Polymorphisms of Glucose Transporter Genes Associated with Type II Diabetes

为了评估葡萄糖转运蛋白基因对非胰岛素依赖型糖尿病（NIDDM， II型）遗传易感性的贡献，分析了GLUT-1 （HepG2/红细胞），GLUT-2（肝脏/胰腺）和GLUT-4（肌肉/脂肪细胞）位点的限制性片段长度多态性（RFLPs）。在GLUT-1基因座BgIII、TaqI、XbaI和PstI位点上观察到4个RFLPs。两两分析和扩展单倍型揭示了多态性位点之间的随机关联（连锁平衡）。在四个不同的人群（白人、美国黑人、皮马印第安人、日本人）中确定了RFLPs的变异性。BgIII RFLP在白色染色体中的频率极低。TagI和PstI多态性在所有人群中都相对不常见，仅提供少量信息。在GLUT-2位点上观察到4个多态性位点，包括EcoRI、HaeIII和2个TaqI RFLPs。每个位点都是通过多次过量酶的二联反应来证实的，而且更多的是通过家族遗传来证实的。EcoRI和HaeIII的RFLPs似乎是由于在同一位置插入和/或删除了200bp的DNA。采用两两分析评估各RFLP之间的连锁不平衡。每对RFLPs的估计单倍型频率与多态性随机关联的预测频率不同。因此，位点之间存在明显的连锁不平衡。这些RFLPs如果存在，可能与该位点的突变处于连锁不平衡状态。glut2基因座RFLPs的频率在不同种族间存在差异。在日本人中观察到极低频率的RFLPs。这个事实要求我们在这个群体中找到一个新的有价值的RFLP。GLUT-4位点存在KpnI多态性。该RFLP的频率在不同种族之间没有差异。在包括日本人在内的少数受试者中，NIDDM受试者中这三个位点的DNA多态性的等位基因、基因型和单倍型频率与非糖尿病受试者的频率没有差异。扩展单倍型分析包括每个个体的整体遗传位点（GLUT-1, 2和-4）和家族连锁分析，以进一步评估这些位点对NIDDM遗传易感性的贡献。少

To assess the contribution of the glucose transporter genes to the inherited susceptibility to Non-insulin Dependent Diabetes Mellitus (NIDDM, type II), restriction fragment length polymorphisms (RFLPs) at GLUT-1 (HepG2/erythrocyte), GLUT-2 (liver/pancreas), and GLUT-4 (muscle/adipocyte) loci were analyzes. Four RFLPs were observed at GLUT-1 locus, including BgIII, TaqI, XbaI and PstI sites. Pairwise analysis and extended haplotypes revealed the random association between the polymorphic sites (linkage equilibrium). The variability of the RFLPs was determined in four different populations (Whites, American Blacks, Pima Indians, Japanese). The frequency of BgIII RFLP was extremely low in White chromosomes. Both the TagI and PstI polymorphisms were relatively infrequent in all populations and were only slightly informative.Four polymorphic sites were observed at GLUT-2 locus, including EcoRI, HaeIII, and two TaqI RFLPs. Each site was confirmed by multiple dihestion with excess enzyme and … More by ingeritence in families. EcoRI and HaeIII RFLPs appear to be due to an insertion and/or deletion of 200 bp of DNA at same locati on. The linkage disequlibrium between each RFLP was assessed by pairwise analysis. The estimated haplotype frequencies for each pair of RFLPs differed from the frequency predicted if the polymorphisms were randomly associated. Thus significant linkage disequlibrium between sites was suggested. It was also suggested that these RFLPs could be in linkage disequlibrium with mutations at this locus if they exists. The frequencies of RFLPs at GLUT-2 locus were different among the racial groups. The extremely low frequency of RFLPs were observed in Japanese. This fact requires us to find a new valuable RFLP in this population. KpnI polymorphisms was observed at GLUT-4 locus. There was no difference in the frequency of this RFLP among the racial groups.The allelic, genotypic, and haplotypic frequencies of the DNA polymorphisms at these three loci in NIDDM subjects did not differ from the frequencies in nondiabetic subjects as far as analyzed in a small number of subjects including Japanese. Analysis for extended haplotypes including overall genetic loci (GLUT-1, -2 & -4) in each individual and family linkage analysis should be completed to further assess the contribution of these loci to the genetic susceptibility of NIDDM. Less