Several Genetic Loci Show Increased Risk of Mortality, Cognitive Impairment in Parkinson Disease

The results of a large-scale assessment of genome-wide association studies (GWAS) presented at the International Parkinson and Movement Disorders Society (MDS) 2022 Congress, September 15-18 in Madrid, Spain, identified 3 new loci associated with progression or mortality are associated with Parkinson’s disease (PD).1

Previous research had identified 90 risk variants for PD, with only 5 nominated for PD progression. In this study, study leader Manuela M. Tan, BPsych, postdoctoral researcher at Oslo University Hospital, and colleagues included data from 11 cohorts of 6766 patients with PD with more than 15,340 visits with a mean follow-up of between 4.2 and 15.7 years. Motor progression was defined by Hoehn and Yahr stage 3 or higher, while cognitive impairment was defined by serial cognitive assessment.

First, Tan et al. a robust effect of the apolipoprotein (APOE) ε4 allele on mortality and cognitive impairment in Parkinson’s disease. Studies have shown that this genotype directly affects the development of α-synuclein pathology in dementia with Lewy bodies (DLB) and PD dementia. Additionally the APOE The ε4 allele remains the strongest known genetic risk factor for Alzheimer’s disease and is also a prominent genetic risk factor for DLB.

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Of the loci identified, the first was within the TBXAS1 Gene encoding thromboxane A synthase 1, which was significantly associated with mortality in PD (HR, 2.0; P = 7.7 x 10e-10). Another place near the SYT10 Gene encoding synaptotagmin 10 was associated just below genome-wide significance (HR, 1.4; P = 5.3 x 10e-8th). The last locus, rs112809886, a single nucleotide polymorphism, was associated with progression to Hoehn and Yahr stage 3 or higher (HR, 4.8; P = 1.9 x 10e-9).

Tan et al. concluded: “Further work is needed to replicate these loci in other independent cohorts and to understand what causal variants exist and how they affect the underlying disease biology. However, these genes and signaling pathways may represent new candidates for disease modification in PD.”

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The last place located nearby GGT5, regulates the expression of ADORA2A in the cerebellum. ADORA2A encodes the adenosine A2A receptor, which is highly expressed in GABAergic striatal-pallidal neurons. In animal models of PD, the use of selective antagonists of adenosine A2A receptors, such as e.g. B. Istradefyllin (Nourianz; Kyowa Hakko Kirin), for the reversibility of the movement disorder. In addition, the use of these antagonists in combination therapy allows reducing levodopa doses, as well as reducing side effects. Istradefylline was approved in the US in August 2019 and was the first adenosine receptor antagonist approved for use in Parkinson’s disease.

KW-6356, another adenosine A2A receptor developed by Kyowa Kirin, is currently being evaluated in Phase 2 studies in patients with Parkinson’s disease. In an analysis presented at MDS 2022, the compound showed a favorable and safe profile as an add-on treatment to levodopa. Compared to placebo, treatment with KW-6356 resulted in significantly greater improvements in MDS-Unified Parkinson’s Disease Rating Scale III scores and OFF time per day.2

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Click here to learn more about MDS 2022.

1. Tan M, Lawton M, Jabbari E et al. Genome-wide determinants of mortality and clinical progression in Parkinson’s disease. Presented at: MDS Congress 2022; September 15-18; Madrid, Span. LBA-19.
2. Maeda T, Sugiyama K, Yamada K, Nishi M, Hattori N. Effect of KW-6356, a Novel Adenosine A2A Receptor Antagonist/Inverse Agonist, on Motor and Non-Motor Symptoms in Parkinson’s Patients as an Adjunct to Levodopa Therapy: Results of the Phase 2b Study. Presented at: MDS Congress 2022; September 15-18; Madrid, Spain. Summary 743

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