val158Met


Longitudinal

Excessive daytime sleepiness

Motor fluctuation Dyskinesia

Dyskinesia

Cross-sectional COMT: rs74745580, rs4633, Motor response rs6267 and rs3838146 (defined by UPDRS) Levodopa dose

Longitudinal

Cross-sectional COMT: rs6269, rs4633, rs4818 and rs4680

Levodopa dose (use of at least 500 mg of levodopa after 5 years of disease)


Cross-sectional COMT: Val158Met MAO-B: A>G íntron 13



Frauscher et al. Austria (2004)

Japan

Watanabe et al. (2003)

Levodopa

The Levodopa Netherlands

Levodopa

Levodopa

Levodopa

Levodopa

Drug studied

De Lau et al. (2012)

Yin et al. (2013) China

Location

Study (year)

COMT Met allele associated with excessive daytime sleepiness

No association with motor fluctuation or dyskinesia

COMT Met allele associated with increased risk of dyskinesia

No association

Polymorphisms that determined higher COMT enzymatic activity and higher mRNA MAO-A levels associated with higher doses of levodopa

Haplotype that encodes higher enzymatic activity form of COMT associated with higher dose of levodopa

COMT Met/Met genotype associated with the use of less than 500 mg of levodopa after 5 years

Main findings

[26]

[25]

[24]

[23]

[22]

[21]

[20]

Ref.



Review

1259

1260


Canada

France

Germany

Chong et al. (2000)

Corvol et al. (2011)

Kaiser et al. (2003)

Levodopa

Levodopa

Entacapone

Tolcapone

36

183

33

24


DRD2: TaqIA, TaqIB, Taq ID, Pro310Ser and Ser311Cys DRD3: Ser9Gly and product of MspI enzyme digestion DRD4: 48 bp, 12 bp and 13 bp VNTR DAT1: 40 bp VNTR

COMT: Val158Met

COMT: Val158Met

COMT: Val158Met

Cross-sectional DAT1: 40 bp VNTR

Retrospective

Clinical trial

Longitudinal (data derived from a clinical trial)

Retrospective

[123I]-FP-CIT SPECT Dyskinesia

Time to develop motor fluctuation, dyskinesia and psychosis

Primary: increased in ‘on’ medication state Secondary: levodopa pharmacokinetic and COMT activity in erythrocytes

Clinical effectiveness of tolcapone (UPDRS III scores change from baseline to 1–2 weeks and 6 months after treatment)

Hallucination

Excessive daytime sleepiness





Drug studied


Italy

Canada

Camicioli et al. (2005)

Contin et al. (2004)

Germany

Location


Study (year)

No association

DAT1 40 bp VNTR 9 repeats allele associated with dyskinesia or psychosis

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

No association

No association

No association

Main findings

[32]

[31]

[30]

[29]

[28]

[27]

Ref.





Brazil

Israel

SchumacherSchuh et al. (2013)

Kaplan et al. (2014)

France

Devos et al. (2014)

Italy

Contin et al. (2005)


104

73

33

99

103

352

DRD2: 12 polymorphisms DAT1: 15 polymorphisms

SLC22A1/OCT1: rs622342



Cross-sectional DDC: rs921451 and rs3837091

Longitudinal (community based)

Cross-sectional COMT: G1947A MAO-B: A644G

Retrospective


Levodopa

South Korea Levodopa

Lee et al. (2001)

Levodopa

The AntiNetherlands parkinsonian drugs

Levodopa

Levodopa

DAT1 rs393795 C allele associated with longer time to develop dyskinesia

DAT1 839C>T C allele associated with visual hallucination DAT1 40 bp VNTR 9 repeats allele associated with lower levodopa equivalent doses

Main findings

Levodopa pharmacokinetic Dyskinesia

Motor response after a levodopa challenge

Motor response (UPDRS III response after a levodopa challenge) Levodopa pharmacokinetic

Levodopa dose

No association

No association

Both polymorphisms influenced the motor response

SLC22A1 rs622342 C allele associated with increased doses of antiparkinsonian drugs

Levodopa dose (use No association of at least 500 mg of levodopa after 5 years of disease)

Dyskinesia

Visual hallucination Levodopa equivalent dose


Cross-sectional DAT1: 40 bp VNTR and 839C>T



Drug studied

Becker et al. (2011)

TorkamanTurkey Boutorabi et al. (2012)

Location

Study (year)

[39]

[38]

[37]

[36]

[35]

[34]

[33]

Ref.



