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PLoS One. 2014 Jan 20;9(1):e84770. doi: 10.1371/journal.pone.0084770. eCollection 2014.

Familial young-onset diabetes, pre-diabetes and cardiovascular disease are associated with genetic variants of DACH1 in Chinese.

Author information

1
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China ; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China ; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
2
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China ; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
3
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
4
School of Biomedical Science, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
5
School of Life Science, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
6
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
7
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and Department of Internal Medicine, College of Medicine, Seoul National University, Chongno-gu, Seoul, Korea.
8
First Department of Medicine, Wakayama Medical University, Wakayama, Japan.
9
Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore.
10
Department of Chemical Pathology, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China ; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
11
Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
12
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China.
13
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China ; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.

Abstract

In Asia, young-onset type 2 diabetes (YOD) is characterized by obesity and increased risk for cardiovascular disease (CVD). In a genome-wide association study (GWAS) of 99 Chinese obese subjects with familial YOD diagnosed before 40-year-old and 101 controls, the T allele of rs1408888 in intron 1 of DACH1(Dachshund homolog 1) was associated with an odds ratio (OR) of 2.49(95% confidence intervals:1.57-3.96, P = 8.4 × 10(-5)). Amongst these subjects, we found reduced expression of DACH1 in peripheral blood mononuclear cells (PBMC) from 63 cases compared to 65 controls (P = 0.02). In a random cohort of 1468 cases and 1485 controls, amongst top 19 SNPs from GWAS, rs1408888 was associated with type 2 diabetes with a global P value of 0.0176 and confirmation in a multiethnic Asian case-control cohort (7370/7802) with an OR of 1.07(1.02-1.12, P(meta)  = 0.012). In 599 Chinese non-diabetic subjects, rs1408888 was linearly associated with systolic blood pressure and insulin resistance. In a case-control cohort (n = 953/953), rs1408888 was associated with an OR of 1.54(1.07-2.22, P = 0.019) for CVD in type 2 diabetes. In an autopsy series of 173 non-diabetic cases, TT genotype of rs1408888 was associated with an OR of 3.31(1.19-9.19, P = 0.0214) and 3.27(1.25-11.07, P = 0.0184) for coronary heart disease (CHD) and coronary arteriosclerosis. Bioinformatics analysis revealed that rs1408888 lies within regulatory elements of DACH1 implicated in islet development and insulin secretion. The T allele of rs1408888 of DACH1 was associated with YOD, prediabetes and CVD in Chinese.

PMID:
24465431
PMCID:
PMC3896349
DOI:
10.1371/journal.pone.0084770
[Indexed for MEDLINE]
Free PMC Article
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