Yi-Jen Hung

Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

Genome-wide association study in a Chinese population with diabetic retinopathy

Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10(-7)), LRP2-BBS5 (rs1399634, P = 2.0 × 10(-6)) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10(-6)). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR.

Association and interaction analyses of genetic variants in ADIPOQ, ENPP1, GHSR, PPARγ and TCF7L2 genes for diabetic nephropathy in a Taiwanese population with type 2 diabetes

BACKGROUND Diabetic nephropathy (DN) is a common microvascular complication of diabetes. In this study, we aimed to explore both primary effects of single-locus and multilocus interactions to test the hypothesis that the type 2 diabetes (T2D) genes may contribute to the aetiology of DN in T2D independently and/or through complex interactions in a Taiwanese population with T2D. METHODS We genotyped six single nucleotide polymorphisms (SNPs) for five common T2D genes including adiponectin, C1Q and collagen domain containing (ADIPOQ), ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1), growth hormone secretagogue receptor (GHSR), peroxisome proliferator-activated receptor gamma (PPARgamma) and transcription factor 7-like 2 (TCF7L2). There were 216 T2D patients diagnosed with DN and 178 age-similar T2D without DN (control) subjects. To investigate gene-gene interactions, we employed both generalized multifactor dimensionality reduction (GMDR) method and logistic regression models. RESULTS Single-locus analyses showed significant main effects of ENPP1 (P = 0.0032; adjusted OR = 1.85; 95% CI = 1.17-2.92) on the risk of DN in T2D. Furthermore, a potential gene-gene interaction involving ENPP1 and GHSR was suggested in the best two-locus GMDR model (P = 0.021). The significant three-locus GMDR model (P < 0.001) was also identified among ADIPOQ, GHSR and TCF7L2. Analyses using logistic regression models confirmed the gene-gene interactions. CONCLUSIONS The results suggest that the SNPs from the T2D-related genes may contribute to the risk of DN in T2D independently and/or in an interactive manner in Taiwanese T2D patients.

Kidney-targeting Smad7 gene transfer inhibits renal TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways, and improves diabetic nephropathy in mice

Aims/hypothesisThe TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways have been shown to play a critical role in the development of renal fibrosis and inflammation in diabetic nephropathy. We therefore examined whether targeting these pathways by a kidney-targeting Smad7 gene transfer has therapeutic effects on renal lesions in the db/db mouse model of type 2 diabetes.MethodsWe delivered Smad7 plasmids into the kidney of db/db mice using kidney-targeting, ultrasound-mediated, microbubble-inducible gene transfer. The histopathology, ultrastructural pathology and pathways of TGF-β/SMAD2/3-mediated fibrosis and NF-κB-dependent inflammation were evaluated.ResultsIn this mouse model of type 2 diabetes, Smad7 gene therapy significantly inhibited diabetic kidney injury, compared with mice treated with empty vectors. Symptoms inhibited included: (1) proteinuria and renal function impairment; (2) renal fibrosis such as glomerular sclerosis, tubulo-interstitial collagen matrix abundance and renal inflammation, including Inos (also known as Nos2), Il1b and Mcp1 (also known as Ccl2) upregulation, as well as macrophage infiltration; and (3) podocyte and endothelial cell injury as demonstrated by immunohistochemistry and/or electron microscopy. Further study demonstrated that the improvement of type 2 diabetic kidney injury by overexpression of Smad7 was associated with significantly inhibited local activation of the TGF-β/SMAD and NF-κB signalling pathways in the kidney.Conclusions/interpretationOur results clearly demonstrate that kidney-targeting Smad7 gene transfer may be an effective therapy for type 2 diabetic nephropathy, acting via simultaneous modulation of the TGF-β/SMAD and NF-κB signalling pathways.

Insulin sensitivity, proinflammatory markers and adiponectin in young males with different subtypes of depressive disorder

Objective  This study was designed to evaluate insulin sensitivity, proinflammatory markers and adiponectin concentration in young males with different subtypes of depressive disorder.

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Plasma protein growth arrest-specific 6 levels are associated with altered glucose tolerance, inflammation, and endothelial dysfunction.

