Host genetic risk factors for West Nile virus infection and disease progression

Abstract

West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035) and MX1, (OR 0.19, p = 0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.

Figure 1. Significant SNPs associated with symptomatic WNV infection or West Nile encephalitis/paralysis (WNE/P).

Three SNPs were significantly associated with symptomatic WNV infection and WNE/P. These include rs2304207 in IRF3 for symptomatic cases vs. asymptomatic controls for a dominant inheritance model, rs7280422 in MX1 for symptomatic cases vs. asymptomatic controls for a recessive inheritance model and rs34137742 in OAS1 for WNE/P vs. West Nile fever/meningitis (WNF/M) using a recessive inheritance model. Contingency table results are presented in A whereas results for the logistic regression are shown in B. The horizontal axis for each plot shows the genomic position arranged in order of chromosomal position for each SNP in the dataset. The vertical axis depicts the negative log p-values generated from the chi-square distribution or the logistic regression model analysis. All p-values were corrected for multiple tests using the Bonferroni correction. The black dashed line indicates the five percent significance threshold corrected for multiple tests. No significant SNP associations were identified for WNE/P versus WNF/M for a dominant inheritance model.

Figure 2. Significant SNP associations depend on control group for symptomatic infection.

Minor allele odds ratios (ORs) (bars) were calculated using a 2×2 contingency table analysis. The 95% confidence intervals (CIs) (lines) were calculated for each significant association. Statistical significance is shown above each bar where * p<0.05, **p<0.01, ***p<0.001, and N.S. is non-significant. A. IRF3 SNP rs2304207 and MX1 SNP rs7280422 were tested for associations with symptomatic WNV infection. B. OAS1 SNP rs34137742 was tested for an association with WNE/P. ORs for a recessive model of inheritance were plotted for MX1 and OAS1. ORs for a dominant model of inheritance were plotted for IRF3. The results of the WNE/P analysis were robust to alterations in the definition of the control group, but the results of the symptomatic infection analysis were not. This suggests that selection of control group affects the SNP associations with symptomatic WNV infection.