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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

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Abstract

Background

Dopamine replacement therapy remains the gold standard for symptomatic management of Parkinson’s disease worldwide. However, most patients will develop debilitating motor levodopa-induced complications (MLIC) in the form of levodopa-induced dyskinesia (LID) and/or motor fluctuations (MF). This study aimed to conduct a systematic review and meta-analysis on the pharmacogenetic association between LID and MF with common genetic variants of the dopamine metabolic and signaling pathways.

Methods

A meta-analysis was conducted according to the PRISMA guidelines. Extracted studies include case–control studies evaluating the association between SLC6A3/DAT rs28363170 and rs393795; COMT rs4680 and rs4633; MAO-B rs1799836, BDNF rs6265, DRD1 rs4532, DRD2 rs1800497, DRD3 rs6280, and DRD5 rs6283 polymorphisms; and the overall risk of MLIC and its subtypes LID or MF. Genotypic frequency were tested for deviation from the Hardy–Weinberg equilibrium (HWE), and the genetic association was examined using the allelic (a vs. A), recessive (aa vs. Aa + AA), dominant (aa + Aa vs. AA), overdominant (Aa vs. aa + AA), homozygous (aa vs. AA), and heterozygous (Aa vs. AA and aa vs. aA) models.

Results

Fourteen studies were included in the meta-analysis. A significant association was found between COMT rs46809 polymorphisms with LID but not MF, with the association observable in Asians but not Caucasians. In Asians, the COMT rs4633 was significantly associated with the occurrence of both LID and MF. The MAO-B rs1799836 was associated with both MF and LID. Among all the dopamine receptor genes analyzed, only DRD2 exhibited an association with LID. No association was observed between the SLC6AT/DAT and BDNF genes with either LID or MF.

Conclusion

Strong associations were observed between polymorphisms of genes regulating dopamine metabolism with the occurrence of LID and/or MF. The MAO-B rs1799836 may be potential for use as a general pharmacogenetic marker of MLIC, while the COMT rs4680 and rs4633 may be used as markers of LID in Asian ethnicities.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

CI:

Confidence interval

COMT:

Catechol-O-methyltransferase

DAT:

Dopamine transporter

DRD:

Dopamine receptor

HWE:

Hardy-Weinberg equilibrium

L-Dopa:

L-dopamine

LID:

Levodopa-induced dyskinesia

MAO:

Monoamine oxidase

MF:

Motor fluctuations

MLIC:

Motor levodopa-induced complications

OR:

Odds ratio

PD:

Parkinson’s disease

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

SLC6:

Solute carrier 6

SNP:

Single nucleotide polymorphism

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia

    Gita Vita Soraya

  2. Department of Neurology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia

    Gita Vita Soraya, Andi Kurnia Bintang & Muhammad Akbar

  3. Department of Biochemistry, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim State Islamic University of Malang, Malang, Indonesia

    Zulvikar Syambani Ulhaq

  4. National Research and Innovation Agency (BRIN), Jakarta, Indonesia

    Zulvikar Syambani Ulhaq

  5. Undergraduate Medical Program, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim State Islamic University of Malang, Malang, Indonesia

    Syifaus Shodry, Muhammad A’raaf Sirojan Kusuma, Sarah Herawangsa, Maharani Oryza Sativa, Aridin Gustaf & Dzakky Avecienna Nur Faridwazdi

  6. Department of Neurology, Faculty of Medicine, Brawijaya University, Malang, Indonesia

    Shinta Wulandari Florentia & Neila Raisa

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Contributions

GS and ZU conceived, designed, and performed the study. GS, ZU, SF, NR, AKB, and MA analyzed and interpreted the data. GS, ZU, SS, MK, SH, MS, AG, and DF aided data collection and extraction. GS and ZU wrote the main draft and revise the manuscript. NR, AKB, and MA critically reviewed the manuscript. All authors reviewed and finally approved the manuscript.

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Correspondence to Zulvikar Syambani Ulhaq.

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Gita Vita Soraya and Zulvikar Syambani Ulhaq have contributed equally to this work and share first authorship.

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Soraya, G.V., Ulhaq, Z.S., Shodry, S. et al. 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. Neurol Sci 43, 3649–3670 (2022). https://doi.org/10.1007/s10072-021-05829-4

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