PLoS ONE (Jan 2014)

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 Nanjo,
  • E 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

DOI
https://doi.org/10.1371/journal.pone.0084770
Journal volume & issue
Vol. 9, no. 1
p. e84770

Abstract

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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.