Review

1261

1262

[41]

No association


COMT Val158Met Entacapone Kim et al. (2011)

Korea

168

Longitudinal

Levodopa diary (time spent in ‘on’ and ‘off’ state) UPDRS COMT Val158Met Entacapone Lee et al. (2002)

Korea

65

Longitudinal

Levodopa diary (time spent in ‘on’ and ‘off’ state) Adverse effect

No association

[40]

Ref. Main findings Genes and polymorphisms Outcomes Study size Design (Parkinson’s disease sample) Drug studied Location Study (year)




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 previous 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 inhibitors, a type of drug available to treat PD [29] . They studied a sample of 24 PD patients derived from a clinical 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 homozygous 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 primary 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 concentration with the use of entacapone. This result suggested that patients homozygous for the Val allele would have more benefit from entacapone use. Nevertheless, 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 [40,41] . MAOB

MAOB degrades dopamine and has an important role in PD pharmacological treatment. This enzyme is encoded by the MOAB gene mapped at chromosome 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 [20] . 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



Japan

China

Germany

USA

Fujii et al. (1999)

Wang et al. (2003)


Strong et al. (2006)

Levodopa

Dopaminergic therapy



Levodopa


Italy

Brazil

De Luca et al. (2009)

SchumacherSchuh et al. (2013)

PD: Pharmacodynamics.

UK

Foltynie et al. (2009)

Italy



Levodopa

Levodopa

Israel

Molchadski et al. (2011)


Pascale et al. (2009)

Israel

Feldman et al. (2006)


Levodopa

Spain

De la FuenteFernández et al. (1999)

Drug studied

Lin et al. (2007) China

Location

Study (year)

205

131

315

120

251

92

264

166

116

155

87

105

Study size (PD sample)

Cross-sectional

Cross-sectional

Longitudinal

Cross-sectional

Cross-sectional

Retrospective

Cross-sectional

Cross-sectional

Cross-sectional

Cross-sectional

Retrospective

Cross-sectional

Design

HOMER1: rs4704559, rs10942891 and rs4704560

HOMER1: rs4704559, rs10942891 and rs4704560

BDNF: Val66Met

ACE: intron 16 Ins/Del

ACE: intron 16 Ins/Del

OPRM1: A118G

HCRT: 909T>C, 22C>T and 20C>A

CCK: 45C>T CCKAR: 779T>C CCKBR: 1550G>A

CCK: 196G>A, 45C>T, 1270C>G and 6662C>T

APOE: E*2, E*3 and E*4 alleles

APOE: E*2, E*3 and E4 alleles

APOE: E*4 allele

Genes and polymorphisms

CCK 45C>T associated with hallucination

No association

APOE E*4 associated with psychosis

APOE E*4 allele associated with hallucination

Main findings

HOMER1 rs4704559 A allele associated with hallucination

BDNF Val66Met Met allele associated with dyskinesia

No association

ACE Ins/Ins genotype associated with psychosis

OPRM1 A118G G allele associated with early onset dyskinesia

HCRT 909T>C T allele associated with sleep attack

Motor fluctuation HOMER1 rs4704559 Dyskinesia G allele associated with Visual hallucination decreased prevalence of visual hallucination

Hallucination

Dyskinesia

Motor fluctuation Dyskinesia Psychosis

Motor fluctuation Dyskinesia Psychosis

Dyskinesia

Sleep attack

Visual hallucination CCK C allele and CCKAR C allele associated with visual hallucination

Hallucination

Dyskinesia

Psychosis

Hallucination

Outcomes

[64]

[63]

[62]

[61]

[60]

[7]

[59]

[58]

[57]

[56]

[55]

[54]

Ref.

Table 2. Studies assessing the effect of genes not associated with dopamine on response to dopaminergic treatment variability in Parkinson’s disease.


Review

1263

1264


PD: Pharmacodynamics.

