Huang H S, Peng J T, She J Y, Zhang L P, Chao C C, Liu K H, She J X
Division of Endocrinology and Metabolism, College of Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
Hum Immunol. 1995 Dec;44(4):210-9. doi: 10.1016/0198-8859(95)00108-5.
HLA-DRB1 and -DQB1 genes were analyzed in 98 Chinese IDDM patients and 205 control subjects from Taiwan. The DRB10301-DQB10201 haplotype conferred strong susceptibility (RR = 7.7, pc < 10(-5)). DRB10405 also conferred susceptibility (RR = 3.1, Pc < 0.0005) whereas DRB10403 (RR = 0.7) and DRB10406 (RR = 0.2) conferred protection. Indeed, the relative risk for the DRB10405-DQB10302 haplotype (RR = 33.7, Pc < 0.002) was 48 and 168 times higher than those conferred by the DRB10403-DQB10302 and DRB10406-DQB10302 haplotypes, respectively, suggesting that the protection conferred by DRB10403 and 0406 is dominant over DQB10302. The strong linkage disequilibrium observed between DQB10302 and DRB10403(0406) can thus explain the surprising finding that the frequency of DQB10302 was not significantly increased in the Chinese IDDM patients (RR = 0.9). Because the DRB10405-DQB10302 haplotype (RR = 33.7) conferred higher susceptibility than the DRB10405-DQB10401 (RR = 2.5) or DRB10405-DQB10301 (RR = 2.1) haplotypes, DQB10302 is indeed a susceptibility factor, while both DQB10301 and DQB10401 may confer protection against IDDM. The increased frequency of the protective DQB10401 allele in patients compared to controls is due to linkage disequilibrium between DRB10405 and DQB10401. Interestingly, the previously demonstrated protective effect of DQB10602 was not very strong in the Chinese (RR = 0.4). Our results suggested that HLA-encoded susceptibility to IDDM is determined by the combined effects of all DR and DQ molecules present in an individual. Therefore, the genotypic combinations of DR and DQ genes as well as their linkage disequilibria can influence IDDM susceptibility. At least four DR and DQ molecules conferring high susceptibility (DRB10301, DRB10405, and DQ alpha/beta 0301/0201 and 0301/0302) occur at high frequency in the Chinese population. However, linkage disequilibria between highly susceptible DR and protective DQ or vice versa (e.g., DRB10405-DQB10301[0401] and DRB10403[0406]-DQB1*0302) are probably responsible for the lower incidence of IDDM in the Chinese.
对来自台湾的98名中国胰岛素依赖型糖尿病（IDDM）患者和205名对照者的HLA-DRB1和-DQB1基因进行了分析。DRB10301-DQB10201单倍型具有很强的易感性（相对风险率RR = 7.7，Pc < 10^(-5)）。DRB10405也具有易感性（RR = 3.1，Pc < 0.0005），而DRB10403（RR = 0.7）和DRB10406（RR = 0.2）具有保护作用。实际上，DRB10405-DQB10302单倍型的相对风险率（RR = 33.7，Pc < 0.002）分别比DRB10403-DQB10302和DRB10406-DQB10302单倍型高48倍和168倍，这表明DRB10403和0406所提供的保护作用强于DQB10302。因此，在DQB10302与DRB10403（0406）之间观察到的强连锁不平衡可以解释在中国IDDM患者中DQB10302频率未显著增加这一惊人发现（RR = 0.9）。由于DRB10405-DQB10302单倍型（RR = 33.7）比DRB10405-DQB10401（RR = 2.5）或DRB10405-DQB10301（RR = 2.1）单倍型具有更高的易感性，所以DQB10302确实是一个易感因素，而DQB10301和DQB10401都可能对IDDM具有保护作用。与对照相比，患者中具有保护作用的DQB10401等位基因频率增加是由于DRB10405与DQB10401之间的连锁不平衡。有趣的是，先前证明的DQB10602的保护作用在中国人群中并不是很强（RR = 0.4）。我们的结果表明，HLA编码的对IDDM的易感性是由个体中存在的所有DR和DQ分子的综合作用决定的。因此，DR和DQ基因的基因型组合及其连锁不平衡会影响IDDM易感性。至少有四种赋予高易感性的DR和DQ分子（DRB10301、DRB10405以及DQα/β 0301/0201和0301/0302）在中国人群中高频出现。然而，高度易感的DR与具有保护作用的DQ之间的连锁不平衡，反之亦然（例如DRB10405-DQB10301[0401]和DRB10403[0406]-DQB1*0302），可能是中国IDDM发病率较低的原因。
