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Chiou K.-R.,Kaohsiung Veterans General Hospital | Chiou K.-R.,National Yang Ming University | Charng M.-J.,Taipei Veterans General Hospital | Charng M.-J.,National Yang Ming University | Chang H.-M.,Vita Genomics Inc.
Atherosclerosis | Year: 2011

Background: Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease with a prevalence of 1 in 500. To date, over 1200 unique pathogenic mutations have been identified in at least 3 genes. The large allelic and genetic heterogeneity of FH requires high-throughput, rapid, and affordable mutation detection technology to efficiently integrate molecular screening into clinical practice. We developed an array-based resequencing assay to facilitate genetic testing in FH patients. Methods and results: We designed a custom DNA resequencing array to detect mutations on all 3 FH-causing genes - LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) - and 290 known insertion/deletion mutations on LDLR. We verified FH array performance by analyzing 35 previously sequenced subjects (21 with point mutations, 2 insertions, 7 deletions, and 5 healthy controls) and blindly screening 125 FH patients. The average microarray call rate was 98.45% and the agreement between microarray and capillary sequencing was 99.99%. The FH array detected mutations by using automated software analysis, followed by manual review in 28 of the 30 subjects (pickup rate, 93.3%). In the blinded study, the FH array detected at least 1 mutation in 77.5% of patients clinically diagnosed with definite FH according to Simon Broome FH criteria and in 52.9% with probable FH diagnosis. Conclusions: The high-throughput FH resequencing array detects LDLR, APOB, and PCSK9 with high efficiency and accuracy and identifies disease-causing mutations. Thus, it facilitates large-scale screening of the heterogeneous FH populations. © 2011 Elsevier Ireland Ltd.


Lin E.,China Medical University at Taichung | Lin E.,Vita Genomics Inc. | Tsai S.-J.,Taipei Veterans General Hospital | Tsai S.-J.,National Yang Ming University
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2016

Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy. © 2015 Elsevier Inc.


Hsiao T.-J.,Taipei Medical University | Hwang Y.,Vita Genomics Inc | Liu C.-H.,Taipei Medical University Hospital | Chang H.-M.,Vita Genomics Inc | And 2 more authors.
Genes and Nutrition | Year: 2013

The relationship between obesity and a single nucleotide polymorphism (SNP), rs5443 (C825T), in the guanine nucleotide binding protein beta polypeptide 3 (GNB3) gene is currently inconsistent. In this study, we aimed to reassess whether the GNB3 rs5443 SNP could influence obesity and obesity-related metabolic traits in a Taiwanese population. A total of 983 Taiwanese subjects with general health examinations were genotyped. Based on the criteria defined by the Department of Health in Taiwan, the terms "overweight" and "obesity" are defined as 24 a BMI < 27 and BMI ≠§ 27, respectively. Compared to the carrier of the combined CT + TT genotypes of the GNB3 rs5443 polymorphism, triglyceride was significantly higher for the carrier of CC genotype in the complete sample population (128.2 ± 93.2 vs. 114.3 ± 79.1 mg/dl; P = 0.041). In addition, the carriers of CC variant had a higher total cholesterol than those with the combined CT + TT variants (194.5 ± 36.8 vs. 187.9 ± 33.0 mg/dl; P = 0.019) in the complete sample population. In the normal controls, both triglyceride (P = 0.018) and total cholesterol (P = 0.011) were also significantly higher in the CC homozygotes than in the combined CT + TT genotypes. However, the GNB3 rs5443 SNP did not exhibit any significant association with obesity or overweight among the subjects. Our study indicates that the CC genotype of the GNB3 rs5443 SNP may predict higher obesity-related metabolic traits such as triglyceride and total cholesterol in non-obese Taiwanese subjects (but not in obese subjects). © 2012 Springer-Verlag.


Lee S.-W.,Taoyuan General Hospital | Chung L.S.-C.,Vita Genomics Inc. | Huang H-H.,Taoyuan General Hospital | Chuang T.-Y.,Taoyuan General Hospital | And 3 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2010

BACKGROUND: Most cases with anti-tuberculosis druginduced hepatotoxicity (ATDH) have been attributed to isoniazid. OBJECTIVE: To evaluate whether the polymorphisms of the cytochrome P450 2EI (CYP2E1) and N-acetyltransferase 2 (NAT2) gene are associated with ATDH. DESIGN: A total of 140 tuberculosis (TB) patients without liver diseases before treatment who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using the TaqMan polymerase chain reaction assay. RESULTS: Forty-fi ve (32.1%) patients were diagnosed with ATDH. No signifi cant differences were reported in age and sex between patients with and without ATDH. Slow acetylators defi ned by NAT2 genotypes had a higher risk of hepatotoxicity than rapid acetylators (51.2% vs. 25.2%, P = 0.0026). Odds ratio (OR) analysis showed that slow acetylator status (OR 3.15, 95%CI 1.47-6.48) was the only independent risk factor for ATDH. Pyrazinamide co-administration induced hepatitis was also associated with NAT2 acetylator status. CYP2E1 c1/c1 homozygotes are prone to developing more severe hepatotoxicity than other c1/c2 and c2/c2 genotypes. CONCLUSION: The slow acetylator status of NAT2 is a signifi cant susceptibility risk factor for ATDH. CYP2E1 is associated with the severity of ATDH. © 2010 The Union.


