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1.  The Chromosome 9p21 Variant Not Predicting Long-Term Cardiovascular Mortality in Chinese with Established Coronary Artery Disease: An Eleven-Year Follow-Up Study 
BioMed Research International  2014;2014:626907.
Introduction. We examined whether the variant at chromosome 9p21, rs4977574, was associated with long-term cardiovascular mortality in Han Chinese patients with coronary artery disease (CAD). Methodology. Subjects who underwent coronary angiography for chest pain were consecutively enrolled. Fasting blood samples were collected for laboratory and genotype assessments. The information was correlated with data collected from the national death database. Results. There were 925 cases with CAD and 634 without CAD enrolled in the present study. The G allele conferred a significant increase in risk of CAD (odds ratio = 1.47, P = 0.003 in the dominant model; odds ratio = 1.36, P = 0.018 in the recessive model). During a median of 11 years (inter-quartile range between 5.2 and 12.5 years) of follow-up, neither the total nor the cardiovascular mortality was different among CAD subjects with different genotypes. Using Cox regression analysis, genotypes of rs4977574 still failed to predict cardiovascular mortality (hazard ratio = 1.25, P = 0.138 in the dominant model; hazard ratio = 1.05, P = 0.729 in the recessive model). Conclusions. The rs4977574 at chromosome 9p21 is associated with presence of CAD in Han Chinese. However, rs4977574 could not predict cardiovascular mortality in these CAD subjects during the eleven-year period of the study.
PMCID: PMC3996981  PMID: 24804228
2.  Correlation between reduction of superior interventricular groove epicardial fat thickness and improvement of insulin resistance after weight loss in obese men 
It has been recognized that reduction of abdominal visceral fat and subcutaneous fat are associated with improvement in insulin-resistance (IR) after weight loss. However, few studies have investigated the correlation of reduction in epicardial adipose tissue (EAT) with improvement of IR index after weight loss in obese non-diabetic men with metabolic syndrome (MetS).
Methods and results
We prospectively enrolled 32 non-diabetic men with MetS for a 3-month weight reduction program mainly by diet control and exercise. Magnetic resonance imaging (MRI) examinations were used to measure EAT, subcutaneous fat, and abdominal visceral fat. Anthropometric parameters, oral glucose tolerance test (OGTT), and serum adipokines were assessed before and after the weight loss program. After a 3-month weight loss program, 27 obese MetS men had significant weight loss >5% (97 ± 14 to 87 ± 14 kg, with a 10.7 % decrease, p < 0.001). Multivariate analysis revealed that the decrement ratio of superior interventricular groove (SIVG) EAT thickness (r = 0.322, p = 0.044) and serum leptin (r = 0.626, p < 0.001) significantly correlated with the percentage improvements of fasting HOMA-IR index. Furthermore, the decrement ratio of SIVG EAT thickness (r = −0.370, p = 0.017) and decrement ratio of subcutaneous fat area (r = −0.673, p = 0.006) were significantly correlated with improvement of OGTT-derived Matsuda insulin-sensitivity index.
The decrement ratio of SIVG EAT correlated with improvement of both HOMA-IR and OGTT-derived Matsuda insulin-sensitivity indexes after weight loss in obese non-diabetic men with MetS.
Clinical trial registration
(Multi-faceted Evaluations Following Weight Reduction in Subjects with Metabolic Syndrome NCT 01065753 on Feb 8, 2010).
PMCID: PMC4223841  PMID: 25383099
Epicardial adipose tissue; Insulin resistance; Leptin; Matsuda index; Metabolic syndrome; Obesity
3.  Genome-wide association study in a Chinese population with diabetic retinopathy 
Human Molecular Genetics  2013;22(15):3165-3173.
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.