Levodopa

UK


Cheshire et al. (2014)

USA

Goetz et al. (2001)


Levodopa

Canada

Camicioli et al. (2005)


Israel

USA

Goldman et al. (2004)


Kaplan et al. (2014)

Israel

Yahalom et al. (2012)


Levodopa

Russia

Ivanova et al. (2012)

Drug studied

Lee et al. (2011) South Korea

Location

Study (year)

285

352

503

88

47

86

349

101

Study size (PD sample)

Longitudinal

Retrospective

Longitudinal

Cross-sectional

Retrospective

Cross-sectional

Retrospective

Cross-sectional

Design

BDNF

BDNF: seven polymorphisms

GRIN2B: 266C>T, 366C>G and 200T>G

APOE: E*4 allele

APOE: E*2, E*3 and E*4

CCK: 45C>T CCKAR: 779T>C CCKBR: 1550G>A

LRRK2 G2019S

GRIN2A: 15 polymorphisms GRIN2B: 9 polymorphisms

Genes and polymorphisms

No association

No association

No association

GRIN2A rs7192557 and rs8057394 associated with dyskinesia

Main findings

Dyskinesia Levodopa dose

Dyskinesia

No association

No association

Dyskinesia: diphasic No association and peak of dose

Visual hallucination No association

Hallucination

Hallucination

Dyskinesia

Dyskinesia

Outcomes

[22]

[34]

[16]

[18]

[28]

[67]

[66]

[65]

Ref.

Table 2. Studies assessing the effect of genes not associated with dopamine on response to dopaminergic treatment variability in Parkinson’s disease (cont.).




response, with no effect on levodopa pharmacok inetics 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.

Review

polymorphism C allele was associated with an 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 potentiate dopamine release and are also related to levodopaTransporter genes induced dyskinesia [51,52] . In the absence of nigral cells, DAT1 these neurons could be involved in levodopa uptake, The cessation of dopamine neurotransmission, apart convert it to dopamine, and release this neurotransmitter from the enzymatic degradation, is also determined into the synaptic cleft. The serotonin transporter gene by presynaptic dopamine transporter (DAT) reuptake. (SLC6A4, SERT ) is mapped at chromosome 17q11. The This transporter is encoded by DAT1. The most studied most investigated variant is a 44 bp insertion/deletion polymorphism in this gene is a VNTR (rs28363170) in functional polymorphism in the 5-HTT gene promoter the 3´-UTR. Alleles with 9 and 10 repeats are the most region (HTTLPR) that led to changes in expression of common. This polymorphism has been found to act as this transporter in humans. This gene was investigated a modulator of gene transcription: the 10-repeat allele in association with sleep attacks [19] and with diphasic being associated with higher levels of DAT expression. and peak of dose dyskinesia [16] , both studies reported In young people, DAT1 expression was reported to be negative results. higher in 9 repeat allele carriers [46] . However, DAT1 OCT1 is a polyspecific organic cation transporter expression decreases with aging and this could be more that is associated with dopamine transport. The gene intense in 9 repeat homozygous individuals [47–49] . encoding this protein is located at chromosome 6q25 Kaiser et al. studied 183 PD patients in a cross- (SLC22A1/OCT1) [53] . Becker et al. used data from a sectional design and retrospectively determined time to community based cohort of 7983 subjects in Rotterdam develop dyskinesia, motor fluctuation and psychosis in with 99 incident cases of PD patients and studied the association with DAT1 VNTR polymorphism [31] . They association between antiparkinsonian drug doses and found that the presence of a 9 repeat allele was associ- SLC22A1/OCT1 rs622342 polymorphism [36] . Patients ated with lower prevalence of dyskinesia or psychosis. with the C allele used higher antiparkinsonian drug Contin et al. assessed the potential association between doses. This polymorphism was also related to a higher DAT genotype, single-photon emission computed mortality rate. This SNP is most likely nonfunctional tomography (SPECT) measures using [123I]-FP-CIT although specific studies have not been performed of striatal dopaminergic function, and oral levodopa DAT1 is the most investigated gene transporter but response pattern in 36 patients with PD, but they did no consistent findings have been pointed out because not identify clinically relevant in vivo DAT neuro different polymorphisms and different outcomes were chemical function phenotypes or levodopa response screened in the studies, as shown in Table 1. patterns associated with DAT1 polymorphisms [32] . Schumacher-Schuh et al. studied visual hallucina- Other genes tions and two polymorphisms in the DAT1 gene [33] . Table 2 lists other genes nonrelated to dopamine that One was the VNTR and the other was DAT1 -839C>T were investigated in PD pharmacogenetic studies, as (rs2652511) in the 5´ region of the gene, which has been with dopaminergic genes the main outcome investigated shown to be potentially related to transcriptional rec- was levodopa adverse effects. ognition sites [50] . In a cross-sectional design with 196 APOE is widely known to be associated with an PD patients they observed that carriers of the DAT1 increased risk of Alzheimer’s disease. This gene has -839C allele presented an increased prevalence of two variants encoding three different isoforms. The visual hallucinations. The 9 repeat allele of the DAT1 E*4 allele determines an up to seven-times increase in VNTR was associated with lower levodopa equivalent disease risk [68] . This polymorphism was also associdose use in this sample. ated with dementia in PD [69] . De la Fuente-Fernández Kaplan et al. evaluated 353 PD patients retro et al. described an association between the APOE E*4 spectively in order to determine the time to levodopa- allele and hallucinations in 105 PD patients in a crossinduced dyskinesia development [34] . A total of 34 poly- sectional study [54] . Feldman et al. showed that this morphisms in three genomic regions (DAT1/SLC6A3, same allele was associated with an increased incidence DRD2 and BDNF) were determined. DAT1 rs393795 of psychosis in PD in a retrospective study with 87 PD