Wang C.-H.,Tainan Municipal Hospital | Ke W.-S.,Kuang Tien General Hospital | Lin E.,China Medical University at Taichung | Lin E.,Vita Genomics Inc
Journal of Investigative Medicine | Year: 2012

Background: Addressing gene-gene interactions is essential in defining a trait implicating complex disease-related mechanisms. In this study, we aimed to explore both main effects of single-locus and multi-locus interactions to test the hypothesis that the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and perilipin (PLIN) genes may contribute to the etiology of type 2 diabetes (T2D) independently and/or through complex interactions in a Taiwanese population. Methods: There were 416 patients with a diagnosis of T2D and 188 ageand sex-similar control subjects. To investigate gene-gene interactions, we used both the generalized multifactor dimensionality reduction method and logistic regression models. Results: Allelic and genotypic analyses showed significant main effects of ENPP1 rs1044498 (P = 0.000005 and 0.00007, respectively) on the risk of T2D after Bonferroni correction (P < 0.05/2 = 0.025). Compared to the carrier of the AA genotype of the ENPP1 rs1044498 polymorphism, the likelihood of T2D was 2.442 (95% confidence interval, 1.592-3.747) for the carrier of combined AC+CC genotypes after adjustment of sex and body mass index. In addition, the carriers of AA variant in the PLIN rs894160 polymorphism had a higher risk to T2D than those with the combined AG+GG variants (adjusted odds ratio, 1.856; 95% confidence interval, 1.106-3.115) after adjustment of sex and body mass index. Furthermore, the significant 2-locus (P = 0.001) generalized multifactor dimensionality reduction model was identified between ENPP1 and PLIN. Analyses using logistic regression models confirmed the gene-gene interaction. Conclusions: The results suggest that the ENPP1 and PLIN genes may contribute to the risk of T2D independently and/or in an interactive manner in a Taiwanese population. Copyright © 2012 American Federation for Medical Research.


Ke W.-S.,Kuang Tien General Hospital | Hwang Y.,Vita Genomics Inc. | Lin E.,Vita Genomics Inc.
Advances and Applications in Bioinformatics and Chemistry | Year: 2010

Chronic hepatitis C (CHC) patients often stop pursuing interferon-alfa and ribavirin (IFN-alfa/RBV) treatment because of the high cost and associated adverse effects. It is highly desirable, both clinically and economically, to establish tools to distinguish responders from nonresponders and to predict possible outcomes of the IFN-alfa/RBV treatments. Single nucleotide polymorphisms (SNPs) can be used to understand the relationship between genetic inheritance and IFN-alfa/RBV therapeutic response. The aim in this study was to establish a predictive model based on a pharmacogenomic approach. Our study population comprised Taiwanese patients with CHC who were recruited from multiple sites in Taiwan. The genotyping data was generated in the high-throughput genomics lab of Vita Genomics, Inc. With the wrapper-based feature selection approach, we employed multilayer feedforward neural network (MFNN) and logistic regression as a basis for comparisons. Our data revealed that the MFNN models were superior to the logistic regression model. The MFNN approach provides an efficient way to develop a tool for distinguishing responders from nonresponders prior to treatments. Our preliminary results demonstrated that the MFNN algorithm is effective for deriving models for pharmacogenomics studies and for providing the link from clinical factors such as SNPs to the responsiveness of IFN-alfa/RBV in clinical association studies in pharmacogenomics. © 2010 Ke et al, publisher and licensee Dove Medical Press Ltd.


Hsiao T.-J.,Taipei Medical University | Hwang Y.,Vita Genomics Inc. | Chang H.-M.,Vita Genomics Inc. | Lin E.,Vita Genomics Inc. | Lin E.,China Medical University at Taichung
Gene | Year: 2014

One particularly interesting single nucleotide polymorphism (SNP), rs6235 (encoding an S690T substitution), in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene has been widely associated with obesity in several European cohorts. The present study was intended to investigate the association between the PCSK1 rs6235 SNP and the prevalence of overweight or obesity, or obesity-related metabolic traits in a Taiwanese population. A total of 964 Taiwanese subjects with general health examinations were analyzed. Our data revealed no association of PCSK1 rs6235 with the risk of obesity or overweight in the complete subjects. However, the PCSK1 rs6235 SNP exhibited a significant association with overweight among the male subjects (P. = 0.03), but not among the female subjects. Furthermore, the carriers of GG variant had a significantly higher waist circumference than those with the CC variant (82.5. ±. 11.5 vs. 81.2. ±. 10.2. cm; P. = 0.01) and those with the CG variant (82.5. ±. 11.5 vs. 81.4. ±. 10.4. cm; P. = 0.021). In addition, the carriers of GG variant had a higher diastolic blood pressure than those with the CC variant (81.9. ±. 14.2 vs. 80.3. ±. 12.9. mm. Hg; P. = 0.023). Our study indicates that the PCSK1 rs6235 SNP may contribute to the risk of overweight in men and predict obesity-related metabolic traits such as waist circumference and diastolic blood pressure in Taiwanese subjects. © 2013 Elsevier B.V.


