Int J Med Sci 2018; 15(4):395-402. doi:10.7150/ijms.23097 This issue

Research Paper

Distribution of Cytotoxic T Lymphocyte-Associated Antigen-4 Promoter Polymorphisms in Taiwanese Patients with Type 2 Diabetes Mellitus

Yung-Luen Shih1,2,3†, Hsu-Feng Lu4†, Chiao-Wan Hsiao5,6*, Kuo-Ting Ho6,7*, Pei-Chi Chen8, Chien-Ning Huang9,10, Yuanmay Chang11, Shang-Jyh Kao12, Ming-Yuh Shiau13✉, Yih-Hsin Chang6✉

1. Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei,
2. School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei,
3. School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City,
4. Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei,
5. Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei,
6. Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei,
7. ​Hi-Q Clinical Laboratory, Quanzhou, Fujian Province, PRC,
8. Divisions of Endocrinology and Metabolism, Shin Kong Wu Ho-Su Memorial Hospital, Taipei,
9. Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung,
10. School of Medicine, Chung Shan Medical University, Taichung,
11. Department of Long Term Care, MacKay Medical College, New Taipei City,
12. Pulmonary Division, Shin Kong Wu Ho-Su Memorial Hospital, Taipei,
13. Department of Nursing, College of Nursing, Hungkuang University, Taichung, Taiwan
Equal contributions as the 1st authors
* Equal contributions as the 3rd authors

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Shih YL, Lu HF, Hsiao CW, Ho KT, Chen PC, Huang CN, Chang Y, Kao SJ, Shiau MY, Chang YH. Distribution of Cytotoxic T Lymphocyte-Associated Antigen-4 Promoter Polymorphisms in Taiwanese Patients with Type 2 Diabetes Mellitus. Int J Med Sci 2018; 15(4):395-402. doi:10.7150/ijms.23097. Available from

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Type 2 diabetes mellitus (T2DM) is associated with chronic inflammation, suggesting the metabolic abnormalities are originated from or exacerbated by cytokine overproduction. Cytokines and counter-regulatory molecules are crucial in keeping the balance of immune responses and, therefore, are potential candidates involved in T2DM etiology, development and complications. Our previous reports identify several significant associations between the genotypes of cytokine genes and T2DM and/or the clinical lipid parameters, which strongly suggest the participation of immune-regulatory molecules in lipid metabolism. The aim of this study is to determine the distribution of gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a T-cell negative regulator, in T2DM patients and health subjects. Genomic DNA was extracted from 287 Taiwanese T2DM patients and 278 ethnic- and age- matched healthy subjects, and two CTLA-4 polymorphisms (-318 C/T and +49 A/G) were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Intriguingly, CTLA-4 -318 genotype was associated with circulatory triglycerides in T2DM subjects (P=0.019) although no significant association between CTLA-4 -318 (P=0.119) and +49 (P=0.2) genotypes with T2DM was identified. In addition, CTLA-4 +49 genotype was significantly associated with the ratio between total cholesterol and high-density lipoprotein (P=0.004) in control subjects. Our results suggest that CTLA-4 may be involved in lipid metabolism and affect T2DM disease progression and/or the development of diabetic complications although this gene does not represent a major risk factor for T2DM.

Keywords: type 2 diabetes mellitus, cytotoxic T lymphocyte-associated antigen-4, genetic polymorphisms