RESUMO
The human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive disease causing paraparesis of the lower limbs. Only a minority of persons infected with HTLV-1 develop HAM/TSP. Universal susceptibility factors for HAM/TSP are not known. The viral genotype is similar in asymptomatic carriers and HAM/TSP patients. High proviral load has been associated consistently with HAM/TSP, but this factor does not explain fully the presence of disease in HTLV-1-infected subjects. Most likely, host genetic factors will play an important role in HAM/TSP development. A two-stage case-control study was carried out to evaluate the association between HAM/TSP and candidate single nucleotide polymorphisms (SNPs) from 45 genes in addition to six human leukocyte antigen (HLA) alleles. Ancestry-informative markers were used to correct for population stratification. Several SNPs belonging to NFKB1A and NKG2D showed a trend of association in both stages. The fact that the direction of the association observed in the first stage was the same in the second stage suggests that NFKB1A and NKG2D may be implicated in the development of HAM/TSP. Further replication studies in independent HTLV-1 patient groups should validate further these associations.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Subunidade p50 de NF-kappa B/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Paraparesia Espástica Tropical/genética , Doenças da Medula Espinal/genética , Adulto , Idoso , Biomarcadores , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Genótipo , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/virologia , Peru , Polimorfismo de Nucleotídeo Único , Provírus/imunologia , Provírus/patogenicidade , Doenças da Medula Espinal/imunologia , Doenças da Medula Espinal/virologia , Carga ViralRESUMO
Human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) affects approximately 5% of HTLV-1-infected individuals. It is poorly understood why only some infected subjects develop this disease, but host genetic factors may determine susceptibility. The innate immune system may influence disease outcome in HTLV-1-infected individuals because of its role in early immune responses to viral infections. Variation in genes encoding killer cell immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) molecule ligands may affect the risk of HAM/TSP. We performed a two-stage case-control study to examine the distribution of KIR genes and HLA-Cw groups in Peruvian HTLV-1-infected HAM/TSP individuals and asymptomatic carriers. We also tested for epistatic effects between specific KIR genes and HLA-Cw groups. In the first stage, we found several trends toward association with HAM/TSP or proviral load (PVL). However, these results were not replicated in the second stage. In conclusion, this is the first report on KIR gene frequencies in the Peruvian population and may be of significance in hematopoietic stem-cell transplants. Our study did not reveal significant associations between KIR genes and HLA-Cw groups and HAM/TSP or PVL. However, because our study was powered to detect only larger effects, additional studies using larger cohorts are needed.
Assuntos
Predisposição Genética para Doença/genética , Antígenos HLA-C/genética , Paraparesia Espástica Tropical/genética , Receptores KIR2DL3/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Paraparesia Espástica Tropical/virologia , PeruRESUMO
Human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a complication that affects up to 5% of HTLV-1-infected individuals. Several host genetic and viral factors have been associated with the risk of HAM/TSP. The aim of this study was to evaluate the performance of a prognostic model for HAM/TSP developed in Japan in a Peruvian population of 71 HAM/TSP patients and 94 asymptomatic carriers (ACs). This model included age, proviral load (PVL), the presence of HLA-A*02 and HLA-Cw*08 alleles, SDF-1 +801, and TNF-alpha -863 polymorphisms, and viral subgroup. We describe frequencies for the four host genetic markers and demonstrate the presence of the HTLV-1 tax B subgroup in Peru. Using cross-validation, we show that the predictive ability of the prognostic model, as characterized by the area under the receiver-operating characteristic curve (AUC), does not differ from a model containing PVL only (both AUC = 0.74). We found some suggestive evidence of a protective effect of the HLA-A*02 allele but failed to replicate the associations with the other three genetic markers and with viral subgroup. A logistic model containing PVL, age, gender, and HLA-A*02 provided the best predictive ability in the Peruvian cohort (AUC = 0.79). J. Med. Virol. 82:460-466, 2010. (c) 2010 Wiley-Liss, Inc.