MIC-A allele profiles and HLA class I associations in Behçet's disease

Abstract

Recently a new family of non-classical MHC molecules, the MHC class I chain-related protein (MIC), encoded by genes located in the major histocompatability complex have been identified. On the basis of the location of MIC genes and the structure and expression of MIC molecules it has been postulated that MIC may be a susceptibility factor in Behçet's disease (BD). We investigated the association of the 16 described external domain alleles and the transmembrane triplet repeats of MIC-A with BD in a Middle Eastern population. DNA from ninety-five patients and 102 age- and sex-matched controls were analyzed by polymerase chain reaction using allele specific primers. Our results show an increase of MIC-A*009 in the BD patient group 44/95 (46%) compared with controls 24/102 (24%) (chi2=11.3, OR=2.8, P=0.00078). MIC-A*009 was also found to be strongly associated with HLA-B51 in the patients 39/44 (88%) when compared with controls 10/24 (42%) (chi2=4, P=0.04). MIC-A*009 was also found in linkage disequilibrium with HLA-B52, but only in controls. The A6 form of a MIC-A transmembrane triplet repeat was found to be significantly raised in the patients (80/95; 84%;) compared with controls (58/102, 57%) (chi2=17.5, OR=4, P=0.000028). Although the MIC-A associations described are highly significant, the association with HLA-B51 independently remains the most significant factor (chi2=56.8, P<10(-6)). The data suggests that as both MIC-A*009 and A6 are in strong linkage disequilibrium with HLA-B51, they are unlikely to be the susceptibility gene for BD but may be markers for additional risk factors.

Association of Major Histocompatibility Complex Class I Chain-Related Gene A and HLA-B Alleles with Behçet's Disease in Turkey

“…This result is consistent with previous studies associating BD and MICA*009 in Japanese, Jordanian, Palestinian, and Caucasian populations. [32][33][34] However, Marin In fact, we found in this study, as has been found in many previous studies, that HLA-B*51 was strongly associated with BD.…”

“…28,29 We have identifi ed a strong association between MICA*009, a genetic polymorphism in the extracellular domains of MICA (α1, exon 2; α2, exon 3; and α3, exon 4), 30,31 and BD. [32][33][34] Therefore, MICA as well as HLA-B may be a pathogenic gene of BD.…”

HLA-B*51 the primary risk in Behçet disease

“…This was supported by analysis of MICA*009 in Middle Eastern patients where the allele was in linkage with both HLA-B*51 and HLA-B*52, which only differ by two amino acids, yet only the B*51/MICA*009 combination was found in patients with BD. By comparison, B*52/MICA*009 was found in 25% of controls (8). Recently genome-wide association studies (GWASs) in different patient populations showed specific genes linked to BD in different ethnic groups; however, all the studies identified the HLA-B loci as the strongest association (9)(10)(11).…”

Behçet’s disease and genes within the major histocompatibility complex region

“…However, it was later found that the interaction between MICA molecules and cd T cells is not restricted by the MICA gene polymorphism and does not require antigen presentation [57]. Subsequent studies in different ethnic groups have shown that the association between the MICA polymorphism and BD is secondary to strong linkage disequilibrium with HLA-B*51 [14,[58][59][60][61]. Despite the lack of a proven genetic association between MICA and BD, the autoreactive CD8?…”