Dataset Information

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

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.

SUBMITTER: Ma RC

PROVIDER: S-EPMC3896349 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Ma Ronald Ching Wan RC Lee Heung Man HM Lam Vincent Kwok Lim VK Tam Claudia Ha Ting CH Ho Janice Siu Ka JS Zhao Hai-Lu HL Guan Jing J Kong Alice Pik Shan AP Lau Eric E Zhang Guozhi G Luk Andrea A Wang Ying Y Tsui Stephen Kwok Wing SK Chan Ting Fung TF Hu Cheng C Jia Wei Ping WP Park Kyong Soo KS Lee Hong Kyu HK Furuta Hiroto H Nanjo Kishio K Tai E Shyong ES Ng Daniel Peng-Keat DP Tang Nelson Leung Sang NL Woo Jean J Leung Ping Chung PC Xue Hong H Wong Jeffrey J Leung Po Sing PS Lau Terrence C K TC Tong Peter Chun Yip PC Xu Gang G Ng Maggie Chor Yin MC So Wing Yee WY Chan Juliana Chung Ngor JC

PloS one 20140120 1

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 periph ...[more]

PMID: 24465431

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Project description:The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach--in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population--can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the "gray zone" of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis.

Project description:BackgroundHeterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment.Materials and methodsA retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study's participants for the occurrence of ASCVD.ResultsA causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305-4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017-1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899-3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523).ConclusionIn this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.

Dataset Information

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

Publications

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

Similar Datasets

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