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 (<i>AQP3</i>) water channel was associated with severe COVID-19 [rs60840586:G; odds ratio (OR): 1.07, <i>P</i> = 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, <i>P</i> = 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], <i>P</i> = 9.13 × 10^-9). Interestingly, we found that the risk of death linked to hyperosmolality is influenced by the <i>AQP3</i> variant rs60840586:G genotype (OR = 1.95 [95% CI = 1.22-3.28], <i>P</i> = 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 <i>AQP3</i>, 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.<b>NEW & NOTEWORTHY</b> A genetic variant near water channel <i>AQP3</i>, 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.