PMCID: PMC3699066  PMID: 23562823
4.  Reduced Health-Related Quality of Life in Body Constitutions of Yin-Xu, and Yang-Xu, Stasis in Patients with Type 2 Diabetes: Taichung Diabetic Body Constitution Study 
Aim. To evaluate how health-related quality of life (HRQOL) and traditional Chinese medicine (TCM) constitutions of Yin-Xu, Yang-Xu, and Stasis are related in type 2 diabetes patients. Method. Seven hundred and five subjects were recruited in 2010 for this study from a Diabetes Shared Care Network in Taiwan. Generic and disease-specific HRQOL were assessed by the short form 36 (SF-36) and the diabetes impact measurement scale (DIMS). Constitutions of Yin-Xu, Yang-Xu, and Stasis were then assessed by the body constitution questionnaire (BCQ), a questionnaire consisting of 44 items that evaluate the physiological state based on subjective symptoms and signs. Results. Estimated effects of the Ying-Xu and Stasis on all scales of the SF-36 were significantly negative, while estimated effects of the Yang-Xu on all scales (except for SF, RE, MH, and MCS) were significantly negative. For DIMS, the estimated effects of the Ying-Xu and Stasis on all scales were significantly negative except for Stasis on well-being, while Yang-Xu has a significantly negative effect only on symptoms. Conclusions. This study demonstrates that TCM constitutions of Yin-Xu, Yang-Xu, and Stasis are closely related to a reduction in HRQOL. These findings support the need for further research into the impact of intervention for TCM constitutions on HRQOL in patients with type 2 diabetes.
PMCID: PMC4100449  PMID: 25093025
5.  Post-meal β-cell function predicts the efficacy of glycemic control in patients with type 2 diabetes inadequately controlled by metformin monotherapy after addition of glibenclamide or acarbose 
This study aimed to explore parameters which will predict good control of HbA1c after adding a second anti-diabetic drug in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy.
Fifty-one patients (M/F: 25/26, mean age: 53.7 ± 8.2 years, mean glycated hemoglobin [HbA1c] 8.4 ± 1.2%) with T2DM inadequately controlled with metformin were randomized to add-on glibenclamide or acarbose for 16 weeks. Before and after combination therapy, the subjects underwent a 2-hour liquid mixed meal tolerance test to determine insulin secretion (HOMA-β, insulinogenic index, and disposition index [DI]) and insulin sensitivity (HOMA-IR and Matsuda insulin sensitivity index).
At baseline, there was a significant inverse relationship between DI120 and HbA1c (p = 0.001) in all subjects. The addition of glibenclamide and acarbose improved HbA1c significantly from 8.6 ± 1.6% to 7.4 ± 1.2% (p < 0.001), and from 8.2 ± 0.8% to 7.5 ± 0.8% (p < 0.001), respectively. In the glibenclamide group, DI120 significantly increased from 51.2 ± 24.2 to 74.9 ± 41.9 (p < 0.05), and in the acarbose group, from 62.5 ± 31.4 to 91.7 ± 36.2 (p < 0.05), respectively. Multiple regression analyses showed that both baseline HbA1c and DI120 independently predicted reduction of HbA1c as well as final HbA1c after combination therapy.
In patients with T2DM inadequately controlled with metformin, add-on oral anti-diabetic agent with glibenclamide or acarbose resulted in the significant HbA1c reduction and improvement of β-cell function. Subjects with greater baseline β-cell function reserve displayed better glycemic response in the combination therapy of metformin with glibenclamide or acarbose.
Trial registration
This study was registered in the with registration number of NCT00417729.
PMCID: PMC4057801  PMID: 24932223
Beta-cell function; Disposition index; Glycated hemoglobin; Glycemic control; Metformin
6.  Performance of HbA1c and Fasting Plasma Glucose in Screening for Diabetes in Patients Undergoing Coronary Angiography 
Diabetes Care  2013;36(5):1138-1140.
The performance of glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) was compared in screening for diabetes by an oral glucose tolerance test (OGTT) in patients undergoing coronary angiography (CAG).
Patients without known diabetes admitted for CAG were eligible. OGTT and HbA1c were assessed 2–4 weeks after hospital discharge. The performance of HbA1c and FPG was evaluated by using receiver operating characteristic (ROC) analysis.
Diabetes was diagnosed in 83 of 400 patients (20.8%). The area under the ROC curve was higher for FPG than for HbA1c (0.81 vs. 0.73, P = 0.032). We proposed a screening algorithm and validated it in another 170 patients. Overall, this algorithm reduced the number of OGTTs by 71.4% (sensitivity 74.4%, specificity 100%).
FPG performed better than HbA1c in screening for diabetes in patients undergoing CAG. A screening algorithm might help to reduce the number of OGTTs.
PMCID: PMC3631876  PMID: 23238660
7.  Brain-derived neurotrophic factor, but not body weight, correlated with a reduction in depression scale scores in men with metabolic syndrome: a prospective weight-reduction study 
Obesity, a critical component of metabolic syndrome (MetS), is associated with depression. Deficiency of brain-derived neurotrophic factor (BDNF) is involved in the mechanism of depression. We hypothesized that weight reduction would improve depressive symptoms via increasing BDNF levels in obese men.
