A Pilot Study of Host Genetic Variants Associated with Influenza-associated Deaths among Children and Young Adults1

Jill M. Ferdinands

, Amy M. Denison, Nicole F. Dowling, Heather A. Jost, Marta L. Gwinn, Lindy Liu, Sherif R. Zaki, and David K. Shay

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract

We compared the prevalence of 8 polymorphisms in the tumor necrosis factor and mannose-binding lectin genes among 105 children and young adults with fatal influenza with US population estimates and determined in subanalyses whether these polymorphisms were associated with sudden death and bacterial co-infection among persons with fatal influenza. No differences were observed in genotype prevalence or minor allele frequencies between persons with fatal influenza and the reference sample. Fatal cases with low-producing MBL2 genotypes had a 7-fold increased risk for invasive methicillin-resistant Staphylococcus aureus (MRSA) co-infection compared with fatal cases with high- and intermediate-producing MBL2 genotypes (odds ratio 7.1, 95% confidence interval 1.6–32.1). Limited analysis of 2 genes important to the innate immune response found no association between genetic variants and fatal influenza infection. Among children and young adults who died of influenza, low-producing MBL2 genotypes may have increased risk for MRSA co-infection.

It is unknown why some apparently healthy persons become severely ill after influenza infection while others infected by the same strain remain asymptomatic or become only mildly ill. The presence of neutralizing antibody to a specific influenza strain is protective, and certain chronic medical conditions increase the risk for severe outcomes of influenza infections, but the risk factors for influenza-associated deaths among previously healthy persons remain largely unknown (1).

Infectious disease mortality risk has a heritable component; children of parents who died of an infectious disease are ≈6× more likely to die of an infectious cause compared with the general population (2). A recent large family study that used genealogic databases found an elevated risk for influenza death among relatives of persons who died of influenza (3). By comparing the influenza mortality rate for relatives of persons who died of influenza with the influenza mortality rate for relatives of spouses of persons who died, the authors showed that the increased risk was not explained by shared exposure to influenza virus and thus may have a genetic component. However, to our knowledge, no published studies have examined the association between specific host genetic variants and severe influenza disease outcomes.

To address the paucity of research on host genomics and influenza, the Centers for Disease Control (CDC) convened a meeting of experts in 2007 to solicit opinions on how to explore the role of host genomics in public health activities for influenza conducted by the agency. A study of host genomic factors related to severe influenza outcomes in children was recommended as an activity that CDC was well positioned to pursue. This article reports the findings of the study implemented in response to that recommendation.

We conducted a hypothesis-generating pilot study to examine if host genetic variants were associated with fatal influenza virus infection by comparing prevalence of selected host genetic variants among children and young adults who died of influenza with population-based prevalence estimates. We focused on 8 single-nucleotide polymorphisms (SNPs) in 2 candidate genes important in the innate immune response to influenza infection and for which national prevalence estimates were available: the gene for tumor necrosis factor superfamily, member 2 (official symbol TNF) and the mannose-binding lectin gene (official symbol MBL2).

Suggested citation for this article: Ferdinands JM, Denison AM, Dowling NF, Jost HA, Gwinn ML, Liu L, et al. A pilot study of host genetic variants associated with influenza-associated deaths among children and young adults. Emerg Infect Dis [serial on the Internet]. 2011 Dec [date cited]. http://dx.doi.org/10.3201/eid1712.111002