Polymorphisms of the dopamine metabolic and signaling pathways are associated with susceptibility to motor levodopa-induced complications (MLIC) in Parkinson’s disease: a systematic review and meta-analysis

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

“…The SLC6A3 polymorphisms (rs3836790 and rs28363170) were associated with motor response to levodopa treatment. However, some of the other studies did not confirm this observation (Moreau et al, 2015;Li et al, 2020Li et al, , 2022Soraya et al, 2022).…”

“…Some studies showed that PD patients with high COMT activity require higher levodopa doses and are at and lower risk of levodopa-induced dyskinesia, compared to the PD patients with low COMT activity. However, other studies provided contradictory results concerning the dyskinesia risk and COMT activity (Bialecka et al, 2008;Andréasson et al, 2017;Erga et al, 2018;Sampaio et al, 2018;Falla et al, 2021;Soraya et al, 2022). One COMT polymorphism (rs4646318) was found linked with impulse control disorder in PD (Erga et al, 2018).…”

A Roadmap for Future Parkinson's Pharmacogenomics in Asia

“…Initially, genetic exploration in PD aimed to identify causative genetics or the genetic architecture of the condition, with first discoveries focused on the autosomal dominant and recessive mutations in PD (SCNA, LRRK2, VPS35 and PINK1, DJ-1, Parkin genes) and environment-gene interactions in the pathobiology of PD (Lill, 2016 ). The work has since extended in to pharmacogenetic profiling in PD, especially regarding the genetic basis of levodopa induced complications to determine whether certain gene polymorphisms can increase an individual's chance of experiencing ineffective levodopa treatment (Espay et al, 2018 ; Kalinderi et al, 2019 ; Falla et al, 2021 ; Soraya et al, 2022 ). This is supported by improved bioinformatics tools such as the PharmCAT (Pharmacogenomics Clinical Annotation Tool) (Klein and Ritchie, 2018 ), or pharmacogenetic and pharmacogenomic databases such as the Pharmacogenomics Knowledge Base (PharmGKB) (Hewett et al, 2002 ), and the CPIC database (Relling and Klein, 2011 ) that provide peer-reviewed information on gene/drug pairs.…”

“…Interestingly, a large subset of these gene polymorphisms are not only highly prevalent in Asians, but also demonstrate stronger associations in the Asian population. An example is the COMT rs4680 and rs4633 which in our previous meta-analysis was found to be markers of dyskinesia in Asian ethnicities (Soraya et al, 2022 ). Together, these imply that genetic aspects are crucial in order to elucidate regional characteristics.…”

“…Levodopa remains the most clinically-effective and cost-effective Parkinon's disease treatment, which can provide an adequate success rate in the majority of cases upon administration that considers the most optimal bioavailability and efficacy. However, a subset of patients may experience the occurrence of motor levodopa-induced complications, including levodopa-induced dyskinesia or motor fluctuations, rendering the levodopa treatment ineffective (Soraya et al, 2022 ).…”