Hsiao T.-J.,Taipei Medical University | Lin E.,Vita Genomics Inc. | Lin E.,China Medical University at Taichung
Journal of Investigative Medicine | Year: 2014

Background: The single-nucleotide polymorphism (SNP), rs1042714 or glutamine 27 glutamic acid (Gln27Glu), in the adrenoceptor β2 surface (ADRB2) gene has previously been examined for association with obesity with inconclusive results. The objective of this study was to determine whether the ADRB2 rs1042714 SNP could influence obesity and obesity-related metabolic traits in a Taiwanese population. Methods: The ADRB2 rs1042714 SNP and obesity-related metabolic traits including blood pressure, total cholesterol, triglyceride, fasting glucose, waist circumference, and body mass index (BMI) were examined in 967 individuals with general health examinations. Results: Our data revealed that the ADRB2 rs1042714 SNP exhibited a significant association with obesity among the subjects (P = 0.021). Furthermore, the carriers of the GG genotype had a significantly higher BMI than those with the CC genotype (26.0 ± 5.6 vs 24.3 ± 3.8 kg/m2; P = 0.009) and those with the CG genotype (26.0 ± 5.6 vs 23.6 ± 3.3 kg/m2; P = 0.001). We also found a nominal association with systolic blood pressure (P = 0.058) and triglyceride (P = 0.055) levels in the ADRB2 rs1042714 SNP. Conclusions: Our study indicates that the ADRB2 rs1042714 SNP may contribute to the risk of obesity and predict obesity-related metabolic traits such as BMI, triglyceride, and systolic blood pressure in Taiwanese subjects. Copyright © 2014 by The American Federation for Medical Research.


Hsiao T.-J.,Taipei Medical University | Lin E.,China Medical University at Taichung | Lin E.,Vita Genomics Inc
Endocrine | Year: 2014

Obesity is considered as an important public health problem in the world. Although the association of a common single nucleotide polymorphism (SNP), rs1801282 (Pro12Ala), in the peroxisome proliferator-activated receptor gamma (PPARG) gene with obesity has been reported in various populations, these data are not conclusive. This study aimed to reassess whether the PPARG rs1801282 SNP is linked with obesity and obesity-related metabolic traits in a Taiwanese population. A total of 674 Taiwanese subjects with general health examinations were genotyped. The rs1801282 genotype was determined by the Taqman SNP genotyping assay. Obesity-related metabolic traits such as triglyceride, waist circumference, systolic and diastolic blood pressure, total cholesterol, and fasting glucose were measured. The PPARG rs1801282 SNP did not exhibit any significant association with obesity among the complete sample population. However, sex-stratified analyses revealed an effect on overweight in female participants where the carriers of the combined CG and GG genotypes had a higher risk to overweight than those with the CC homozygotes (OR = 4.05; 95 % CI = 1.28-12.83; P = 0.017). Compared to the carriers of CC homozygotes, BMI was significantly higher for the carriers of the combined CG and GG genotypes in the female subjects (24.4 ± 3.7 vs. 23.5 ± 3.8 kg/m2; P = 0.033). In addition, the carriers of the CC homozygotes had a higher total cholesterol level than those with the combined CG and GG genotypes in the female subjects (197.0 ± 37.3 vs. 180.7 ± 33.7 mg/dl; P = 0.026). Our study indicates that PPARG rs1801282 may significantly predict overweight, BMI, and total cholesterol in female but not male Taiwanese subjects. © 2014 Springer Science+Business Media New York.


Lin E.,China Medical University at Taichung | Lin E.,Vita Genomics Inc. | Lane H.-Y.,China Medical University at Taichung
Pharmacogenomics | Year: 2015

Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Doctors must prescribe antidepressants based on educated guesses due to the fact that it is unmanageable to predict the effectiveness of any particular antidepressant in an individual patient. With the recent advent of scientific research, the genome-wide association study (GWAS) is extensively employed to analyze hundreds of thousands of single nucleotide polymorphisms by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been utilized to investigate the determinants of antidepressant response to therapy. In this study, we reviewed GWAS studies, their limitations and future directions with respect to the pharmacogenomics of antidepressants in MDD. © 2015 Future Medicine Ltd.

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