Abstract
Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.
Highlights
IntroductionBehçet’s disease (BD) [MIM 109650] is a complex and immune-mediated systemic syndrome characterised by inflammatory lesions of various blood vessels throughout the body (though small vessels are most frequently involved), which lead to a wide range of clinical phenotypes such as recurrent oral and genital ulceration, ocular involvement (mainly uveitis) and skin lesions, amongst others
Behçet’s disease (BD) [MIM 109650] is a complex and immune-mediated systemic syndrome characterised by inflammatory lesions of various blood vessels throughout the body, which lead to a wide range of clinical phenotypes such as recurrent oral and genital ulceration, ocular involvement and skin lesions, amongst others
The strongest association signals with BD were located within the HLA region, some suggestive signals were detected in non-HLA loci (Fig 2)
Summary
Behçet’s disease (BD) [MIM 109650] is a complex and immune-mediated systemic syndrome characterised by inflammatory lesions of various blood vessels throughout the body (though small vessels are most frequently involved), which lead to a wide range of clinical phenotypes such as recurrent oral and genital ulceration, ocular involvement (mainly uveitis) and skin lesions, amongst others. The particular geographical distribution of this type of vasculitis (along the ancient route known as ‘The Silk Road’, stretching from China to the Mediterranean area) [2], the reported familial aggregation and some specific associations of genes [3, 4], are data that together support a substantial genetic contribution to the pathogenesis of this disease. In this regard, as observed in most of the immune-mediated diseases, the region of the human Major Histocompatibility Complex (HLA) harbours the main genetic associations with BD. The identification of the most important amino acid positions that would be desirable for a better understanding of the functional implications of the HLA system in BD pathophysiology, have not yet been possible [6]
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