Yen-Feng Chiu

ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment

Objective ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood–brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood–brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD). Methods Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S-CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8. Results The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety. Conclusion Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD.

Common PCSK1 haplotypes are associated with obesity in the Chinese population.

Prohormone convertase subtilisin/kexin type 1 (PCSK1) genetic polymorphisms have recently been associated with obesity in European populations. This study aimed to examine whether common PCSK1 genetic variation is associated with obesity and related metabolic phenotypes in the Chinese population. We genotyped nine common tag single‐nucleotide polymorphisms (tagSNP) of the PCSK1 gene in 1,094 subjects of Chinese origin from the Stanford Asia‐Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. One SNP in the PCSK1 gene (rs155971) were nominally associated with risk of obesity in the SAPPHIRe cohort (P = 0.01). A common protective haplotype was associated with reduced risk of obesity (23.79% vs. 32.89%, P = 0.01) and smaller waist circumference (81.71 ± 10.22 vs. 84.75 ± 10.48 cm, P = 0.02). Another common haplotype was significantly associated with increased risk of obesity (37.07% vs. 23.84%, P = 0.005). The global P value for haplotype association with obesity was 0.02. We also identified a suggestive association of another PCSK1 SNP (rs3811951) with fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMAIR), triglycerides, and high‐density lipoprotein cholesterol (P = 0.05, 0.003, 0.001, 0.04, and 0.04, respectively). These data indicate common PCSK1 genetic variants are associated with obesity in the Chinese population.

Replication of genome‐wide association signals of type 2 diabetes in Han Chinese in a prospective cohort

Background  A recent genome‐wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort.

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.

Taiwanese vegetarians and omnivores: dietary composition, prevalence of diabetes and IFG.

Introduction Vegetarian diets have been shown to improve glucose metabolism and reduce risk for diabetes in Westerners but whether Chinese vegetarian diets have the same benefits is unknown. Methods We evaluated the association between diet and diabetes/impaired fasting glucose (IFG) among 4384 Taiwanese Buddhist volunteers and identified diabetes/IFG cases from a comprehensive review of medical history and fasting plasma glucose. Results Vegetarians had higher intakes of carbohydrates, fiber, calcium, magnesium, total and non-heme iron, folate, vitamin A, and lower intakes of saturated fat, cholesterol, and vitamin B12. Besides avoiding meat and fish, vegetarians had higher intakes of soy products, vegetables, whole grains, but similar intakes of dairy and fruits, compared with omnivores. The crude prevalence of diabetes in vegetarians versus omnivores is 0.6% versus 2.3% in pre-menopausal women, 2.8% versus 10% in menopausal women, and 4.3% versus 8.1% in men. Polytomous logistic regression adjusting for age, body mass index, family history of diabetes, education, leisure time physical activity, smoking and alcohol, showed that this vegetarian diet was negatively associated with diabetes and IFG in men (OR for diabetes: 0.49, 95% CI: 0.28–0.89; OR for IFG: 0.66, 95% CI: 0.46–0.95); in pre-menopausal women (OR for diabetes: 0.26, 95% CI: 0.06–1.21; OR for IFG: 0.60, 95% CI: 0.35–1.04); and in menopausal women (OR for diabetes: 0.25, 95% CI: 0.15–0.42; OR for IFG: 0.73, 95% CI: 0.56–0.95). Conclusion We found a strong protective association between Taiwanese vegetarian diet and diabetes/IFG, after controlling for various potential confounders and risk factors.

Detecting Gene-Environment Interactions in Genome-Wide Association Data

Despite the importance of gene‐environment (G×E) interactions in the etiology of common diseases, little work has been done to develop methods for detecting these types of interactions in genome‐wide association study data. This was the focus of Genetic Analysis Workshop 16 Group 10 contributions, which introduced a variety of new methods for the detection of G×E interactions in both case‐control and family‐based data using both cross‐sectional and longitudinal study designs. Many of these contributions detected significant G×E interactions. Although these interactions have not yet been confirmed, the results suggest the importance of testing for interactions. Issues of sample size, quantifying the environmental exposure, longitudinal data analysis, family‐based analysis, selection of the most powerful analysis method, population stratification, and computational expense with respect to testing G×E interactions are discussed. Genet. Epidemiol. 33 (Suppl. 1):S68–S73, 2009.

