Objective: We examined the association between NOH and PD-related Single Nucleotide Polymorphism (SNPs) and mapped their effects on gene expression and metabolic and signaling pathways.

Background: The genetic basis of Neurogenic Orthostatic Hypotension (NOH) in Parkinson’s Disease (PD) has been inadequately explored.

Method: Patients with PD, free from pathological conditions associated with OH, and not taking OH-associated medications were selected from the “Parkinson’s Progression Marker Initiative (PPMI)” database. NOH was defined as a change in systolic (≥20 mmHg) or diastolic (≥10 mmHg) blood pressure within 3 minutes after standing at the baseline visit. Logistic regression was used to relate SNPs to NOH. Linkage-disequilibrium analysis, expression quantitative trait loci, and enrichment analysis were used to assess the effects on gene expression and metabolic/signaling pathways.

Results: Of 304 patients meeting entry criteria, 35 had NOH (11.5%). The characteristics of patients are shown in Table 1. NOH was more frequent in patients with SNPs in SNCA, TMEM175, FAM47E-STBD1, CCDC62, SCN3A, MIR4696, SH3GL2, and LZTS3/DDRGK1 and less frequent in those with SNPs in ITGA8, IP6K2, SIPA1L2, NDUFAF2 (Table 2). These SNPs affected gene expression associated with the major hierarchical central structures of the autonomic nervous system (Table 3) and influenced several metabolic/signaling pathways, most notably, IP3/Ca⁺⁺ signaling, the PKA-CREB pathway, and the metabolism of fatty acids (Table 4).

Conclusion: NOH was associated with PD-related SNPs, influencing gene expression and metabolic/signaling pathways of functional pertinence to blood pressure control. These findings provide new insights into the pathophysiology of NOH in PD and may provide targets for future therapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetics-of-neurogenic-orthostatic-hypotension-in-parkinsons-disease/