1265

Review Schumacher-Schuh, Rieder & Hutz patients [55] . However, two other studies did not replicate these findings [18,28] . One study reported absence of association between APOE and dyskinesia [56] . CCK modulates dopaminergic neurotransmission [70] . Polymorphisms in the promoter region of the CCK gene that may affect CCK transcription based on its Sp1 cisbinding element location and in genes encoding CCK receptors (CCKAR and CCKBR) were studied in PD pharmacogenetics by three groups [57,58,67] . Fujii et al. and Wang et al. reported an association of CCK polymorphisms and hallucinations in cross-sectional design studies in Asian PD patients [57,58] . This association was not observed in European PD patients [67,71] . 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 supporting a relationship with dopaminergic transmission 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 associated 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 levodopainduced complications, mainly dyskinesia [73,74] . Foltynie et al. followed 315 PD patients free of dyskinesia at baseline and observed that the BNDF Val66Met 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, SchumacherSchuh et al. reported that the HOMER1 rs4704559 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 polymorphism is in the 5´-UTR, close to the gene promoter, a role in transcription regulation would be plausible.

1266


Ivanova et al. studied hyperkinetic involuntary movements in tardive dyskinesia in schizophrenia, Huntington’s disease and PD [65] . In 101 PD patients, an association 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 associated with chronic use of dopaminergic drugs, mainly dopamine agonists [75] . The most important enzyme involved in COMT inhibitor (tolcapone and entacapone) biotransformation 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 monogenic form of disease and almost 20 loci were identified as being causative of the disorder [77] . The role of variants in these loci and their relation to pharmacological response was poorly investigated. PARK8 is mapped at chromosome 12q12 and encodes LRRK2. Mutations 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 dyskinesia 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. Dyskinesia was the outcome with more significant findings (Table 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



the CNS. DRD2 was the most investigated gene as the main action of dopamine on motor control is mediated through this receptor. COMT Val158Met polymorphism was also widely studied; this gene has a role in dopamine degradation. More recently, complications of chronic use of dopaminergic therapy, especially dyskinesia, 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 consequence of the lack of precise and widely accepted definitions and clinical instruments to adequately measure 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 Disorder Society (MDS)-UPDRS was revised to improve previous questions and included others [79] . This new version includes questions about impulse control disorder, 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

Review

is a complete assessment constructed by renowned specialists [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 classifications. 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 progressive and dynamic disorder and longitudinal studies evaluating pharmacological response would be preferred 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 different 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 variability 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 transporters 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.



