Heritable disposition may affect influenza mortality risk

February 2008

Results from a study involving Utah residents who died of influenza during the last 100 years found that both close and distant relatives of those individuals also had a significantly increased risk for dying of influenza. The results support the existence of a heritable contribution to the predisposition toward death due to influenza.

“Familial clusters of infection are thought to be a consequence of shared exposure,” the researchers wrote. “Inherited host factors that also could account for the variability of illness and familial clustering include increased susceptibility to infection, decreased ability to control infection and/or an ineffective immune response.”

Generally, identification of genetic contributors to influenza is difficult due to high rates of infectivity and a low case-fatality rate. The Utah Population Data Base (UPDB), which includes genealogical data for the original Utah pioneers, provided researchers a method for tracking influenza-related genetic contributions. The UPDB’s genealogical data have been record-linked to disease data for Utah; this includes death certificates dating from 1904.

Among the more than 2 million individuals tracked within the UPDB, 388,221 had a death certificate available. Of those, influenza was listed as the cause of death for 4,855 individuals between 1904 and 2004. The genetic relationships among these individuals were analyzed in order to “describe the familiality of death due to influenza,” the researchers wrote.

The study results found that relative risks for death due to influenza were significantly higher among all first-degree relatives (siblings, parents, children), considered both collectively and separately. There were 638 deaths due to influenza among all first-degree relatives vs. an expected number of 413.12 (RR=1.54; 95% CI, 1.42-1.67). The researchers wrote, however, that the elevated relative risk among first-degree relatives cannot distinguish between shared genetics or shared effects of environment or exposure to virus. Thus, an analysis was also conducted for more distant relatives.

Both second-degree (grandparents and grandchildren, avuncular relatives) and third-degree (first cousins) relatives had significantly increased risk for death due to influenza. There were 1,090 deaths among second-degree relatives vs. 897.0 expected deaths (RR=1.22; 95% CI, 1.14-1.29), and 1,446 deaths among third-degree relatives vs. 1,241.9 expected deaths (RR=1.16; 95% CI, 1.11-1.23).

A further analysis aimed at discriminating between environmental and genetic effects compared the relative risks of relatives of individuals dying of influenza with the relative risks of the relatives of spouses of individuals dying of influenza. For each type of relative (sibling, parent, grandparent and third-degree), the relative risk was higher for the relatives of the individual than the relatives of the spouse of the individual (See table). These results were corroborated when the researchers showed significantly higher average relatedness among individuals dying of influenza.

Date of death correlations

The date of death of individuals dying of influenza also can elucidate whether environmental or exposure-related effects could be responsible for the increased risk for relatives. The researchers analyzed the dates of death for all third-degree relative pairs of influenza deaths. “Evidence for the increased relative risk of influenza death being due to shared environment and/or exposure would be supported if the date of death occurred within days — or weeks — for the paired relative deaths,” the researchers wrote.

According to study researcher Lisa A. C. Albright, PhD, professor of biomedical informatics at the University of Utah in Salt Lake City, these analyses show that an individual’s response to influenza infection is partially due to genetics. “The study of high-risk pedigrees could allow us to identify the gene [or genes] responsible and lead to a better understanding of how different genetic variants affect risk,” Albright said in an interview.

Albright also said that an understanding of the genetic component of influenza might eventually help epidemic and pandemic prevention and response. “Identification and understanding of the genes affecting host response to influenza infection could allow identification of individuals at greatest risk and could allow development of more effective vaccinations or medications to combat influenza,” she said.

For more information:

• Albright FS, Orlando P, Pavia AT, et al. Evidence for a heritable predisposition to death due to influenza. J Infect Dis. 2008;197:18-24.