The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications

Introduction Differences in catechol-O-methyltransferase (COMT) activity and genotype may determine individual variations in the therapeutic response to levodopa or Parkinson's disease (PD) susceptibility. The role of functional COMT haplotypes in PD susceptibility and treatment response has not been examined. Objectives In this case-control study, we investigated the association of the most common COMT gene haplotypes (formed by single nucleoticle polymorphisms (SNPs): rs6269:A > G; rs4633C > T; rs4818:C > G; and rs4680:A > G) with PD risk and the association of the COMT haplotypes with the dose and complications of levodopa therapy in PD patients. Methods A total of 679 study participants (322 PD and 357 controls) were included. Each participant was genotyped for four SNPs in the COMT gene, located in a common haploblock, that has been shown to influence COMT enzymatic activity. The influence of COMT haplotypes on the dose of levodopa administered during fifth year of treatment and occurrence of motor complications were examined in PD patients. The EH program (Jurg Oft, Rockefeller University, New York, USA) was used to estimate haplotype frequencies. Results The estimated frequencies of low (A_C_C_G) and medium (AT C A) activity haplotypes tended to be slightly lower among PD patients when compared with controls (P=0.09, G-C-G-G-high activity haplotype as reference). The frequency of G_C_G_G (high activity) haplotype carriers was higher in late onset PD patients (P=0.04) compared with controls. The mean levodopa dose increased with the activity of the functional haplotypes (low < medium < high). Doses prescribed for G-C-G-G (high activity) haplotype carriers (mean 604.2 +/- 261.9 mg) were significantly higher than those for the noncarriers (mean 512.2 +/- 133.5 mg, P<0.05). The COMT haplotype seemed to have little influence on the development of levodopa-induced dyskinesias. Conclusion Our study showed a possible association of functional COMT haplotypes with the risk of PD. Both nonsynonymous and synonymous SNPs within functional COMT haplotype blocks may be more relevant than individual SNPs in conferring PD susceptibility. The doses of levodopa treatment can be influenced by specific COMT haplotypes and this may be useful in instituting individualized therapy for PD patients.