The role of genetic factors in the occurrence of levodopa-induced motor complications in Parkinson's disease.

BACKGROUND

The genetic contribution to the development of levodopa-induced motor complications in Parkinson's disease (PD) remains poorly understood.

OBJECTIVES

We aimed to investigate the association between selected polymorphisms of the catechol-O-methyltransferase (COMT), dopamine receptor D2 (DRD2), ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine transporter (DAT) genes and the occurrence of motor complications in the group of PD patients.

METHODS

A total of 234 PD patients undergoing levodopa therapy for at least two years were genotyped for the following polymorphisms: rs4680 in COMT; rs6277, rs1076560, and rs2283265 in DRD2; rs1800497 and rs2734849 in ANKK1; and a VNTR (Variable Number of Tandem Repeats) polymorphism in the 3'-UTR (3'-untranslated region) of the DAT gene.

RESULTS

Levodopa-induced dyskinesia (LID) was significantly more frequent in carriers of the AA genotype of rs4680 in COMT compared to AG and GG carriers. Motor fluctuations occurred more frequently in carriers of the ANKK1/DRD2 haplotypes GGAAA and AGGAA than in non-carriers. Independent predictors of motor fluctuations included younger age at disease onset, longer disease duration, daily levodopa dose ≥ 500 mg, and greater disease severity. Independent predictors of LID included female gender, longer disease duration, levodopa equivalent daily dose (LEDD) ≥900 mg, greater disease severity, and the AA genotype of rs4680 in COMT, which conferred a 2.8-fold higher risk of dyskinesia.

CONCLUSION

These findings suggest that genetic variants, particularly in the COMT and ANKK1/DRD2 loci, may contribute to the development of levodopa-induced motor complications in PD. These preliminary results require confirmation in larger, longitudinal studies.