Elsevier

Neurobiology of Aging

Volume 33, Issue 4, April 2012, Pages 836.e1-836.e3
Neurobiology of Aging

Genetic reports abstract
Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson's disease

https://doi.org/10.1016/j.neurobiolaging.2011.06.015Get rights and content

Abstract

Histamine is a central neurotransmitter degraded by histamine-N-methyltransferase (HNMT). Several abnormalities in the histaminergic system were found in patients with Parkinson's disease (PD), thus we tested the possible association of a Thr105Ile functional polymorphism in HNMT with PD. A total of 913 patients with PD and 958 controls were genotyped using a TaqMan RT-PCR Genotyping Assay (Foster City, California, USA). Lower frequency of HNMT Ile105 allele that is associated with decreased enzymatic activity was found in patients compared with controls (χ2 = 11.65; p = 0.0006). We performed meta-analysis to confirm the association of Thr105Ile functional polymorphism with PD. Our results indicate that lower HNMT activity plays a role in the pathogenesis of PD.

Introduction

Histamine is a central neurotransmitter synthesized from histidine by histidine decarboxylase (HDC; EC 4.1.1.22) and degraded by histamine-N-methyltransferase (HNMT, EC 2.1.1.8). A common genetic polymorphism in exon 4 of the HNMT gene leads to change of threonine to isoleucine at position 105 (Thr105Ile). Individuals heterozygous for Ile105 allele have 30% to 50% lower HNMT activity, while homozygous individuals have decreased enzyme activity of about 60% (Horton et al., 2001, Preuss et al., 1998, Rutherford et al., 2008). Because abnormalities in the histaminergic system were found in patients with Parkinson's disease (PD) (Haas et al., 2008), we examined the association of this functional polymorphism with PD.

Section snippets

Methods

A total of 913 patients with PD and 958 controls were examined using a case-control approach. Two subsets of Caucasian patients, 299 with origin from the USA and 614 from Europe were tested. All patients met UK Brain Bank clinical criteria for PD (Hughes et al., 1992) and controls were healthy individuals of similar age, sex, and ethnicity without neurodegenerative diseases and with no family history of Parkinsonism. A TaqMan RT-PCR Genotyping Assay was used to detect the HNMT Thr105Ile

Results

A significantly lower frequency of the HNMT Ile105 allele (χ2 = 11.65; p = 0.0006; OR, 1.42; 95% CI, 1.16–1.73) was found among the PD patients (9.97%) in comparison with the healthy subjects (13.57%). We also detected a significant difference among HNMT Thr105Ile genotypes (χ2 = 11.765; p = 0.00278; OR, 1.47; 95% CI, 1.18–1.82) between the PD and control samples. When analyzing the PD patients with origin from the USA and Europe separately, there was a significant difference of the HNMT

Discussion

In this study we found an association of the HNMT Thr105Ile functional polymorphism with PD. Association of this polymorphism with PD has been debated, since 1 previous study from Europe revealed a significant association (Agundez et al., 2008), that was not confirmed in a subsequent study from the USA (Keeling et al., 2010). These results could be attributed to sample size and population stratification due to different ethnic origin of tested individuals. Analyzing a larger number of PD and

Disclosure statement

Dr. Johann Hagenah receives research support from the Bachmann-Strauss Dystonia Parkinson Foundation and received honoraria as an invited speaker from GlaxoSmithKline. Dr. Christine Klein received consulting fees from Boehringer Ingelheim and Centogene and received honoraria for speaking from Boehringer Ingelheim and Merz Pharma. Dr. Klein is the recipient of a career development award from the Hermann and Lilly Schilling Foundation. She is funded by the Volkswagen Foundation, the Deutsche

Acknowledgements

This study was sponsored by National Parkinson Foundation (DK), GENEPARK (EU-LSHB-CT-2006-037544) grant (DK), Volkswagen Foundation, Hermann and Lilly Schilling Foundation, and NGFN Plus PNP-01GS08135-3 (BMBF, CK).

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