Lack of association between IFITM3 rs34481144 polymorphism and RSV disease severity in infants

ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. Numerous factors can increase the risk of severe disease; however, the majority of severe cases occur in previously healthy children, and the specific predictors of life-threatening RSV disease remain unknown. The IFITM3 rs34481144 (C/T) polymorphism is a known loss-of-function variant associated with severe influenza. We investigated whether this SNP influences RSV severity in pediatric patients. We conducted a prospective cohort study in infants (<12 months) in Buenos Aires, Argentina. Severity was categorized as mild (no supplementary oxygen), severe (oxygen requirement), and life-threatening disease (LTD; ICU admission). Genotyping was performed using real-time PCR allelic discrimination. Eighty-eight RSV-positive patients were studied. No significant association was observed between the rs34481144 T-allele and disease severity. Specifically, no statistically significant association was observed when comparing the mild vs. the severe group ( P = 0.14) or when comparing the mild vs. the LTD group ( P = 0.11). Viral load and RSV subtypes did not correlate with clinical outcomes or genotype. Our findings suggest that IFITM3 rs34481144 is not a primary driver of RSV severity in previously healthy infants. This contrast with influenza studies highlights the virus-specific nature of host genetic susceptibility. These “negative” results are crucial for refining our understanding of RSV immunopathology and direct future research toward alternative pathways. IMPORTANCE Respiratory syncytial virus (RSV) is a major threat to infant health, often causing severe lung infections. However, it remains unclear why some otherwise healthy babies develop critical illness, while others do not. This study examined a specific genetic variation in the IFITM3 gene, which has been associated with increased susceptibility to severe influenza. By studying a group of hospitalized infants, we found that this variant is not a major risk factor for severe RSV. These findings are important because they highlight that genetic factors influencing susceptibility may differ between viruses.