Rubinstein P, Walker M, Ginsberg-Fellner F
Diabetes. 1986 Sep;35(9):985-9. doi: 10.2337/diab.35.9.985.
The HLA-DR genotypes of 158 new type I diabetic probands from simplex families are compared with those of 43 multiply affected sibships. There were no significant differences in the gene frequencies of the insulin-dependent diabetes mellitus (IDDM)-associated alleles, DR3 and DR4, and whereas the DR3/4 heterozygotes were as frequent among simplex probands as among the first affected of multiplex sibships, subsequently affected sibs displayed lower frequencies of this genotype in this as well as in previously reported samples, indicating that the excessive risk associated with DR3/4 heterozygosity depends on the order of affection and thus on environmental factors. It is proposed that the penetrance of the susceptibility gene is enhanced by epistatic effects of this genotype and that this enhancement is strongest under conditions of low environmental liability. Thus, the excessive risk for DR3/4 individuals appears to depend on secondary interactions between DR and the environmental factors that trigger the onset of this disease and does not in itself indicate the existence of distinct susceptibility alleles in coupling with these genes, i.e., of genetic heterogeneity or overdominance.
将来自单纯家庭的158名I型糖尿病先证者的HLA - DR基因型与43个多例受累同胞对的基因型进行了比较。胰岛素依赖型糖尿病（IDDM）相关等位基因DR3和DR4的基因频率没有显著差异，并且DR3/4杂合子在单纯先证者中的频率与在多例受累同胞对中首个受累者中的频率相同，然而在随后受累的同胞中，该基因型在此样本以及先前报道的样本中的频率较低，这表明与DR3/4杂合性相关的额外风险取决于受累顺序，因而也取决于环境因素。有人提出，该基因型的上位效应增强了易感基因的外显率，并且这种增强在低环境易感性条件下最为强烈。因此，DR3/4个体的额外风险似乎取决于DR与触发该疾病发病的环境因素之间的二次相互作用，其本身并不表明与这些基因连锁存在不同的易感等位基因，即不存在遗传异质性或超显性。
