Vafiadis P, Bennett S T, Todd J A, Grabs R, Polychronakos C
McGill University-Montreal Children's Hospital Research Institute and the Department of Pediatrics, McGill University, Quebec, Canada.
J Clin Endocrinol Metab. 1998 Aug;83(8):2933-9. doi: 10.1210/jcem.83.8.5048.
The IDDM2 susceptibility locus in type 1 diabetes corresponds to a variable number of tandem repeats (VNTR) upstream of the insulin (INS) and insulin-like growth factor 2 (IGF2) genes. Large VNTR alleles (class III) are dominantly protective, whereas small alleles (class I) are predisposing. IGF2 has been considered a prime candidate for mediating IDDM2-encoded susceptibility because of its proximity to the VNTR, mitogenic properties and parental effects at IDDM2 suggest the involvement of an imprinted gene. IGF2 is imprinted with exclusive expression of the paternal gene. However, there is polymorphic relaxation of IGF2 imprinting in leukocytes. VNTR allelic variation affecting either the extent of relaxation or transcription independent of parental origin might explain the IDDM2 effect. To test this, we compared IGF2 expression between chromosomes with a class III or I allele in leukocytes and stimulated lymphocytes. No significant difference was detected between the two classes. Furthermore, the (+) allele of an ApaI polymorphism in the 3'-untranslated region of IGF2 was associated with significantly higher IGF2 messenger ribonucleic acid levels than the (-) allele, but was not associated with type 1 diabetes. The absence of transcriptional effects in leukocytes on IGF2 by the VNTR, which is the disease-predisposing locus, and the presence of a strong association between IGF2 levels and ApaI, which is not associated with the disease, argue against IGF2 expression in leukocytes as the mediator of IDDM2-encoded susceptibility. Taken together, these results support studies suggesting that INS expression in the thymus is a primary target of the IDDM2 susceptibility locus.
1型糖尿病中的IDDM2易感基因座对应于胰岛素（INS）和胰岛素样生长因子2（IGF2）基因上游的可变数目串联重复序列（VNTR）。大的VNTR等位基因（III类）具有显性保护作用，而小等位基因（I类）则易引发疾病。IGF2因其与VNTR的接近程度、促有丝分裂特性以及在IDDM2的亲本效应，被认为是介导IDDM2编码易感性的主要候选基因，提示涉及一个印记基因。IGF2呈印记状态，父本基因独家表达。然而，白细胞中IGF2印记存在多态性松弛。影响松弛程度或转录的VNTR等位基因变异，与亲本来源无关，可能解释了IDDM2效应。为验证此，我们比较了白细胞和刺激淋巴细胞中具有III类或I类等位基因的染色体之间的IGF2表达。两类之间未检测到显著差异。此外，IGF2 3'非翻译区ApaI多态性的（+）等位基因与显著更高的IGF2信使核糖核酸水平相关，而与（-）等位基因无关，但与1型糖尿病无关。作为疾病易感基因座的VNTR在白细胞中对IGF2无转录效应，以及IGF2水平与ApaI之间存在强关联（而ApaI与疾病无关），表明白细胞中IGF2表达并非IDDM2编码易感性的介导因素。综上所述，这些结果支持了相关研究，提示胸腺中INS表达是IDDM2易感基因座的主要靶点。
