Mizuki N, Ohno S, Ando H, Kimura M, Ishihara M, Miyata S, Nakamura S, Mizuki N, Inoko H
Department of Ophthalmology, Yokohama City University School of Medicine, Japan.
Hum Immunol. 1996 Sep 15;50(1):47-53. doi: 10.1016/0198-8859(96)00122-x.
Behçet's disease has been known to be strongly associated with a particular HLA-B allele, B51. To address the possibility that the HLA-C gene, which is closely linked to HLA-B but has been poorly defined for allo-antigen specificity by the serologic method is involved in the susceptibility to Behçet's disease, HLA-C genotyping was performed for 90 Japanese Behçet's disease patients by the PCR-SSP method. The frequencies of HLA-Cw14 and -Cw15 were significantly higher in the patient with Behçet's disease as compared to the controls (48.9% vs. 24.0%, p = 0.0005, and 17.8% vs. 7.3%, p = 0.0434, respectively). On the other hand, the frequencies of HLA-Cw0304 and -Cw01 were significantly decreased in the patient group as compared to the control group (7.8% vs. 25.0%, p = 0.0027, and 23.3% vs. 37.5%, p = 0.0398, respectively). The significantly higher HLA-Cw14 and -Cw15 alleles may tightly correlate with the B51 antigen, and hence may have increased as a result of a linkage disequilibrium with B51. Accordingly, the HLA-C allele frequencies were compared for the B51-positive or -negative patients and controls, but there was no HLA-C allele showing a significant difference between these patient and control groups. Conversely, analysis of the HLA-B allelic distribution in association with HLA-Cw14 revealed that in the healthy controls, B44 and B51 were present at the frequencies of 57.1% and 35.7% of the HLC-Cw14-positive individuals, respectively. In contrast, in the Cw14-positive patients the frequency of B44 was merely 14.0% (p = 0.0001) and that of B51 was significantly high, amounting to 82.0% (p = 0.0001). These facts suggest that the pathogenic gene of Behçet's disease is not the HLA-C gene (HLA-Cw14 and/or HLA-Cw*15) but the HLA-B gene (HLA-B51) itself or a non-HLA gene residing in the centromeric side of the HLA-B gene rather than in the telomeric side around the HLA-C gene. This finding supports our previous mapping result, which located the susceptible gene between the TNF and HLA-B genes.
白塞病一直被认为与特定的HLA - B等位基因B51密切相关。为了探讨与HLA - B紧密连锁但通过血清学方法对同种异体抗原特异性定义不佳的HLA - C基因是否参与白塞病的易感性，采用PCR - SSP方法对90例日本白塞病患者进行了HLA - C基因分型。与对照组相比，白塞病患者中HLA - Cw14和 - Cw15的频率显著更高（分别为48.9%对24.0%，p = 0.0005；17.8%对7.3%，p = 0.0434）。另一方面，与对照组相比，患者组中HLA - Cw0304和 - Cw01的频率显著降低（分别为7.8%对25.0%，p = 0.0027；23.3%对37.5%，p = 0.0398）。显著更高的HLA - Cw14和 - Cw15等位基因可能与B51抗原紧密相关，因此可能由于与B51的连锁不平衡而增加。相应地，对B51阳性或阴性患者及对照组的HLA - C等位基因频率进行了比较，但在这些患者和对照组之间没有HLA - C等位基因显示出显著差异。相反，与HLA - Cw14相关的HLA - B等位基因分布分析显示，在健康对照组中，HLC - Cw14阳性个体中B44和B51的频率分别为57.1%和35.7%。相比之下，在Cw14阳性患者中，B44的频率仅为14.0%（p = 0.0001），而B51的频率显著较高，达到82.0%（p = 0.0001）。这些事实表明，白塞病的致病基因不是HLA - C基因（HLA - Cw14和/或HLA - Cw*15），而是HLA - B基因（HLA - B51）本身或位于HLA - B基因着丝粒侧而非HLA - C基因端粒侧附近的非HLA基因。这一发现支持了我们之前的定位结果，即易感基因位于TNF和HLA - B基因之间。
