Abstract
Background: Studies in animal models have suggested that aldehyde dehydrogenase 1 (encoded by ALDH1A1) protects against Parkinson’s disease (PD) by reducing toxic metabolites of dopamine. Herein we aimed to investigate whether ALDH1A1 was genetically associated with PD susceptibility in humans.Methods: A Han Chinese population of 1,039 subjects was recruited to analyze six tag-single nucleotide polymorphisms (SNPs), followed by haplotype analyses and variants interaction analyses. Real-time PCR was used to analyze mRNA levels of ALDH1A1 in peripheral blood of 42 subjects.Results: The tag-SNP rs7043217 of ALDH1A1 was significantly associated with PD susceptibility with the T serving as a risk allele (genotype frequency, P = 0.030; allele frequency, P = 0.013, OR = 1.258, 95% CI = 1.050–1.508). Multiple haplotypes were linked to abnormalities of PD risk, topped by a 4-SNP GGTA module in the order of rs4646547, rs1888202, rs7043217, and rs647880 (P = 9.610 × 10–8, OR = 6.420, 95% CI = 2.944–13.998). Interaction analyses showed that a simultaneous presence of the CC genotype of rs7043217 and the TT genotype of ALDH2 variant rs4767944 conferred an elevated protection against PD (P = 4.68 × 10–4, OR = 0.378, 95% CI = 0.219–0.652). The mRNA expression of ALDH1A1 showed a trend of reduction (P = 0.084) in PD patients compared to the controls.Conclusion: Our results provide novel genetic insights into the role of ALDH1 in PD pathogenesis.
Highlights
Parkinson’s disease (PD) is mainly of sporadic origin and the second most common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)
Significant differences were found in both genotype (P = 0.030) and allele (P = 0.013) frequencies of rs7043217 between the cases and controls, with the T allele serving as a risk allele for PD (OR = 1.258, 95% CI = 1.050–1.508)
Analyzing of rs7043217 using three genetic models showed that rs7043217 was significantly associated with PD in the dominant model (P = 0.009; Table 2) and additive model (P = 0.015; Table 2), further suggesting that the T allele was a risk allele for PD
Summary
Parkinson’s disease (PD) is mainly of sporadic origin and the second most common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Aldehyde dehydrogenase (ALDH) is a family of enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids. ALDH converts the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) into 3,4-dihydroxyphenylacetic acid (DOPAC), which is further metabolized to form homovanillic acid (Grunblatt and Riederer, 2016; Masato et al, 2019). DOPAL is neurotoxic by triggering α-synuclein aggregates, provoking the loss of dopaminergic neurons (Marchitti et al, 2007; Burke et al, 2008). Studies in animal models have suggested that aldehyde dehydrogenase 1 (encoded by ALDH1A1) protects against Parkinson’s disease (PD) by reducing toxic metabolites of dopamine. We aimed to investigate whether ALDH1A1 was genetically associated with PD susceptibility in humans
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