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

Ronald Ching Wan Ma, Heung Man Lee, Vincent Kwok Lim Lam, Claudia Ha Ting Tam, Janice Siu Ka Ho, Hai Lu Zhao, Jing Guan, Alice Pik Shan Kong, Eric Lau, Guozhi Zhang, Andrea Luk, Ying Wang, Stephen Kwok Wing Tsui, Ting Fung Chan, Cheng Hu, Wei Ping Jia, Kyong Soo Park, Hong Kyu Lee, Hiroto Furuta, Kishio NanjoE. Shyong Tai, Daniel Peng Keat Ng, Nelson Leung Sang Tang, Jean Woo, Ping Chung Leung, Hong Xue, Jeffrey Wong, Po Sing Leung, Terrence C.K. Lau, Peter Chun Yip Tong, Gang XU, Maggie Chor Yin Ng, Wing Yee So, Juliana Chung Ngor Chan

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14 Citations (Scopus)

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, Pmeta = 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.

Original languageEnglish
Article numbere84770
JournalPLoS ONE
Volume9
Issue number1
DOIs
Publication statusPublished - 20 Jan 2014

Scopus Subject Areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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