Male adults with obesity were enrolled in a weight-reduction program for twelve weeks. All subjects underwent daily caloric restriction and an exercise program which was regularly assessed in group classes. Fasting blood samples and Zung Self-Rating Depression Scale (Zung SDS) scores were collected for assessments before and after the study.
A total of 36 subjects completed this program. The average reduction in body weight was 8.4 ± 5.1 kg (8.8 ± 5.1%, P < 0.001). Fasting serum BDNF significantly increased after the study (from 40.4 ± 7.8 to 46.9 ± 8.9 ng/ml, P < 0.001). However, the depression symptoms, as assessed by the Zung Self-Rating Depression Scale (Zung SDS), did not reduce significantly (P = 0.486). Divided into subgroups based on changes in BDNF, Zung SDS scores were significantly reduced in subjects with greater BDNF increase than in those with minor BDNF change (-3.9 ± 6.2 vs. 2.3 ± 6.7, P = 0.009). The increased percentage of BDNF was inversely correlated with the change in Zung SDS (r = -0.380, P = 0.022). Multivariate regression analysis showed that reduction in BDNF was independently associated with change in Zung SDS (95% confidence interval -0.315 to -0.052, P = 0.008).
Zung SDS only significantly improved in men with increased fasting BDNF levels after a lifestyle intervention.
Trial registration
PMCID: PMC3925444  PMID: 24524285
Exercise; Lifestyle intervention; Obesity; Zung self-rating depression scale
8.  Trans-ethnic fine mapping identifies a novel independent locus at the 3′ end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population 
Diabetologia  2013;56(12):2619-2628.
Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.
A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.
We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10−12 for KCNQ1; p = 5.0 × 10−8 for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3′ end of CDKAL1.
These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-3047-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3825282  PMID: 24013783
Ethnic difference; Genetic association; Type 2 diabetes
9.  Chinese Medicinal Formula (MHGWT) for Relieving Diabetic Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled Trial 
Objective. To investigate the effects of modified Hungqi Guizhi Wuwu Tang (MHGWT), a formula that comprises Chinese medicinal herbs, in relieving neuropathic pain in diabetics. Method. Between March 2008 and April 2009, 112 participants were randomly assigned to either the MHGWT group, whose members received MHGWT (n = 56), or the control group, whose members received a placebo (n = 56). Diabetic neuropathic pain (DNP) was rated using the 15-item Short-Form Brief Pain Inventory (SF-BPI), the 17-item Short-Form McGill Pain Questionnaire (SF-MPQ), the 13-item Modified Michigan Neuropathy Screening Instrument (MMNSI), and the 36-item “SF-36.” Nerve conduction studies (NCSs) were performed before and after treatment. Results. After 12 weeks of treatment, the SF-MPQ and SF-BPI scores of the MHGWT group were significantly (P < 0.05) reduced and a significant difference between the groups was observed (P < 0.05). The levels of NCS in the MHGWT group were nonsignificantly (P > 0.05) reduced, and no significant difference in NCS level was observed between the groups (P > 0.05). Conclusions. MHGWT shows promise in relieving DNP and deserves further investigation.
PMCID: PMC3766986  PMID: 24062790
10.  Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained 
Wu, Ying | Waite, Lindsay L. | Jackson, Anne U. | Sheu, Wayne H-H. | Buyske, Steven | Absher, Devin | Arnett, Donna K. | Boerwinkle, Eric | Bonnycastle, Lori L. | Carty, Cara L. | Cheng, Iona | Cochran, Barbara | Croteau-Chonka, Damien C. | Dumitrescu, Logan | Eaton, Charles B. | Franceschini, Nora | Guo, Xiuqing | Henderson, Brian E. | Hindorff, Lucia A. | Kim, Eric | Kinnunen, Leena | Komulainen, Pirjo | Lee, Wen-Jane | Le Marchand, Loic | Lin, Yi | Lindström, Jaana | Lingaas-Holmen, Oddgeir | Mitchell, Sabrina L. | Narisu, Narisu | Robinson, Jennifer G. | Schumacher, Fred | Stančáková, Alena | Sundvall, Jouko | Sung, Yun-Ju | Swift, Amy J. | Wang, Wen-Chang | Wilkens, Lynne | Wilsgaard, Tom | Young, Alicia M. | Adair, Linda S. | Ballantyne, Christie M. | Bůžková, Petra | Chakravarti, Aravinda | Collins, Francis S. | Duggan, David | Feranil, Alan B. | Ho, Low-Tone | Hung, Yi-Jen | Hunt, Steven C. | Hveem, Kristian | Juang, Jyh-Ming J. | Kesäniemi, Antero Y. | Kuusisto, Johanna | Laakso, Markku | Lakka, Timo A. | Lee, I-Te | Leppert, Mark F. | Matise, Tara C. | Moilanen, Leena | Njølstad, Inger | Peters, Ulrike | Quertermous, Thomas | Rauramaa, Rainer | Rotter, Jerome I. | Saramies, Jouko | Tuomilehto, Jaakko | Uusitupa, Matti | Wang, Tzung-Dau | Boehnke, Michael | Haiman, Christopher A. | Chen, Yii-Der I. | Kooperberg, Charles | Assimes, Themistocles L. | Crawford, Dana C. | Hsiung, Chao A. | North, Kari E. | Mohlke, Karen L.
