Familial Young-Onset Diabetes, Pre-Diabetes and Cardiovascular Disease Are Associated with Genetic Variants of DACH1 in Chinese

Ma, R. C. W., Lee, H. M., Lam, V. K. L., Tam, C. H. T., Ho, J. S. K., Zhao, H. L., … & Chan, J. C. N. (2014). Familial Young-Onset Diabetes, Pre-Diabetes and Cardiovascular Disease Are Associated with Genetic Variants of DACH1 in Chinese. PloS one, 9(1), e84770.

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.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084770