AQP3 and COVID‑19 Severity

Recent multi‑patient studies have implicated AQP3 in modulating the severity of COVID‑19. The evidence comes from large-scale genome‑wide association studies, including one with 11,939 COVID‑19 positive cases recruited from 34 hospitals across Spain (PMID:35708486), and a replication cohort involving 1,598 cases with 1,068 controls (PMID:38543725). These studies highlight specific risk loci where regulatory variants appear to influence AQP3 expression, suggesting its role in the host response to SARS‑CoV‑2 infection.

The clinical validity of the AQP3–COVID‑19 association is assessed as Strong. This categorization is based on statistically robust GWAS findings where genome‑wide significance was reached, and independent replication was achieved. Although the genetic architecture underlying COVID‑19 severity is complex, the convergence of findings in multi‑centre studies supports a direct involvement of AQP3 in the disease phenotype (PMID:35708486; PMID:38543725).

Genetic evidence is characterized by the identification of risk loci associated with COVID‑19 severity. While traditional familial segregation data are not available in these GWAS datasets (affected relatives = 0), the robust association signals across independent cohorts and the prioritization of regulatory variants provide compelling support. No specific coding variant in AQP3 was reported in the current evidence; rather, the association appears to be driven by non‑coding regulatory changes that modulate gene expression.

Functional evidence, though not as extensive as the genetic findings, is bolstered by fine‑mapping analyses that suggest these regulatory variants alter the transcriptional activity of AQP3. This effect may influence biological processes such as immune function and barrier integrity in pulmonary and other barrier tissues. However, direct experimental validation using in vitro or in vivo COVID‑19 models remains limited, hence a Functional Evidence tier of Moderate is assigned.

Importantly, no conflicting studies have been identified that refute the association between AQP3 and COVID‑19 severity. The genetic and emerging functional evidence together provide a coherent narrative which supports AQP3 not only as a potential biomarker for risk stratification but also as a candidate for future therapeutic targeting.

Key take‑home message: The strong genetic association and supportive functional prioritization of AQP3 underscore its clinical utility in informing diagnostic decision‑making and guiding future research in COVID‑19 pathogenesis.

References

• Human Molecular Genetics • 2022 • Novel genes and sex differences in COVID‑19 severity PMID:35708486
• Viruses • 2024 • Molecular Profile of Variants Potentially Associated with Severe Forms of COVID‑19 in Amazonian Indigenous Populations PMID:38543725

Evidence Based Scoring (AI generated)