PLoS Genetics  2013;9(3):e1003379.
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.
Author Summary
Lipid traits are heritable, but many of the DNA variants that influence lipid levels remain unknown. In a genomic region, more than one variant may affect gene expression or function, and the frequencies of these variants can differ across populations. Genotyping densely spaced variants in individuals with different ancestries may increase the chance of identifying variants that affect gene expression or function. We analyzed high-density genotyped variants for association with TG, HDL-C, and LDL-C in African Americans, East Asians, and Europeans. At several genomic regions, we provide evidence that two or more variants can influence lipid traits; across loci, these additional signals increase the proportion of trait variation that can be explained by genes. At some association signals shared across populations, combining data from individuals of different ancestries narrowed the set of likely functional variants. At PCSK9 and APOA5, the data suggest that different variants influence trait levels in different populations. Variants previously reported to alter gene expression or function frequently exhibited the strongest association at those signals. The multiple signals and population-specific characteristics of the loci described here may be shared by genetic loci for other complex traits.
PMCID: PMC3605054  PMID: 23555291
11.  Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: Gene-environmental interaction with alcohol consumption 
Genetic 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.
Three 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.
Over 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.
ALDH2 genetic variants were associated with progression to hypertension in a prospective Chinese cohort. The association was modified by alcohol consumption.
PMCID: PMC3476438  PMID: 22839215
ALDH2; Hypertension; SNP; Chinese
12.  Central obesity is important but not essential component of the metabolic syndrome for predicting diabetes mellitus in a hypertensive family-based cohort. Results from the Stanford Asia-pacific program for hypertension and insulin resistance (SAPPHIRe) Taiwan follow-up study 
Metabolic abnormalities have a cumulative effect on development of diabetes, but only central obesity has been defined as the essential criterion of metabolic syndrome (MetS) by the International Diabetes Federation. We hypothesized that central obesity contributes to a higher risk of new-onset diabetes than other metabolic abnormalities in the hypertensive families.
Non-diabetic Chinese were enrolled and MetS components were assessed to establish baseline data in a hypertensive family-based cohort study. Based on medical records and glucose tolerance test (OGTT), the cumulative incidence of diabetes was analyzed in this five-year study by Cox regression models. Contribution of central obesity to development of new-onset diabetes was assessed in subjects with the same number of positive MetS components.
Among the total of 595 subjects who completed the assessment, 125 (21.0%) developed diabetes. Incidence of diabetes increased in direct proportion to the number of positive MetS components (P ≪ 0.001). Although subjects with central obesity had a higher incidence of diabetes than those without (55.7 vs. 30.0 events/1000 person-years, P ≪ 0.001), the difference became non-significant after adjusting of the number of positive MetS components (hazard ratio = 0.72, 95%CI: 0.45-1.13). Furthermore, in all participants with three positive MetS components, there was no difference in the incidence of diabetes between subjects with and without central obesity (hazard ratio = 1.04, 95%CI: 0.50-2.16).
In Chinese hypertensive families, the incidence of diabetes in subjects without central obesity was similar to that in subjects with central obesity when they also had the same number of positive MetS components. We suggest that central obesity is very important, but not the essential component of the metabolic syndrome for predicting of new-onset diabetes. (Trial registration: NCT00260910,
PMCID: PMC3476431  PMID: 22537054
Metabolic syndrome; Incidence; New-onset diabetes; Obesity

Results 1-12 (12)