Objective: To evaluate the role of COMT gene variations on the pharmacokinetics (PK) of L-dopa in PD patients.

Background: Genetic variations in enzymes (MAO-B, COMT), involved in metabolism of dopamine, may contribute to variations in response to levodopa and motor complications in Parkinson’s disease.

Method: A total of 30 PD patients were recruited based on UKPDS Brain Bank criteria. Patient’s motor improvement following L-dopa administration was reported as L-dopa response (aLR, %LR). Five hours (0 hr -4 hrs after L-dopa administration) blood samples were collected and peak plasma concentrations were analysed by HPLC method. DNA was isolated and genotyping done by RFLP method and validated by Sanger’s sequencing.

Results: Among 30 PD cases 60% were male with mean age 57.26, and 40% were females with mean age 58.3(p=0.56). On average, duration of disease was significantly (p=0.0035*) higher in male individuals (Mean ± SD = 8.55 ± 3.68,) compared to females (Mean ± SD = 5 ± 1.41). Mean motor ‘off’ score was higher in male patients (51.9 ± 9.13) compared to female PD patients (49.91 ± 8.36) but not significant (p=0.34). There is no significant change in (p=0.61) mean absolute L-dopa response in male (37.22 ± 11.5) when compared to female PD patients (35.33 ± 7.01). When considering genotypes association with AUC of L-dopa, the COMT gene SNP at the promoter region rs6269 (G/A) (GG VS AA = 3811 ± 1010, N=2; 1662 ± 306.6, N= 12; P=0.02) and one nonsynonymous change rs4680 (G/A: Val158Met) (GG VS AA = 2881 ± 361.5, N=12; 1237 ± 321.4, N=9; P=0.004) have shown a significant association with AUC of L-dopa (Figure 1). The two synonymous changes rs4633 (C/T) and rs4818 (G/C, Leu136Leu) were not significant. When considering genotypes association with dyskinesia score, the COMT gene SNP at the promoter region rs6269 (G/A) (GG VS AA = 3811 ± 1010, N=2; 1662 ± 306.6, N= 12; P=0.02) and one nonsynonymous change rs4680 (G/A: Val158Met) (GG VS AA = 2881 ± 361.5, N=12; 1237 ± 321.4, N=9; P=0.004) have shown a significant association with AUC of levodopa.

Conclusion: The variant allele Frequency of COMT rs4633 (C/T), rs4680 (G/A) polymorphisms was high in EOPD patients. The AUC of Levodopa was found significantly high with variant alleles of rs4633 (C/T), rs4680 (G/A) of COMT polymorphisms in LOPD patients. These variant alleles are significantly associated with Dyskinesias.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-genetic-polymophisms-with-pharmacokinetics-of-levodopa-in-south-indian-pd-patients/