Field L L
Baillieres Clin Endocrinol Metab. 1991 Sep;5(3):413-38. doi: 10.1016/s0950-351x(05)80139-9.
The focus of this chapter is on the contribution of genes outside the HLA region to insulin dependent diabetes mellitus (IDDM) susceptibility. We review laboratory evidence for such genes from published studies and also present unpublished data from our recent research. The existence of genes predisposing to IDDM in the region of the insulin (INS) gene now appears established. Association analysis has demonstrated an increased frequency of class 1 alleles of the 5' INS polymorphism in diabetics compared with controls, and a new method of analysis (AFBAC) has shown that this association is not an artefact of population stratification. Interestingly, the effect of INS region susceptibility on IDDM cannot be detected by linkage analysis, suggesting that if a genetic marker locus is close to a disease susceptibility locus, association analysis may be a more sensitive method than linkage analysis for detecting the susceptibility locus. There is no convincing evidence that genes in the T cell receptor beta chain (TCRB) or alpha chain (TCRA) regions influence predisposition to IDDM, either directly, or indirectly through interaction with HLA region genes. However, we present new evidence for interaction between TCRB and immunoglobulin heavy chain (Gm) region genes in IDDM: diabetics who are positive for the IgG2 allotype G2m(23) have significantly different frequencies of a TCRB restriction fragment length polymorphism (RFLP) than those who are negative for the allotype. Gm region genes also appear to have indirect effects on IDDM susceptibility through interaction with HLA and INS region genes: DR3/4 and non-DR3/4 diabetics have significantly different frequencies of G2m(23), and INS1/1 and non-INS1/1 diabetics also have significantly different frequencies of this allotype. To our knowledge, there are no other studies of Gm-TCRB or Gm-INS interaction in IDDM susceptibility. Evidence for Gm-HLA interaction in IDDM has been published by several other groups of investigators, however the specific phenotypic interaction effects reported have differed. Nevertheless, pooled data from three studies of Gm/HLA haplotype segregation in affected sib pairs shows significantly increased sharing of Gm haplotypes in affected pairs who share both HLA haplotypes. The biological mechanisms underlying the direct (HLA, INS) and indirect (Gm-TCRB, Gm-HLA, Gm-INS) effects of these genetic regions on IDDM susceptibility remain to be elucidated.
本章重点关注HLA区域以外的基因对胰岛素依赖型糖尿病（IDDM）易感性的影响。我们回顾了已发表研究中关于此类基因的实验室证据，并展示了我们近期研究中的未发表数据。现在看来，胰岛素（INS）基因区域存在易患IDDM的基因这一点已得到证实。关联分析表明，与对照组相比，糖尿病患者中5' INS多态性1类等位基因的频率有所增加，并且一种新的分析方法（AFBAC）显示这种关联并非群体分层的假象。有趣的是，通过连锁分析无法检测到INS区域易感性对IDDM的影响，这表明如果一个遗传标记位点靠近疾病易感位点，那么关联分析可能是检测易感位点比连锁分析更敏感的方法。没有令人信服的证据表明T细胞受体β链（TCRB）或α链（TCRA）区域的基因直接或通过与HLA区域基因相互作用间接影响IDDM的易感性。然而，我们展示了IDDM中TCRB与免疫球蛋白重链（Gm）区域基因之间相互作用的新证据：IgG2同种异型G2m(23)呈阳性的糖尿病患者与该同种异型呈阴性的患者相比TCRB限制性片段长度多态性（RFLP）频率有显著差异。Gm区域基因似乎也通过与HLA和INS区域基因相互作用对IDDM易感性产生间接影响：DR3/4和非DR3/4糖尿病患者的G2m(23)频率有显著差异，INS1/1和非INS1/1糖尿病患者的这种同种异型频率也有显著差异。据我们所知，尚无其他关于IDDM易感性中Gm - TCRB或Gm - INS相互作用的研究。其他几组研究人员已发表了IDDM中Gm - HLA相互作用的证据，然而所报道的具体表型相互作用效应有所不同。尽管如此，对受影响同胞对中Gm/HLA单倍型分离的三项研究的汇总数据显示，共享两个HLA单倍型的受影响对中Gm单倍型的共享显著增加。这些遗传区域对IDDM易感性的直接（HLA、INS）和间接（Gm - TCRB、Gm - HLA、Gm - INS）影响背后的生物学机制仍有待阐明。
