Pharmacogenetics

European Journal of Clinical Pharmacology

, Volume 68, Issue 11, pp 1493-1499

Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson’s disease patients

  • Marco FerrariAffiliated withCenter for Research in Medical Pharmacology, University of Insubria
  • , Emilia MartignoniAffiliated withDepartment of Clinical Medicine, Section of Neurology, University of Insubria
  • , Fabio BlandiniAffiliated withInterdepartmental Research Center for Parkinson’s Disease, IRCCS Neurological Institute “C. Mondino”
  • , Giulio RiboldazziAffiliated withDepartment of Clinical Medicine, Section of Neurology, University of Insubria
  • , Giorgio BonoAffiliated withCenter for Research in Medical Pharmacology, University of Insubria
  • , Franca MarinoAffiliated withCenter for Research in Medical Pharmacology, University of Insubria
  • , Marco CosentinoAffiliated withCenter for Research in Medical Pharmacology, University of Insubria Email author 

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Abstract

Purpose

To investigate the association between adverse reactions to catechol-O-methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity.

Methods

The study included 52 Parkinson’s disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR.

Results

The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P = 0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94–8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P = 0.014; OR 9.33, 95 % CI 1.71–50.78).

Conclusions

In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors.

Keywords

UGT1A9 Catechol-O-methyltransferase inhibitors Adverse reactions Parkinson’s disease