Gene cluster implicated in Behçet's disease

Mar 5 2013

By Lynda Williams, Senior medwireNews Reporter

Scientists may have uncovered an underlying genetic susceptibility for Behçet's disease (BD) in East Asian patients.

The study linked the systemic inflammatory disorder to single nucleotide polymorphisms (SNPs) within the GTPase of the immunity-associated protein family (GIMAP) cluster of genes.

GIMAP is known to play a role in T-cell development and peripheral T-cell function; patients with BD experience T-cell tissue infiltration and disease activity correlates with increasing numbers of interferon-gamma T-helper type 1 cells, the researchers explain.

"This finding could shed new light on the role of GIMAP in T-cell-mediated diseases and could be helpful for understanding the contribution of T-cell aberration in the pathophysiology of BD," say Eun Bong Lee (Seoul National University College of Medicine, South Korea) and co-authors.

The scientists conducted a genome-wide association study using samples from 379 Korean patients with BD and 800 healthy controls.

This revealed a new link between BD and the SNP rs11769828 located between GIMAP7 and GIMAP4. Four other SNP within the GIMAP cluster were also identified and strong linkage disequilibrium was detected between four of the five SNP.

Fine mapping analysis identified links between 10 SNP within the GIMAP cluster and BD, with the strongest association detected for rs1522596 within GIMAP1. The link to BD remained after adjusting for the HLA-B51 susceptibility allele within BD patients, the researchers note.

When the study was repeated using samples from 363 BD patients and 272 controls from Japan, the researchers found a significant link between BD and five SNP within the GIMAP2 and GIMAP4 regions.

Further analysis showed that peripheral CD4 T cells from 31 BD patients had significantly lower levels of GIMAP1 transcripts than cells taken from age- and gender-matched healthy controls, while CD8 T cells had significantly lower levels of GIMPA2 RNA levels.

Research also indicated that the rs1608158 SNP has a significant impact on GIMAP4 promoter activity depending on the allele status of rs1608157. Furthermore, targeted silencing of GIMAP4 expression in Jurkat T cells protected the cells against Fas-mediated apoptosis.

This suggests that "the lower expression of GIMAP4 could contribute resistance to T-cell apoptosis in BD," Lee et al say.

Noting that GIMAP SNPs have previously been linked to lupus and Type 1 diabetes, the team concludes: "When more physiological roles of GIMAP are elucidated in future studies, we will be able to understand better how GIMAP are involved in the pathogenesis of T-cell-mediated diseases."

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