This result suggests that the MICB gene itself is not responsible for the development of BD, and that the candidate gene(s) for BD is located between the MICA and HLA-C genes.
The results of this mapping study, and the results of an earlier study of ours, suggest that MICA is a strong candidate gene for the development of Behçet disease.
This study revealed in Greek patients a strong association of BD with a particular MICA-TM allele, MICA-A6, providing insight into the molecular mechanism underlying the development of BD.
Stratification analysis suggested that significant associations of BD with MICA and other microsatellites resulted from a linkage disequilibrium with HLA-B51.
Previously, using Japanese BD patients, our group has narrowed down a BD-causative gene to 46 kb between the MICA and HLA-B genes by means of fine mapping analysis with eight microsatellite markers distributed within a 1100 kb segment around the HLA-B gene.
MICA is reported to be strongly associated with Behçet's disease (BD), a multisysytemic inflammation disorder characterized by oral apthous ulcers, skin lesions and genital ulcers.
Since the identification of HLA-B*5101 (and more recently of MICA) as a susceptibility locus for BD, the identification of additional genetic locus/loci, whether inside, or perhaps more importantly outside the MHC has clearly stalled.
Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10(-50)).
SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10(-8)).
Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in Iran is strongly associated with HLA-B*51, MICA-A6, and the three HLA-linked SNPs (odds ratio (OR) = 3.38, P = 6.21 × 10(-14); OR = 2.08, P = 1.58 × 10(-13); and OR = 1.67-4.05, P = 1.45 × 10(-04) to 4.79 × 10(-34), respectively).
We found that HLA-B*51 (P = 4.11 × 10(-41), OR [95% CI] = 4.63[3.66-5.85]) and B*15 confer risk for BD (P = 2.83 × 10(-2), OR [95% CI] = 1.75[1.08-2.84]) in Iranian, and in B*51 negative individuals, only the B*15 allele is significantly associated with BD (P = 2.51 × 10(-3), OR [95% CI] = 2.40[1.37-4.20]). rs76546355, formerly known as rs116799036, located between HLA-B and MICA (MHC class I polypeptide-related sequence A), demonstrated the same level of association with BD as HLA-B*51 (P adj = 1.78 × 10(-46), OR [95% CI] = 5.46[4.21-7.09], and P adj = 8.34 × 10(-48), OR [95% CI] = 5.44[4.20-7.05], respectively) in the HLA-B allelotyped subset, while rs2848713 was less associated (P adj = 7.14 × 10(-35), OR [95% CI] = 3.73[2.97-4.69]) and rs9260997 was not associated (P adj = 1.00 × 10(-1)).
Neither the BD-associated genetic risk locus within the HLA-B/MICA region nor being on immunosuppressive medications explained the differences between patients and controls.