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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jun 10, 2015; 6(5): 715-725
Published online Jun 10, 2015. doi: 10.4239/wjd.v6.i5.715
Recent progress in the genetics of diabetic microvascular complications
Yi-Cheng Chang, Emily Yun-Chia Chang, Lee-Ming Chuang
Yi-Cheng Chang, Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100, Taiwan
Yi-Cheng Chang, Department of Medicine, National Taiwan University Hospital, HsinChu branch, HsinChu 300, Taiwan
Yi-Cheng Chang, Lee-Ming Chuang, Department of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Emily Yun-Chia Chang, Lee-Ming Chuang, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
Lee-Ming Chuang, Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei 100, Taiwan
Author contributions: Chang YC and Chang EYC drafted the manuscript and drew figures; Chuang LM conceived the outlines and approved the final manuscript.
Conflict-of-interest: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Lee-Ming Chuang, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung Shan S. Rd, Taipei 100, Taiwan. leeming@ntu.edu.tw
Telephone: +886-2-23123456 Fax: +886-2-23938859
Received: September 9, 2014
Peer-review started: September 9, 2014
First decision: December 17, 2014
Revised: March 2, 2015
Accepted: March 16, 2015
Article in press: March 18, 2015
Published online: June 10, 2015
Abstract

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 (h2) 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.

Keywords: Microvascular complications, Nephropathy, Retionopathy, Neuropathy, Diabetes

Core tip: Most risk genetic loci identified by genome-wide association studies (GWAS) for diabetic nephropathy could not be replicated by independent studies with a few exceptions including those in ELMO1, FRMD3, CARS, MYO16/IRS2, and APOL3-MYH9 genes. These findings highlighted the importance of cytoskeleton reorganization, phagocytosis of apoptotic cells, fibroblast migration, insulin signaling, and epithelial clonal expansion in the pathogenesis of diabetic nephropathy. Conclusive results from GWAS for diabetic retinopathy and diabetic neuropathy are currently lacking.