Gita Vita Soraya1,2, Zulvikar Syambani Ulhaq3,4, Syifaus Shodry5, Muhammad A'raaf Sirojan Kusuma5, Sarah Herawangsa5, Maharani Oryza Sativa5, Aridin Gustaf5, Dzakky Avecienna Nur Faridwazdi5, Shinta Wulandari Florentia6, Neila Raisa6, Andi Kurnia Bintang2, Muhammad Akbar2. 1. Department of Biochemistry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. 2. Department of Neurology, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. 3. Department of Biochemistry, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim State Islamic University of Malang, Malang, Indonesia. zulhaq@kedokteran.uin-malang.ac.id. 4. National Research and Innovation Agency (BRIN), Jakarta, Indonesia. zulhaq@kedokteran.uin-malang.ac.id. 5. Undergraduate Medical Program, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim State Islamic University of Malang, Malang, Indonesia. 6. Department of Neurology, Faculty of Medicine, Brawijaya University, Malang, Indonesia.
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.
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.
Authors: Werner Poewe; Angelo Antonini; Jan Cm Zijlmans; Pierre R Burkhard; François Vingerhoets Journal: Clin Interv Aging Date: 2010-09-07 Impact factor: 4.458
Authors: Marika Falla; Alessio Di Fonzo; Andrew Anthony Hicks; Peter Paul Pramstaller; Giovanni Fabbrini Journal: Parkinsonism Relat Disord Date: 2021-01-31 Impact factor: 4.891