Sheehy M J, Scharf S J, Rowe J R, Neme de Gimenez M H, Meske L M, Erlich H A, Nepom B S
Research Department, American Red Cross Blood Services, Madison, Wisconsin 53705.
J Clin Invest. 1989 Mar;83(3):830-5. doi: 10.1172/JCI113965.
HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allele-specific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, Dw10, Dw13, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and Dw10, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR less than 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination of certain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQ alpha). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/[DQ3.2, Dw4] or DR3/[DQ3.2, Dw10] had a relative risk of 38.0 and an absolute risk of 1 in 15.
在许多人群中，HLA - DR4与胰岛素依赖型糖尿病（IDDM）相关。最近的许多研究表明，DR4的效应实际上是由于附近DQB1基因座的一个等位基因DQ3.2所致。我们使用T细胞克隆、单克隆抗体和等位基因特异性寡核苷酸，对IDDM患者和对照受试者进行DR4亚型（Dw4、Dw10、Dw13和Dw14）以及与DR4相关的DQB1等位基因（DQ3.1和DQ3.2）检测。我们发现：（a）IDDM与DRB1基因座的等位基因（Dw4和Dw10，合并相对风险，RR = 6.4）以及DQB1基因座的等位基因（DQ3.2，RR = 5.9）的关联性大致相同；（b）在统计学意义上，这些DR和DQ等位基因在IDDM中存在显著的相互作用。唯一与IDDM相关的DR4单倍型是那些在两个基因座上都携带与IDDM相关等位基因的单倍型（RR = 12.1）；带有Dw4或10但不带有DQ3.2的单倍型，或者反之，其RR小于1。其他解释包括：（a）易感性需要DR和DQ基因座的特定等位基因产物；（b）某些DR和DQ等位基因的组合标记了在第三个基因座上带有真正易感等位基因的单倍型；或者（c）Dw4和10标记了在另一个基因座上带有与DQ3.2相互作用的等位基因的单倍型。如前所述，这个第三个基因座不太可能是DQA1（DQα）。因此，这些数据难以与HLA - DQ的排他性效应相协调。这一信息提高了我们通过基因分型预测IDDM的能力：在所研究的人群中，杂合子DR3/[DQ3.2，Dw4]或DR3/[DQ3.2，Dw10]的相对风险为38.0，绝对风险为十五分之一。
