Yi-Cheng Chang, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100, Taiwan.
World J Diabetes. 2015 Jun 10;6(5):715-25. doi: 10.4239/wjd.v6.i5.715.
Diabetic complications including diabetic nephropathy, retinopathy, and neuropathy are as major causes of morbidity and mortality in diabetes individuals worldwide and current therapies are still unsatisfactory. One of the reasons for failure to develop effective treatment is the lack of fundamental understanding for underlying mechanisms. Genetic studies are powerful tools to dissect disease mechanism. The heritability (h (2)) was estimated to be 0.3-0.44 for diabetic nephropathy and 0.25-0.50 for diabetic retinopathy respectively. Previous linkage studies for diabetic nephropathy have identified overlapped linkage regions in 1q43-44, 3q21-23, 3q26, 10p12-15, 18q22-23, 19q13, 22q11-12.3 in multiple ethnic groups. Genome-wide association studies (GWAS) of diabetic nephropathy have been conducted in several populations. However, most of the identified risk loci could not be replicated by independent studies with a few exceptions including those in ELMO1, FRMD3, CARS, MYO16/IRS2, and APOL3-MYH9 genes. Functional studies of these genes revealed the involvement of cytoskeleton reorganization (especially non-muscle type myosin), phagocytosis of apoptotic cells, fibroblast migration, insulin signaling, and epithelial clonal expansion in the pathogenesis of diabetic nephropathy. Linkage analyses of diabetic retinopathy overlapped only in 1q36 region and current results from GWAS for diabetic retinopathy are inconsistent. Conclusive results from genetic studies for diabetic neuropathy are lacking. For now, small sample sizes, confounding by population stratification, different phenotype definitions between studies, ethnic-specific associations, the influence of environmental factors, and the possible contribution of rare variants may explain the inconsistencies between studies.
糖尿病并发症包括糖尿病肾病、视网膜病变和神经病变，是全球糖尿病患者发病率和死亡率的主要原因，而目前的治疗方法仍不尽如人意。未能开发出有效治疗方法的原因之一是对潜在机制缺乏基本了解。遗传研究是剖析疾病机制的有力工具。糖尿病肾病的遗传率（h (2)）估计为 0.3-0.44，糖尿病视网膜病变的遗传率为 0.25-0.50。先前对糖尿病肾病的连锁研究已经在多个种族中确定了重叠的连锁区域，包括 1q43-44、3q21-23、3q26、10p12-15、18q22-23、19q13 和 22q11-12.3。多个群体已经对糖尿病肾病进行了全基因组关联研究（GWAS）。然而，大多数已识别的风险位点不能被独立研究复制，只有少数例外，包括 ELMO1、FRMD3、CARS、MYO16/IRS2 和 APOL3-MYH9 基因。这些基因的功能研究表明，细胞骨架重排（特别是非肌肉型肌球蛋白）、凋亡细胞的吞噬作用、成纤维细胞迁移、胰岛素信号传导和上皮克隆扩增参与了糖尿病肾病的发病机制。糖尿病视网膜病变的连锁分析仅在 1q36 区域重叠，目前 GWAS 对糖尿病视网膜病变的结果不一致。糖尿病神经病变的遗传研究尚无定论。目前，遗传研究的样本量较小、人群分层的混杂、研究之间表型定义的不同、特定种族的关联、环境因素的影响以及罕见变异的可能贡献可能解释了研究之间的不一致性。
