Identification of Genes Associated with Inhibitor Development in Hemophilia a by Microarray Analysis.

The risk of factor VIII (FVIII) inhibitor development increases by the disease severity, presence of family history and patient-related environment. Recently, FVIII genotypes and genes related to immune response were found to be decisive risk factors for inhibitor development. To identify the differentially expressed genes (DEGs) for developing inhibitory antibodies in hemophilia A, we analyzed the gene expression profiles between inhibitor and non-inhibitor by microarray technique. The results show that the 384 genes were up-regulated and 161 genes were down-regulated in inhibitor patients as compared with non-inhibitor patients. The 545 of DEGs were classified by the functional gene grouping using Panther classification method. Of interest was the finding that the expression levels of immunity and signal transduction related genes were significantly modified in inhibitor patients. For 7 genes, validation of these bead-array data was carried out by semi-quantitative RT-PCR. Finally, we performed Real Time PCR analysis for the significantly changed DEG450. As a result, expression of DEG450 was significantly down-regulated in inhibitor patients. We demonstrate that inhibitor development is closely related to the expression levels of immune-related genes and that these genes can be used as biomarker genes for prediction of inhibitor development