Polymorphism in the interleukin-10 promoter affects both provirus load and the risk of human t lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis

Abstract

To investigate candidate genes that influence the risk of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), we analyzed 6 single nucleotide polymorphisms (SNP) in the interleukin-10 (IL-10) promoter region. METHODS: 280 cases of HAM/TSP patients and 255 HTLV-I seropositive asymptomatic carriers (HCs) from Kagoshima, Japan were studied. All subjects gave written informed consent and the study approved by local ethics committee. PCR-RFLP method used for SNP typing. HTLV-I provirus load was measured by quantitative PCR. RESULTS: The IL-10 -592A/C SNP showed a significant difference in allele frequency between HAM/TSP patients and HCs (p=0.014). Possession of the IL-10 -592 A allele was associated with a >2-fold reduction in the odds of HAM/TSP (2p=0.011, OR=0.50). This effect remains significant even after taking into account the other two known predictors such as provirus load and HLA-A*02 genotype. Given the OR and the observed frequency of the IL-10 -592 A allele, we can estimate that IL-10 -592 A allele prevents 44.7%( 13.1%SD) of potential cases of HAM/TSP in the study population. The presence of the IL-10 592 A allele is also a significant predictor of lower provirus load in the entire cohort (p=0.001). Furthermore, HTLV-I Tax transactivates the IL-10 promoter in the human T-cell line Jurkat and this transactivation was higher with the IL-10 -592 C allele than the A allele. Among more than 90 non-HLA candidate gene loci we have so far examined, IL-10 -592 A/C SNP is the only non-HLA candidate gene locus associated with a significant reduction in both the provirus load and the risk of HAM/TSP. These data demonstrate that the IL-10 -592 A allele influences the provirus load in HTLV-I infected individuals, and defines a further component of the genetic susceptibility to HAM/TSP.