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Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection
Adrienne G Randolph1,2, Wai-Ki Yip3, Emma Kaitlynn Allen4
1Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital.
Background:
Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza severity in adults. IFITM3 has not been evaluated in pediatric influenza.
Methods:
The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA.
Results:
In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the Δ21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified.
Conclusions:
rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.
Insights
The IFITM3 rs12252_C variant did not impact pediatric influenza infection risk or severity. This study found no association between this genetic marker and critical illness in children with influenza.
Area of Science:
- Virology
- Genetics
- Pediatrics
Background:
- Interferon-induced transmembrane protein 3 (IFITM3) is known to restrict influenza virus fusion.
- A specific IFITM3 variant, rs12252_C, has been linked to influenza severity in adults.
- The role of IFITM3 in pediatric influenza has not been previously investigated.
Purpose of the Study:
- To evaluate the association of the IFITM3 rs12252 genetic variant with influenza infection and severity in children.
- To determine if rs12252 acts as a splice site influencing IFITM3 expression in pediatric influenza.
Main Methods:
- The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza.
- IFITM3 rs12252 was genotyped in pediatric patients and analyzed for association with infection and critical illness.
- Splice site analysis was performed using patient RNA to investigate the functional impact of rs12252_C.
Main Results:
- The IFITM3 rs12252 variant was not associated with influenza infection susceptibility in population or family-based analyses.
- No association was found between rs12252 genotype and critical illness severity in children with influenza.
- The study did not identify the Δ21 IFITM3 isoform or confirm rs12252 as a functional splice site.
Conclusions:
- The IFITM3 rs12252 genetic variant is not associated with susceptibility to or severity of influenza-related critical illness in children.
- The findings do not support rs12252 acting as a splice site in the context of pediatric influenza.
