Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles
Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles
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DOI：
10.2337/diabetes.49.1.126
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发表时间：
2000-01-01
期刊：
影响因子：
7.7
通讯作者：
McCarthy, MI
中科院分区：
文献类型：
--
作者：
Huxtable, SJ;Saker, PJ;McCarthy, MI
胰岛素基因（INS）5'端可变数目串联重复序列（VNTR）小卫星变异与几种表型相关，包括1型糖尿病、多囊卵巢综合征和出生体重。病例对照研究表明III类VNTR等位基因也与2型糖尿病相关，但结果不一致，可能反映了人群分层。为了进一步探索INS-VNTR在2型糖尿病易感性中的作用，我在来自英国糖尿病协会Warren Trios储存库的155个父母-后代三人组中使用了基于家庭的关联方法，每个人都通过Europid先证者与2型糖尿病确定。总体而言，糖尿病和INS-VNTR基因型之间没有显著关联，119个杂合子父母中有65个（55%）传递III类和54个I类（P = 0.16，单侧）。然而，尽管母体传播遵循孟德尔预期，但49名杂合父亲的III类传播明显过量（34 [69%] vs. 15，P = 0.003 vs. 50%预期，P = 0.003 vs.母体传播）。这些结果证实，TH-INS-IGF 2基因座内的变异，最可能是在VNTR本身，影响2型糖尿病的易感性。通过证明这种效应完全由父系来源的等位基因介导，这些发现暗示印记基因在2型糖尿病的发病机制中。
Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, me used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission hom the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.