Association of Single-Nucleotide Polymorphisms in IL28B, but Not TNF-α, With Severity of Disease Caused by Andes Virus

Abstract

Background: Andes virus (ANDV) is the sole etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in Chile, with a fatality rate of about 35%. Individual host factors affecting ANDV infection outcome are poorly understood. In this case-control genetic association analysis, we explored the link between single-nucleotide polymorphisms (SNPs) rs12979860, rs8099917 and rs1800629 and the clinical outcome of ANDV-induced disease. The SNPs rs12979860 and rs8099917 are known to play a role in the differential expression of the interleukin 28B gene (IL28B), whereas SNP rs1800629 is implicated in the expression of tumor necrosis factor α gene (TNF-α).

Methods: A total of 238 samples from confirmed ANDV-infected patients collected between 2006 and 2014, and categorized according to the severity of the disease, were genotyped for SNPs rs12979860, rs8099917, and rs1800629.

Results: Analysis of IL28B SNPs rs12979860 and rs8099917 revealed a link between homozygosity of the minor alleles (TT and GG, respectively), displaying a mild disease progression, whereas heterozygosity or homozygosity for the major alleles (CT/CC and TG/TT, respectively) in both IL28B SNPs is associated with severe disease. No association with the clinical outcome of HCPS was observed for TNF-α SNP rs1800629 (TNF -308G>A).

Conclusions: The IL28B SNPs rs12979860 and rs8099917, but not TNF-α SNP rs1800629, are associated with the clinical outcome of ANDV-induced disease, suggesting a possible link between IL28B expression and ANDV pathogenesis.

Keywords: ANDV; HCPS; IL28B; SNP; TNF-alpha.

Figure 1.

Interferon λ single-nucleotide polymorphisms (SNPs) among the studied population. A, Distribution of rs12979860 and rs8099917 SNP genotypes among 238 Andes virus (ANDV)–infected patients. B, Frequency of the genotype combination for the 2 SNPs rs12979860 and rs8099917 in control population (n = 405) and ANDV-infected (n = 238) population. The total number of individuals in each group was defined as 100%, and the percentages of individuals with 1 of the 9 possible genotypes were calculated. The numbers within each box correspond to the percentage of individuals with a particular genotype. Control group data were sourced from a previous report [25].

Figure 2.

Association between the severity of Andes virus (ANDV) pathogenesis and interferon λ single-nucleotide polymorphism (SNP) genotype. Patients were grouped according to the SNP rs12979860 (A) and rs8099917 (B) genotypes. Each genotype was divided into 2 groups: those with a homozygous status for the minor allele, and those with a heterozygous or homozygous status for the major allele. The total number of patients in each group was defined as 100%, and the severity of ANDV-associated disease was evaluated as a dichotomous variable using a Fisher exact test. The number within each box corresponds to the percentage of patients with mild or severe disease. C, Total number of deceased patients was grouped according to the genotype for SNPs rs12979860 and rs8099917. The number within each box corresponds to the percentage of patients with a protective genotype (homozygous for the minor allele) and with a risk genotype (heterozygous or homozygous status for the major allele).

Figure 3.

Polymorphism analysis for tumor necrosis factor α gene (TNF-α). A, Distribution of TNF-α single-nucleotide polymorphism (SNP) rs1800629 among 500 noninfected individuals obtained from a well characterized DNA library considered e representative of the Chilean population [–28]. The total number of individuals was defined as 100%. B, Distribution of TNF-α SNP rs1800629 among 238 patients infected with Andes virus (ANDV). The total number of patients was defined as 100%. C, ANDV-infected patients were grouped into those with a homozygous status for the major allele (GG) and those with a heterozygous or homozygous (non-GG) status for the minor allele. The total number of patients in each group was defined as 100%, and the severity of ANDV-associated disease was evaluated as a dichotomous variable using a Fisher exact test. The number within each box corresponds to the percentage of patients with mild or severe disease.