A DIABETES-SUSCEPTIBLE HLA HAPLOTYPE IS BEST DEFINED BY A COMBINATION OF HLA-DR AND HLA-DQ ALLELES
A DIABETES-SUSCEPTIBLE HLA HAPLOTYPE IS BEST DEFINED BY A COMBINATION OF HLA-DR AND HLA-DQ ALLELES
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DOI：
10.1172/jci113965
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发表时间：
1989-03-01
影响因子：
15.9
通讯作者：
NEPOM, BS
中科院分区：
文献类型：
--
作者：
SHEEHY, MJ;SCHARF, SJ;NEPOM, BS
在许多人群中，HLA-DR4与胰岛素依赖型糖尿病（IDDM）有关。最近的许多研究表明，DR4效应实际上是由于DQ3.2，这是附近DQB1位点的一个等位基因。我们使用T细胞克隆、单抗和等位基因特异性寡核苷酸检测IDDM和对照受试者的DR4亚型（Dw4、Dw10、Dw13和Dw14）和DR4相关的DQB1等位基因（DQ3.1和DQ3.2）。我们发现(a) IDDM与DRB1位点（Dw4和Dw10，合并相对危险度，RR = 6.4）和DQB1位点（DQ3.2, RR = 5.9）的等位基因的相关性大致相等；(b)在IDDM中，DR和DQ等位基因之间存在统计学意义上的显著相互作用。唯一与iddm相关的DR4单倍型是在两个位点都携带iddm相关等位基因的个体（RR = 12.1）；具有Dw4或10但不具有DQ3.2的单倍型，反之亦然，RR < 1。其他解释包括：(a)易感性需要DR和DQ位点的特定等位基因产物；(b)某些DR和DQ等位基因的组合在第三个位点标记了具有真正易感等位基因的单倍型；或者(c) Dw4和dw10标记的单倍型在另一个与DQ3.2相互作用的位点上有一个等位基因。如前所述，这第三个位点不太可能是DQA1 （dq . α）。因此，这些数据不容易与HLA-DQ的排他性作用相一致。这些信息增加了我们通过遗传分型预测IDDM的能力：在研究的人群中，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1 / 15。
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 allels 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 < 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.