Deciphering Genetic Modulators of Long COVID Cognitive Impairment (LCCI) (P1-10.007), 2025, Gouvea et al

Deciphering Genetic Modulators of Long COVID Cognitive Impairment (LCCI) (P1-10.007)

Elisa Gouvea, Elielson da Silva, Andreza Salvio, Renan Fernandes, Jessica Raposo-Vedovi, Larissa Duarte, Helena Alcaraz, and Soniza Alves-Leon

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Objective
To pinpoint genetic variations influencing Long COVID Cognitive Impairment (LCCI).

Background
LCCI is a frequent and poorly understood consequence of COVID-19, imposing a growing burden on society.

Design/Methods
We employed next-generation sequencing to analyze a pre-selected 400-variant panel associated with neuroinflammation and related pathways. We analyzed 49 LCCI cases and 57 post-COVID controls without cognitive impairment. Fisher’s exact test, Benjamini-Hochberg and Bonferroni methods (p<0.05), and in-silico functional evaluation were performed.

Results
LCCI patients exhibited significantly higher frequency of rs40030 (G/A>G) variant in the S-Phase Kinase-Associated Protein 2 (SKP2) gene (p=0.006), while controls exhibited significantly higher frequency of the alternative genotype (A/A>G) for the same variant (p=0.036). The region where the variant is located corresponds to regions associated with the cognitive areas of the brain.

One proposed mechanism of LCCI is SARS-CoV-2 inhibits autophagy, leading to dysregulated cellular metabolism and excessive inflammatory and autoimmune responses. Interestingly, SKP2 is an inhibitor of autophagy. In-silico analysis showed the G/A variant amplifies the expression of SKP2 in the brain, while the A/A variant does the opposite. Thus, SKP2 may play a vital role in LCCI.

rs3212227 (T/G>T) of IL-12B presented higher frequency in LCCI cases (p=0.011). IL-12B is widely related to neurodegenerative disorders such as Alzheimer’s disease (AD). This genotype is known to amplify IL-12B expression and was significantly related to AD risk.

Finally, LCCI patients exhibited a significantly higher frequency of rs35362851 (T/G>T) in the Retinoid X Receptor Alpha (RXRA) gene. This genomic region corresponds to an enhancer in frontal cortex, cingulate gyrus and hippocampus. Several variants in RXRA are associated with general cognitive ability and AD risk.

Conclusions
This investigation revealed distinct genetic variants influencing LCCI and warrants further investigation to elucidate their precise roles in this disease. This knowledge could guide the development of personalized prognostic tools and potentially therapeutic strategies.

Link (Neurology) [Abstract Only)

 

RXRA previously mentioned on the forum:

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing (2024, Journal of Translational Medicine)

GeneCards:
RXRA
IL-12b
SKP2