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Association of Catechol-O-Methyltransferase Gene Polymorphisms and Haplotypes in the Levodopa-Induced Adverse Events in Subjects with Parkinson’s Disease

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Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

The presence of dyskinesia is the most common side effect of chronic administration of levodopa in Parkinson’s disease (PD) subjects. Genetic polymorphisms in levodopa metabolizing gene, catechol-O-methyl transferase (COMT), is shown to influence the inter-individual variability in drug response and adverse events. In the present study, the association of COMT rs6269, rs4633, rs4818, and rs4680 polymorphisms and haplotypes on pharmacokinetics and adverse events with levodopa was investigated in 150 PD patients. The age of onset of PD was 58.00 ± 10 yrs. The most common side effect faced by 78% of the subjects was dyskinesia. The AUC of levodopa was found to be significantly higher in subjects with dyskinesia (1695 ± 113 ng/ml/hr, p < 0.0001) than those without dyskinesia (1550 ± 122 ng/ml/hr). We found that the frequency of subjects presenting dyskinesia was significantly higher in subjects carrying variant genotype of COMT rs6269, rs4633, and rs4680 than that with wild genotype and these subjects presented higher AUC of levodopa. In addition, in subjects with dyskinesia, the AUC of levodopa was found to be significantly higher with low COMT (ACCG) haplotype. The association of COMT rs6269, COMT rs4633, COMT rs4818, and COMT rs4680 variant genotypes with the risk of dyskinesia due to levodopa therapy showed an ROC AUC of 0.67 indicating the moderate prediction of dyskinesia (p = 0.0021) with these COMT variants. In conclusion, PD subjects carrying the variant genotypes of COMT strongly influence high levodopa-induced dyskinesia. Hence the genotyping of COMT before the levodopa therapy will be useful to reduce the adverse events associated with the chronic levodopa treatment.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, 500082, India

    Tasneem SD Fatima & Boddupally Sreenu

  2. Department of Neurology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, 500082, India

    Syed Tazeem Fathima, Rukmini Mridula Kandadai & Rupam Borgohain

  3. Department of Biochemistry, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, 500082, India

    Vijay Kumar Kutala

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Contributions

The study was conceived and designed by RMK, RB and VKK. The recruitment of subjects, extraction of DNA and genotyping were performed by TFSD, STF and HPLC analysis was performed by BS. The data analysis was performed by TFSD and VKK. The manuscript was drafted by TFSD and VKK. The manuscript was revised for the critical content by RMK and RB. The final version of the manuscript was approved by all the authors.

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Correspondence to Vijay Kumar Kutala.

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This study was approved by the Institutional Ethics Committee of Nizam’s Institute of Medical Sciences, Hyderabad (approval no. EC/NIMS/1895/2017).

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Fatima, T.S., Fathima, S.T., Kandadai, R.M. et al. Association of Catechol-O-Methyltransferase Gene Polymorphisms and Haplotypes in the Levodopa-Induced Adverse Events in Subjects with Parkinson’s Disease. Ind J Clin Biochem 38, 262–274 (2023). https://doi.org/10.1007/s12291-022-01046-8

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  • DOI: https://doi.org/10.1007/s12291-022-01046-8

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