Pharmacogenetics of drug response in Parkinson's disease

Abstract

Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs.

Personalized medicine in Parkinson's disease: Time to be precise

“…Possible clinical implications are outlined in Table ; however, it must be pointed out that there are contradicting studies, and at this moment no definitive recommendations can be provided . Pharmacogenetic strategies could also potentially be useful for excessive daytime sleepiness (COMT polymorphism, DRD2, and DRD4 [both linked to “sleep attacks”]), hypocretin neuropeptide precursor (HCRT) (prepro‐hypocretin), and psychosis (dopamine receptor D4 (DRD4), cholecystokinin (CCK), apolipoprotein E (APOE4), angiotensin convertin enzyme (ACE)) in PD, although clinical implications are unclear and controversial …”

“…Potential role of checking MTHFR C677T polymorphism of the MTHFR gene in severe hyperhomocysteinaemia…”

“…12 Pharmacogenetic strategies could also potentially be useful for excessive daytime sleepiness (COMT polymorphism, DRD2, and DRD4 [both linked to "sleep attacks"]), hypocretin neuropeptide precursor (HCRT) (prepro-hypocretin), and psychosis (dopamine receptor D4 (DRD4), cholecystokinin (CCK), apolipoprotein E (APOE4), angiotensin convertin enzyme (ACE)) in PD, although clinical implications are unclear and controversial. 18,19 Age: Biology, Chronology, and Personalized Medicine…”

“…The application of personalised medicine strategy based on pharmacogenomic factors and clinical presentation[17][18][19] …”

Viewpoint: Developing drugs for levodopa‐induced dyskinesia in PD: Lessons learnt, what does the future hold?

“…Genetic variability in risk factors for or against development of LID has been investigated. These range from polymorphisms in dopamine D2 and D3 receptors; growth factors such as brain‐derived neurotropic factor (BDNF) to MAOB and COMT enzyme activity (e.g., Džoljić, Novaković, Krajinovic, Grbatinić, & Kostić, ; Kusters et al., ; Sampaio et al., ). Future genotyping PD subjects in therapeutic LID trials may be required to stratify subjects and reduce false negative.…”