Broad Institute, Cambridge, MA, USA.
Diabetologia. 2010 Nov;53(11):2334-9. doi: 10.1007/s00125-010-1861-2. Epub 2010 Aug 12.
AIMS/HYPOTHESIS: Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues.
We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling.
Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver.
CONCLUSIONS/INTERPRETATION: This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined.
目的/假设:遗传图谱已经确定了 20 多个与 2 型糖尿病遗传风险相关的基因位点。下一步是确定调节遗传风险对疾病贡献的基因和机制。本研究的目的是评估年龄、身高、体重和风险等位基因对三个相关人类组织中糖尿病相关区域候选基因表达的影响。
我们通过定量 RT-PCR 测量了人类胰腺(n=50)、结肠(n=195)和肝脏(n=50)中 WFS1、KCNJ11、TCF2(也称为 HNF1B)、PPARG、HHEX、IDE、CDKAL1、CDKN2A、CDKN2B、IGF2BP2、SLC30A8 和 TCF7L2 的转录丰度。组织样本对与 2 型糖尿病相关的单核苷酸多态性(SNP)进行了基因分型。通过线性模型测试年龄、身高、体重、组织和 SNP 对 RNA 表达的影响。
所有基因的表达都表现出组织偏倚。免疫组织化学证实了 HHEX、IDE 和 SLC30A8 的发现,这些基因表现出最强的组织特异性 mRNA 表达偏倚。年龄、身高或体重均与基因表达无关。我们没有发现 2 型糖尿病相关 SNP 影响结肠、胰腺和肝脏中邻近基因表达(顺式表达数量性状基因座)的证据。
结论/解释:本研究提供了新的证据,表明组织类型,而不是年龄、身高、体重或与 2 型糖尿病风险增加相关的候选基因内或附近的 SNP,是所研究基因和组织中差异基因表达的重要贡献因素。