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Genetic analysis in Behçet’s disease identifies novel loci associated with ocular and neurological involvement.

International clinical researchers at several collaborating institutes, from Pennsylvania to Istanbul, have reported results on the genetic contribution of the HLA-B/MICA genetic region to the risk of ocular involvement in Behçet’s disease.  HLA-B/MICA comprises a complex of genes of the human leukocyte antigen (HLA) system which encode cell-surface peptides or proteins responsible for regulation of the immune system. New research in Behçet’s disease shows that genetic data might provide HLA associations of “new insights into the risk and pathogenesis of specific clinical manifestations” of the disease, including ocular and neurological involvement.

Behçet’s disease is a chronic inflammatory disorder which may affect small and large vessels of the venous and arterial systems. Multiorgan involvement can be characterized by clinical symptoms of recurrent oral and genital ulcers, ocular and neurological manifestations, and skin lesions, such as erythema nodosum (showing a positive skin pathergy test).  The disease affects both male and females arising in the third and fourth decade of life and the prevalence of clinical features vary among different geographical locations with the highest prevalence described in East Asia and the Mediterranean region.  According to the researchers, the pathogenesis of Behçet’s disease may remain unclear, with environmental and genetic factors been hypothesized to contribute to the disease evolution.  The most robust genetic association described in Behçet’s disease points to the HLA class I region, consistent with the inflammatory nature of the disease.

Researchers worked with multiple clinicians from the Division of Rheumatology, at the Department of Pediatrics, University of Pittsburgh, Pennsylvania, including several research institutes in Istanbul (Marmara University, Kocaeli University, Ankara University, Çukurova University, University of Health Sciences Turkey, Akdeniz University, Osmangazi University, and Istanbul University).  Genetic association analyses had previously identified susceptibility loci that revealed a genetic association between ocular lesions and HLA-B/MICA (rs116799036: OR=1.85, 95% CI=1.35-2.52, p-value=1.1×10-4). The current study showed that a genetic risk score was significantly higher in Behçet’s disease patients with ocular lesions, compared with those without ocular involvement, supporting the genetic variation in the HLA region. New genetic loci predisposing to specific clinical features in Behçet’s disease were suggested when genome-wide variants were evaluated. The most significant associations were observed in ocular involvement with “SLCO4A” (rs6062789: OR=0.41 (95% CI=0.30-0.58), p-value=1.92×10-7), and neurological involvement with “DDX60L” (rs62334264: OR= 4.12 (95% CI 2.34 to 7.24), p-value = 8.85×10-7).  SLCO4A1 gene encodes for a solute carrier organic anion transporter expressed in numerous epithelial and cancer tissues, and DDX60L encodes a helicase family member, described as an interferon-stimulated gene due to its role during virus infection.  Commenting on their study, the researchers stated, “our results emphasize the role of genetic factors in predisposing to specific clinical manifestations in Behçet’s disease, and might shed additional light into disease heterogeneity, pathogenesis, and variability of Behçet’s disease presentation across populations”.