Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease

Abstract

Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behcet's disease (BD). Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01x10(-8) in a minor allele dominant model; rs11769828, allele based p=1.60x10(-6)). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70x10(-6)) in GIMAP4; rs10266069 (OR=1.32, p=2.67x10(-4)) and rs10256482 (OR=1.27, p=5.27x10(-4)) in GIMAP2; and rs2286900 (OR=1.61, p=3.53x10(-5)) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.