1267

Review Schumacher-Schuh, Rieder & Hutz a similar methodology, with the same polymorphisms and in different populations are urgently needed. Second, 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 polymorphisms 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, costeffective 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. Although no clinical recommendation could be made at present it is expected that clear guidelines will be developed. With the cost of genotyping 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 Científico e Tecnológico (CNPq, Brazil). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

the dopaminergic system in Parkinson’s disease patients with impulse control disorders. Parkinsonism Relat. Disord. 18(4), 397–399 (2012).

References Papers of special note have been highlighted as: • of interest; •• of considerable interest

1268

1

Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain 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 levodopainduced dyskinesias in PD. Neurology 53(7), 1425–1430 (1999).

•

First study to investigate pharmacogenetics of levodopa-induced dyskinesia.

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

Rieck M, Schumacher-Schuh AF, Altmann V et al. DRD2 haplotype is associated with dyskinesia induced by levodopa therapy in Parkinson’s disease patients. Pharmacogenomics 13(15), 1701–1710 (2012).

9

Makoff 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


11

Rissling I, Geller F, Bandmann O et al. Dopamine receptor gene polymorphisms in Parkinson’s disease patients reporting “sleep attacks.” Mov. Disord. 19(11), 1279–1284 (2004).

12

Paus S, Grünewald A, Klein C et al. The DRD2 TaqIA 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 disease. 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 (2001).

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 (2009).

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).

•

Shows the genetic differences between peak of dose dyskinesia and diphasic dyskinesia.

17

Paus S, Gadow F, Knapp M, Klein C, Klockgether 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



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) and catechol-Omethyltransferase (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, Opala G, Tan E-K, Drozdzik M. The association of functional catechol-O-methyltransferase haplotypes 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).

•

An important study with 285 pathologically confirmed Parkinson’s disease patients using a longitudinal design.

23

Yin B, Chen Y, Zhang L. Association between catecholO-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

25

26

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). Watanabe M, Harada S, Nakamura T et al. Association between catechol-O-methyltransferase gene polymorphisms and wearing-off and dyskinesia in Parkinson’s disease. Neuropsychobiology 48(4), 190–193 (2003). 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 (2006).

28

Camicioli R, Rajput A, Rajput M et al. Apolipoprotein E epsilon4 and catechol-O-methyltransferase alleles in autopsyproven Parkinson’s disease: relationship to dementia and hallucinations. Mov. Disord. 20(8), 989–994 (2005).

29

30

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), 143–148 (2000). 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).

••

First clinical trial oriented by pharmacogenetic information.

31

Kaiser R, Hofer A, Grapengiesser A et al. l-dopa-induced adverse effects in PD and dopamine transporter gene polymorphism. Neurology 60(11), 1750–1755 (2003).

32

Contin M, Martinelli P, Mochi M et al. Dopamine transporter gene polymorphism, spect imaging, and


Review

levodopa response in patients with Parkinson disease. Clin. Neuropharmacol. 27(3), 111–115 (2004). 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 Brazilians with Parkinson’s disease. Int. J. Neuropsychopharmacol. doi:http://dx.doi.org/10.1017/ S1461145712001666 (2013) (Epub ahead of print).

34

Kaplan N, Vituri A, Korczyn AD et al. Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopainduced 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, van Schaik RHN, Hofman A, Uitterlinden AG, Stricker BHC. OCT1 polymorphism is associated with response and survival time in antiParkinsonian drug users. Neurogenetics 12(1), 79–82 (2011).

37

Devos D, Lejeune S, Cormier-Dequaire F et al. Dopadecarboxylase 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 disease. 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 disease. Neurology 58(4), 564–567 (2002).

41

Kim JS, Kim 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-Serrano 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 (2007).

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 (1990).


1269

Review Schumacher-Schuh, Rieder & Hutz 46

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 human dopamine transporter gene: the 5´-flanking region reveals five diallelic polymorphic sites in a Caucasian population sample. Neurosci. Lett. 297(2), 125–128 (2001).

of l-dopa-induced adverse effects. J. Neurol. Sci. 276(1–2), 18–21 (2009). 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 analysis 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 variants 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. NMDA receptor genotypes associated with the vulnerability to develop dyskinesia. Transl. Psychiatry 2, e67 (2012).

