Structural Properties of Gene Promoters Highlight More than Two Phenotypes of Diabetes

Genome-wide association studies (GWAS) published in the last decade raised the number of loci associated with type 1 (T1D) and type 2 diabetes (T2D) to more than 50 for each of these diabetes phenotypes. The environmental factors seem to play an important role in the expression of these genes, acting through transcription factors that bind to promoters. Using the available databases we examined the promoters of various genes classically associated with the two main diabetes phenotypes. Our comparative analyses have revealed significant architectural differences between promoters of genes classically associated with T1D and T2D. Nevertheless, five gene promoters (about 16%) belonging to T1D and six gene promoters (over 19%) belonging to T2D have shown some intermediary structural properties, suggesting a direct relationship to either LADA (Latent Autoimmune Diabetes in Adults) phenotype or to non-autoimmune type 1 phenotype. The distribution of these promoters in at least three separate classes seems to indicate specific pathogenic pathways. The image-based patterns (DNA patterns) generated by promoters of genes associated with these three phenotypes support the clinical observation of a smooth link between specific cases of typical T1D and T2D. In addition, a global distribution of these DNA patterns suggests that promoters of genes associated with T1D appear to be evolutionary more conserved than those associated with T2D. Though, the image based patterns obtained by our method might be a new useful parameter for understanding the pathogenetic mechanism and the diabetogenic gene networks.近十年发表的全基因组关联研究（Genome-wide Association Studies, GWAS）已将与1型糖尿病（T1D）和2型糖尿病（T2D）这两种糖尿病表型相关的基因座数量分别提升至50个以上。环境因素似乎通过结合启动子的转录因子发挥作用，在这些基因的表达调控中扮演重要角色。本研究依托现有数据库，对与这两种主要糖尿病表型经典相关的各类基因的启动子进行了分析。比较分析结果显示，经典关联T1D与T2D的基因启动子之间存在显著的结构差异。不过，属于T1D的5个基因启动子（占比约16%）以及属于T2D的6个基因启动子（占比超19%）呈现出一定的中间结构特征，提示其与成人隐匿性自身免疫糖尿病（Latent Autoimmune Diabetes in Adults, LADA）表型或非自身免疫性1型表型存在直接关联。这些启动子至少可分为三个独立类别，这一分布似乎指向特定的致病通路。由与这三种表型相关的基因启动子所产生的基于图像的DNA图谱（DNA patterns），印证了典型T1D与T2D特定病例之间存在平滑过渡的临床观察结果。此外，这些DNA图谱的全局分布表明，与T1D相关的基因启动子在进化上比与T2D相关的启动子更为保守。尽管如此，本研究方法所获得的基于图像的图谱，或可成为解析致病机制与致糖尿病基因网络的一项全新且实用的参数。