P2RX7, an adaptive immune response gene, is associated with Parkinson's disease risk and age at onset
- PMID: 39957192
- DOI: 10.1177/1877718X241296015
P2RX7, an adaptive immune response gene, is associated with Parkinson's disease risk and age at onset
Abstract
Background: The adaptive immune response has a role in Parkinson's disease (PD). Patients with LRRK2 or GBA1 mutations often exhibit distinct clinical characteristics.
Objective: To evaluate the involvement of adaptive immune response genes in three PD groups: GBA1-PD, LRRK2-PD, and non-carrier (NC)-PD.
Methods: Differentially expressed genes (DEGs) associated with PD were identified using four datasets. Of them, adaptive immune response genes were evaluated using whole-genome-sequencing of 201 unrelated Ashkenazi-Jewish (AJ) PD patients. Potential pathogenic variants were identified, and P2RX7 variants were assessed in 1200 AJ-PD patients. Burden analysis of rare variants (allele frequencies (AF) < 0.01) on disease risk, and association analyses of common variants (AF ≥ 0.01) with disease risk and age-at-onset (AAO) were conducted. AFs were compared to AJ-non-neuro cases reported in gnomAD. Variants associated with PD were further examined in an independent AJ cohort from AMP-PD.
Results: Of the four adaptive immune DEGs identified, CD8B2, P2RX7, IL27RA, and ZC3H12A, three common variants in P2RX7 were statistically significant: Tyr155His was associated with NC-PD (allelic OR = 1.15, p = 0.015) ; Arg276His was associated with LRRK2-PD (allelic OR = 2.10, p = 0.037), while Glu496Ala was associated with earlier AAO in LRRK2-PD (p = 0.014). Burden analysis showed no significant effect on PD-risk. In the AMP-PD cohort, odds ratios of the two risk variants were similar to the primary cohort, but did not reach significance, probably due to small control sample size (n = 263).
Conclusions: Common variants within P2RX7 are likely associated with PD-risk and earlier AAO. These findings further suggest P2RX7's involvement in PD and its potential interplay with LRRK2.
Keywords: GBA1; LRRK2; P2RX7; Parkinson's disease; adaptive immune response.
Plain language summary
Among many causes, evidence suggest that the immune system plays a role in the development of Parkinson's disease (PD). This study focused on understanding how certain immune-related genes might be involved in PD risk, including people who carry already known genetic risk mutations in LRRK2 and GBA1 genes. Four genes related to the adaptive immune response, CD8B2, P2RX7, IL27RA, and ZC3H12A, demonstrated different expression in the substantia nigra (a primary brain region of neuronal loss in PD) between PD patients and healthy individuals. We focused on P2RX7 (Purinergic Receptor P2X 7) gene and examined the potential enrichment of its genetic variations in a large group of 1200 PD patients of Ashkenazi-Jewish origin, compared to healthy individuals, which may suggest genetic involvement in the disease. Three common DNA variations in this gene were found to be associated with PD. Two of them were linked to a higher risk of PD, and another one was linked to an earlier disease onset in patients who carry a LRRK2 mutation. P2RX7 activation has been linked to inflammation. Our results suggest that this gene could play a role in PD development, which may lead to new approaches for treatment and prevention.
Conflict of interest statement
Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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