A genetic variant associated with aquaporin 3 expression is correlated to in-hospital death in COVID-19 patients with extracellular hyperosmolality.

Hyperosmolality is increasingly recognized as a factor contributing to severe COVID-19. Recently, a genetic variant near the aquaporin 3 (AQP3) water channel was associated with severe COVID-19 [rs60840586:G; odds ratio (OR): 1.07, P = 2.5 × 10^-9]. The variant is known to increase gene expression of AQP3 in several organs, including the lung [normalized expression scores (NES) = 0.33, P = 4.1 × 10^-20] in GTEx. In this study, we investigated 576 patients in the Biobanque Quebecoise de la COVID-19 (BQC-19) with both genetic and clinical data available. We estimated plasma osmolality using the formula: eOSM = 2 × [Na⁺] + 2 × [K⁺] + [Urea] + [Glucose]. Using a logistic regression of mortality against eOSM, genotype at rs60840586, sex, age, and the first 10 genetic principal components, we confirm that hyperosmolality is associated with COVID-19 mortality (OR = 2.06 [95% CI = 1.62-2.65], P = 9.13 × 10^-9). Interestingly, we found that the risk of death linked to hyperosmolality is influenced by the AQP3 variant rs60840586:G genotype (OR = 1.95 [95% CI = 1.22-3.28], P = 0.0075). However, the rs60840586 genotype did not independently affect mortality in this cohort. These findings suggest that the body's ability to regulate and accommodate hyperosmolality may be disrupted by overexpression of AQP3, potentially worsening outcomes in COVID-19. Given the role of AQP3 in water transport and homeostasis, further defining the functionality of its variants may provide key insights into COVID-19 severity and guide clinical management strategies, particularly in critically ill patients with hyperosmolality.NEW & NOTEWORTHY A genetic variant near water channel AQP3, linked to severe COVID-19, amplifies the risk of death in patients with elevated plasma osmolality. In patients hospitalized with COVID-19, we show that although the variant does not affect systemic osmolality directly, it interacts with hyperosmolality to increase mortality risk. These findings highlight a potential mechanism where AQP3 overexpression disrupts cellular water handling during critical illness, offering new insight into the role of water balance in COVID-19 pathophysiology.