OBJECTIVE Plasma protein growth arrest–specific 6 (Gas6) is important to the inflammatory process and is involved in the development of diabetic renal and vascular complications. We set out to determine whether plasma Gas6 levels are associated with altered glucose tolerance, insulin sensitivity, inflammation, and endothelial dysfunction. RESEARCH DESIGN AND METHODS A total of 278 adults, including 96 with normal glucose tolerance (NGT), 82 with impaired glucose tolerance (IGT), and 100 with type 2 diabetes were recruited. Plasma Gas6 concentration and biochemical, proinflammatory, and endothelial variables were determined. Insulin sensitivity was examined by homeostasis model assessment. RESULTS Plasma Gas6 concentration was significantly lower among patients with type 2 diabetes compared with subjects with NGT (P < 0.001). The plasma Gas6 value was inversely correlated with fasting glucose, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and vascular cell adhesion molecule (VCAM)-1. In multivariate logistic regression analysis, after adjustment for established diabetes risk factors, higher plasma Gas6 concentrations were significantly associated with a decreased risk of type 2 diabetes. Moreover, the association became slightly stronger after further adjustment for TNF-α, IL-6, high-sensitive C-reactive protein, E-selectin, intercellular adhesion molecule-1, and VCAM-1. CONCLUSIONS Plasma Gas6 is associated with altered glucose tolerance, inflammation, and endothelial dysfunction. It also may represent a novel independent risk factor of type 2 diabetes and a potential surrogate marker of inflammation and endothelial dysfunction.

Soluble Form of Receptor for Advanced Glycation End Products Is Associated with Obesity and Metabolic Syndrome in Adolescents

The aim of this cross-sectional study was to investigate the relationship between soluble form of receptor for advanced glycation end products (sRAGE), obesity, and metabolic syndrome (MetS) in adolescents. A total of 522 male and 561 female adolescents were enrolled into the final analyses. Anthropometric parameters, blood pressure, blood biochemistry, fasting insulin, and plasma sRAGE levels were measured. In males, sRAGE was significantly and inversely correlated with waist circumference (WC), body mass index (BMI), systolic blood pressure, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR). Only WC and BMI were significantly and inversely correlated with sRAGE in females. Using linear regression analysis adjusting for age and gender, significant association was found between sRAGE and WC, BMI, TG, LDL-C, and HOMA-IR in adolescents of either gender (P < 0.05). This association was abolished when further adjusting BMI. In addition, sRAGE was significantly and inversely correlated with the increasing number of components of MetS in males (P for trend = 0.006) but not in females (P for trend = 0.422). In conclusion, plasma sRAGE is associated with obesity and MetS among adolescents. BMI may be the most important determinant of sRAGE levels in adolescents.

Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: Gene-environmental interaction with alcohol consumption

BackgroundGenetic variants near/within the ALDH2 gene encoding the mitochondrial aldehyde dehydrogenase 2 have been associated with blood pressure and hypertension in several case–control association studies in East Asian populations.MethodsThree common tag single nucleotide polymorphisms (tagSNP) in the ALDH2 gene were genotyped in 1,134 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. We examined whether the ALDH2 SNP genotypes predicted the development of hypertension in the prospective SAPPHIRe cohort.ResultsOver an average follow-up period of 5.7 years, carriers homozygous for the rs2238152 T allele in the ALDH2 gene were more likely to progress to hypertension than were non-carriers (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.06-7.84, P = 0.03), corresponding to a population attributable risk of ~7.1%. The risk associated with the rs2238152 T allele were strongest in heavy/moderate alcohol drinkers and was reduced in non-drinkers, indicating an interaction between ALDH2 genetic variants and alcohol intake on the risk of hypertension (P for interaction = 0.04). The risk allele was associated with significantly lower ALDH2 gene expression levels in human adipose tissue.ConclusionALDH2 genetic variants were associated with progression to hypertension in a prospective Chinese cohort. The association was modified by alcohol consumption.

Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves’ hyperthyroidism

objective  The present study was to compare the efficacy of a single daily dose of methimazole (MMI) and propylthiouracil (PTU) in the treatment of Graves’ hyperthyroidism.