Analysis of FOXO1A as a candidate gene for type 2 diabetes
Analysis of FOXO1A as a candidate gene for type 2 diabetes
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DOI：
10.1016/j.ymgme.2006.01.003
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发表时间：
2006-06-01
影响因子：
3.8
通讯作者：
Elbein, Steven C.
中科院分区：
文献类型：
--
作者：
Karim, Mohammad A.;Craig, Rebekah L.;Elbein, Steven C.
染色体13q14.1上的人叉头框O 1A（FOX 01 A）基因是肝脏和脂肪组织中胰岛素信号传导的关键转录因子，并且在关键胰腺P细胞基因（包括IPF 1）的调节中起核心作用。我们假设FOX 01 A的序列变异导致观察到的肝脏和外周胰岛素作用的缺陷和改变的β细胞代偿，这是2型糖尿病（T2 DM）的特征。为了验证这一假设，我们在早发（< 45岁）T2 DM的高加索人和非洲裔美国人个体中筛选了3个外显子、3'非翻译区和5'侧翼区的序列变异。我们只发现了6个变异体，没有一个改变了编码序列，除了3'非翻译区的一个变异体，它们在高加索人中很少见或不存在。为了增加基因的覆盖率，我们在大的第一内含子和5'侧翼区选择了7个额外的变体，从而提供了13个跨越116.4kb的变体。基于频率和连锁不平衡模式在一个子集的个人，我们选择了8个SNPs类型的高加索人群，包括192个无关的非糖尿病对照个体和192个个体与T2 DM，和10个SNPs类型的182个对照和352个糖尿病个体的非洲裔美国人血统。无变异与T2 DM相关（非裔美国人，p > 0.08;白人，p > 0.09）。在8个高加索SNP中，6个包含跨越100 kb的单个单倍型块，并且包括大部分的第一内含子。相反。在非裔美国人的SNPs分型中没有观察到阻滞。没有单倍型与T2 DM相关。FOX 01 A变异很罕见，不太可能导致高加索人或非洲裔美国人人群中的T2 DM。(c)2006年爱思唯尔公司All rights reserved.
The human forkhead box O1A (FOX01A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic P-cell genes including IPF1. We hypothesized that sequence variants of FOX01A contribute to the observed defects in hepatic and peripheral insulin action and altered beta-cell compensation that characterize type 2 diabetes (T2DM). To test this hypothesis, we screened the three exons, 3' untranslated region, and 5' flanking region for sequence variants in Caucasian and African-American individuals with early onset (< 45 years) T2DM. We identified only six variants; none altered the coding sequence, and except for one variant in the 3' untranslated region, they were rare or absent in Caucasians. To increase coverage of the gene, we selected seven additional variants in the large first intron and 5' flanking region, thus providing 13 variants that spanned 116.4kb. Based on frequency and linkage disequilibrium patterns in a subset of individuals, we selected eight SNPs to type in a Caucasian population comprising 192 unrelated nondiabetic control individuals and 192 individuals with T2DM, and 10 SNPs to type in 182 controls and 352 diabetic individuals of African-American ancestry. No variant was associated with T2DM (African-Americans, p > 0.08; Caucasians, p > 0.09). Of the 8 Caucasian SNPs, six comprised a single haplotype block spanning over 100 kb and including most of the large first intron. In contrast. no block was observed among SNPs typed in African-Americans. No haplotype was associated with T2DM. FOX01A variation is rare and is unlikely to contribute to T2DM in either Caucasian or African-American populations. (c) 2006 Elsevier Inc. All rights reserved.