Cross-sectional and longitudinal comparisons of metabolic profiles between vegetarian and non-vegetarian subjects: a matched cohort study

Several previous cross-sectional studies have shown that vegetarians have a better metabolic profile than non-vegetarians, suggesting that a vegetarian dietary pattern may help prevent chronic degenerative diseases. However, longitudinal studies on the impact of vegetarian diets on metabolic traits are scarce. We studied how several sub-types of vegetarian diets affect metabolic traits, including waist circumference, BMI, systolic blood pressure (SBP), diastolic blood pressure, fasting blood glucose, total cholesterol (TC), HDL, LDL, TAG and TC:HDL ratio, through both cross-sectional and longitudinal study designs. The study used the MJ Health Screening database, with data collected from 1994 to 2008 in Taiwan, which included 4415 lacto-ovo-vegetarians, 1855 lacto-vegetarians and 1913 vegans; each vegetarian was matched with five non-vegetarians based on age, sex and study site. In the longitudinal follow-up, each additional year of vegan diet lowered the risk of obesity by 7 % (95 % CI 0·88, 0·99), whereas each additional year of lacto-vegetarian diet lowered the risk of elevated SBP by 8 % (95 % CI 0·85, 0·99) and elevated glucose by 7 % (95 % CI 0·87, 0·99), and each additional year of ovo-lacto-vegetarian diet increased abnormal HDL by 7 % (95 % CI 1·03, 1·12), compared with non-vegetarians. In the cross-sectional comparisons, all sub-types of vegetarians had lower likelihoods of abnormalities compared with non-vegetarians on all metabolic traits (P<0·001 for all comparisons), except for HDL and TAG. The better metabolic profile in vegetarians is partially attributable to lower BMI. With proper management of TAG and HDL, along with caution about the intake of refined carbohydrates and fructose, a plant-based diet may benefit all aspects of the metabolic profile.

Induction chemotherapy with gemcitabine, oxaliplatin, and 5-fluorouracil/leucovorin followed by concomitant chemoradiotherapy in patients with locally advanced pancreatic cancer: a Taiwan cooperative oncology group phase II study.

PURPOSE To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS Chemonaïve patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m2) infusion at a fixed dose rate (10 mg/m2/min), followed by 85 mg/m2 oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m2) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m2 gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected for surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity. RESULTS Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2-42.5%) and 70% (95% CI, 44.4-99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8-12.8) months and 14.5 (95% CI, 11.9-17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. Neutropenia was the most common Grade 3-4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18%). CONCLUSION Three months of triplet ICT followed by gemcitabine-based CCRT is feasible, moderately active, and associated with encouraging survival in patients with LAPC.

SVM-based generalized multifactor dimensionality reduction approaches for detecting gene-gene interactions in family studies.

Gene‐gene interaction plays an important role in the etiology of complex diseases, which may exist without a genetic main effect. Most current statistical approaches, however, focus on assessing an interaction effect in the presence of the genes main effects. It would be very helpful to develop methods that can detect not only the genes main effects but also gene‐gene interaction effects regardless of the existence of the genes main effects while adjusting for confounding factors. In addition, when a disease variant is rare or when the sample size is quite limited, the statistical asymptotic properties are not applicable; therefore, approaches based on a reasonable and applicable computational framework would be practical and frequently applied. In this study, we have developed an extended support vector machine (SVM) method and an SVM‐based pedigree‐based generalized multifactor dimensionality reduction (PGMDR) method to study interactions in the presence or absence of main effects of genes with an adjustment for covariates using limited samples of families. A new test statistic is proposed for classifying the affected and the unaffected in the SVM‐based PGMDR approach to improve performance in detecting gene‐gene interactions. Simulation studies under various scenarios have been performed to compare the performances of the proposed and the original methods. The proposed and original approaches have been applied to a real data example for illustration and comparison. Both the simulation and real data studies show that the proposed SVM and SVM‐based PGMDR methods have great prediction accuracies, consistencies, and power in detecting gene‐gene interactions.

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.

BackgroundMetabolic 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.MethodsNon-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.ResultsAmong 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).ConclusionIn 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, ClinicalTrials.gov).