Rowe J R, Mickelson E M, Hansen J A, MacDonald M J, Allen C I, Gabbay K H, Yunis E J, Sheehy M J
Research Department, American Red Cross Blood Services, Madison, Wisconsin 53705.
Hum Immunol. 1988 May;22(1):51-60. doi: 10.1016/0198-8859(88)90051-1.
In most populations studied, HLA-DR4, a DRB1 (formerly DR beta I) allele, is increased in frequency among patients with insulin-dependent diabetes mellitus (IDDM). Using T-cells, one can distinguish five subtypes of DR4 (Dw4, Dw10, Dw13, Dw14, and Dw15). Two of these (Dw4 and Dw10) are IDDM-associated in the populations studied here. Therefore, Dw4 and Dw10 could be causative or merely markers for a linked diabetes allele. If they are causative, one might expect them to share some unique structural element or at least to associate consistently with IDDM in different populations. Published sequence data show no structural element unique to Dw4 and Dw10; moreover, the associations of these DR4-Dw subtypes with diabetes vary considerably in different populations. Thus the DRB1 locus probably cannot account for the DR4 association in IDDM. The strong linkage disequilibrium between IDDM and Dw4 and Dw10 suggests that the diabetes susceptibility locus should be in the vicinity of the DR region or the DQ region of the HLA complex. Alternative hypotheses are discussed, relating DR- and DQ-region alleles to IDDM. We further postulate that the evolutionary event that produced the Dw10 allele occurred on a Dw4 haplotype that happened to carry a diabetes susceptibility allele at another locus.
在大多数被研究的人群中，HLA - DR4（一种DRB1等位基因，以前称为DRβI）在胰岛素依赖型糖尿病（IDDM）患者中的频率升高。利用T细胞，可以区分DR4的五种亚型（Dw4、Dw10、Dw13、Dw14和Dw15）。在这里研究的人群中，其中两种（Dw4和Dw10）与IDDM相关。因此，Dw4和Dw10可能是致病因素，或者仅仅是与糖尿病相关的等位基因的标记。如果它们是致病因素，人们可能期望它们共享一些独特的结构元件，或者至少在不同人群中始终与IDDM相关。已发表的序列数据显示，Dw4和Dw10没有独特的结构元件；此外，这些DR4 - Dw亚型与糖尿病的关联在不同人群中差异很大。因此，DRB1基因座可能无法解释IDDM中与DR4的关联。IDDM与Dw4和Dw10之间强烈的连锁不平衡表明，糖尿病易感基因座应该在HLA复合体的DR区域或DQ区域附近。讨论了将DR区域和DQ区域等位基因与IDDM相关联的其他假说。我们进一步推测，产生Dw10等位基因的进化事件发生在一个碰巧在另一个基因座携带糖尿病易感等位基因的Dw4单倍型上。
