One of the identified loci related to clinical progression in Parkinson disease expresses ADORA2A in the cerebellum, which encodes the adenosine A2A receptor, a promising target for therapeutics in PD.
Findings from a large-scale assessment of genome-wide association studies (GWAS) presented at the 2022 International Parkinson and Movement Disorders Society (MDS) Congress, September 15-18, in Madrid, Spain, identified 3 novel loci associated with progression or mortality in Parkinson disease (PD).1
Previous research had identified 90 risk variants for PD, with only 5 that had been nominated for PD progression. In this study, lead investigator Manuela M. Tan, BPsych, postdoctoral research fellow, 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 greater, while cognitive impairment was defined by serial cognitive examination.
Firstly, Tan et al found a robust effect of apolipoprotein (APOE) ε4 allele on mortality and cognitive impairment in PD. Studies have shown that this genotype directly influences the development of α-synuclein pathology in dementia with Lewy bodies (DLB) and PD dementia. Additionally, the APOE ε4 allele remains the strongest known genetic risk factor for Alzheimer disease and is also a prominent genetic risk factor for DLB.
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 locus, near the SYT10 gene encoding synaptotagmin 10, was associated just below genome-wide significance (HR, 1.4; P = 5.3 x 10e-8). 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, as well as to understand which are the causal variants and how they affect underlying disease biology. However, these genes and pathways may represent new candidates for disease modification in PD."
The final locus, located near GGT5, regulates expression of ADORA2A in the cerebellum. ADORA2A encodes the adenosine A2A receptor, which is highly expressed in GABA-ergic striatal-pallidal neurons. In animal models of PD, the use of selective antagonists of adenosine A2A receptors, such as istradefylline (Nourianz; Kyowa Hakko Kirin), led to the reversibility of movement dysfunction. Furthermore, the use of these antagonists in combination therapy enables the reduction of levodopa doses, as well as a reduction of side effects. Approved in the US in August 2019, istradefylline represented the first adenosine receptor antagonist labeled for use in PD.
KW-6356, another adenosine A2A receptor developed by Kyowa Kirin, is currently being assessed in phase 2 studies of patients with PD. In an analysis presented at MDS 2022, the agent showed a favorable and safe profile as an adjunct treatment to levodopa. Compared with 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