Elbein S C, Hoffman M D, Matsutani A, Permutt M A
Department of Internal Medicine, Veterans Affairs Medical Center, Salt Lake City, Utah 84148.
Diabetes. 1992 Dec;41(12):1660-7. doi: 10.2337/diab.41.12.1660.
Familial NIDDM probably results from combined inherited defects of insulin secretion and action. Members of the facilitative glucose transporter family are strong candidates for both defects, and RFLPs for both GLUT1 (erythrocyte) and GLUT2 (liver/islet) genes have been associated with NIDDM in some populations. To test the hypothesis that GLUT1 and GLUT2 mutations contribute to the inherited predisposition to NIDDM, we examined linkage of these loci with NIDDM in 18 large Utah white pedigrees (two and three generation) ascertained for > or = 2 NIDDM siblings. We used two RFLPs detected with Xba1 and Stu1 for the GLUT1 transporter. For the GLUT2 (liver/beta-cell) transporter gene, we used an RFLP detected with EcoR1 and a highly polymorphic (6-allele) dinucleotide (microsatellite) repeat. Analysis was performed with the MLINK program of the LINKAGE package. We tested four models for each locus: dominant and recessive, with IGT alternately considered as unknown affection status, or affected if IGT was diagnosed < or = 45 yr of age and unknown if > 45 yr. Disease gene frequencies were chosen to give approximate disease prevalence in American whites (q = 0.03, dominant; q = 0.25, recessive). Linkage of GLUT1 and NIDDM was strongly and significantly rejected under all models, with total (pooled) LOD scores of -5.7 to -8.9, indicating > 500,000:1 odds against linkage. Pooled LOD scores were significantly negative (< -2.0, or 100:1 odds against linkage) to a recombination fraction of > 5%. No heterogeneity was apparent. Analysis of GLUT2 gave similar results, with LOD scores of < -4.0 under each model, indicating at least 10,000:1 odds against linkage.(ABSTRACT TRUNCATED AT 250 WORDS)
家族性非胰岛素依赖型糖尿病（NIDDM）可能源于胰岛素分泌及作用方面的遗传性综合缺陷。易化性葡萄糖转运蛋白家族成员很可能是这两种缺陷的主要候选因素，并且在某些人群中，葡萄糖转运蛋白1（GLUT1，红细胞）和葡萄糖转运蛋白2（GLUT2，肝脏/胰岛）基因的限制性片段长度多态性（RFLP）均与NIDDM相关。为检验GLUT1和GLUT2突变导致NIDDM遗传易感性这一假说，我们在18个大型犹他州白人系谱（两代和三代）中研究了这些基因座与NIDDM的连锁关系，这些系谱中确诊有≥2名NIDDM同胞。我们用Xba1和Stu1检测到的两种RFLP来分析GLUT1转运蛋白。对于GLUT2（肝脏/β细胞）转运蛋白基因，我们用EcoR1检测到的一种RFLP以及一个高度多态性的（6个等位基因）二核苷酸（微卫星）重复序列。分析采用LINKAGE软件包中的MLINK程序。我们对每个基因座测试了四种模型：显性和隐性模型，将糖耐量受损（IGT）交替视为未知患病状态，或者若IGT在45岁及以下被诊断则视为患病，若超过45岁则视为未知。选择疾病基因频率以得出美国白人的大致疾病患病率（显性模型中q = 0.03；隐性模型中q = 0.25）。在所有模型下，GLUT1与NIDDM的连锁均被强烈且显著地排除，总（合并）对数优势计分（LOD）为 -5.7至 -8.9，表明连锁的可能性小于500,000:1。合并LOD计分在重组率大于5%时显著为负（< -2.0，即连锁可能性小于100:1）。未发现明显的异质性。对GLUT2的分析得出类似结果，每个模型下的LOD计分均< -4.0，表明连锁可能性至少为10,000:1。（摘要截短于250词）