51

Carta M, Carlsson T, Kirik D, Björklund A. Dopamine released from 5-HT terminals is the cause of l-DOPAinduced dyskinesia in parkinsonian rats. Brain J. Neurol. 130(7), 1819–1833 (2007).

66

Yahalom G, Kaplan N, Vituri A et al. Dyskinesias in patients with Parkinson’s disease: effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. Parkinsonism Relat. Disord. 18(9), 1039–1041 (2012).

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).

67

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).

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 metaanalysis. Arch. Neurol. 63(2), 189–193 (2006).

54

1270

Van de Giessen E, de Win MM, Tanck MW, van den Brink W, Baas F, Booij J. Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J. Nucl. Med. 50(1), 45–52 (2009).

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 disease. Clin. Neuropharmacol. 22(4), 226–230 (1999).

55

Feldman B, Chapman J, Korczyn AD. Apolipoprotein epsilon4 advances appearance of psychosis in patients with Parkinson’s disease. Acta Neurol. Scand. 113(1), 14–17 (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).

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).

71

57

Fujii C, Harada S, Ohkoshi N et al. Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson’s disease. Clin. Genet. 56(5), 394–399 (1999).

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, DominguezMeijide A, Valenzuela R, Villar-Cheda B, Rodríguez-Perez AI. Dopamine-angiotensin interactions in the basal ganglia and their relevance for Parkinson’s disease. Mov. Disord. 28(10), 1337–1342 (2013).

73

Linazasoro G. New ideas on the origin of l-dopa-induced dyskinesias: age, genes and neural plasticity. Trends Pharmacol. Sci. 26(8), 391–397 (2005).

••

An interesting review that proposes that neural plasticity and levodopa chronic complications could be related.

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).

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 (2003).

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, Passarelli E et al. Genetic polymorphism of angiotensin-converting enzyme is not associated with the development of Parkinson’s disease and




76

Ferrari M, Martignoni E, Blandini F et al. Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson’s disease patients. Eur. J. Clin. Pharmacol. 68(11), 1493–1499 (2012).

79

Goetz CG, Tilley BC, Shaftman SR et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov. Disord. 23(15), 2129–2170 (2008).

77

Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson’s disease: progress and therapeutic implications. Mov. Disord. 28(1), 14–23 (2013).

80

Goetz CG, Nutt JG, Stebbins GT. The Unified Dyskinesia Rating Scale: presentation and clinimetric profile. Mov. Disord. 23(16), 2398–2403 (2008).

78

Fahn S, Elton RL, 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).

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).



Review

1271

ADHD pharmacogenetics across the life cycle: New findings and perspectives.

Cancer pharmacogenomics, challenges in implementation, and patient-focused perspectives.

European Medicines Agency initiatives and perspectives on pharmacogenomics.

Gut microbiota and allergic disease: new findings.

Clinician Perspectives on Using Pharmacogenomics in Clinical Practice.

Pharmacogenomics of hypertension and heart disease.

Parietal cells-new perspectives in glomerular disease.

Caffey disease: new perspectives on old questions.

Intravenous immunoglobulin, pharmacogenomics, and Kawasaki disease.

Treating children with inflammatory bowel disease: Current and new perspectives.

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.

New people, new publisher, and new perspectives.

The mirror mechanism: recent findings and perspectives.

Parkinson's Disease: From Pathogenesis to Pharmacogenomics.

Pharmacometabolomics-aided Pharmacogenomics in Autoimmune Disease.

Coeliac Disease - New Pathophysiological Findings and Their Implications for Therapy.

Breathing new perspectives into chronic obstructive pulmonary disease.

New perspectives and insights to Asian systemic lupus erythematosus: renal disease, genetic predisposition and disease activity.

Premotor Symptoms as Predictors of Outcome in Parkinsons Disease: A Case-Control Study.

Developments in renal pharmacogenomics and applications in chronic kidney disease.

Diabetic kidney disease and the cardiorenal syndrome: old disease, new perspectives.

New oral anticoagulants vs. warfarin treatment: no need for pharmacogenomics?

The black disease of Arabia, Sowda-onchocerciasis. New findings.

Alpha-synuclein Toxicity in the Early Secretory Pathway: How It Drives Neurodegeneration in Parkinsons Disease.