Biomedical subjects

Hui-Ju Tsai

Publications and source records attributed to Hui-Ju Tsai.

16 recordsLinked to original sources

PubMed2006

The PTGDR gene is not associated with asthma in 3 ethnically diverse populations.

BACKGROUND: The prostanoid DP receptor (PTGDR) gene on chromosome 14q22.1 has been identified as an asthma susceptibility gene. A haplotype with decreased transcription factor binding and transcription efficiency was associated with decreased asthma susceptibility in African American and white subjects. The significance of PTGDR gene variants in asthma has yet to be determined in Latinos, the largest US minority population, nor has the association been replicated in other populations. OBJECTIVE: To determine the role of PTGDR gene variants in asthma susceptibility and asthma-related traits among the Mexican, Puerto Rican, and African American populations. METHODS: We determined whether single nucleotide polymorphisms (SNPs) and haplotypes in PTGDR were associated with asthma and asthma-related traits by family-based and cross-sectional cohort analyses in 336 Puerto Rican and 273 Mexican asthmatic trios and by case-control analysis among African American subjects with asthma and healthy controls (n = 352). RESULTS: We identified 13 SNPs in the PTGDR gene, and 6 were further analyzed. There was no significant association between PTGDR variants and asthma by family-based or case-control analyses. SNPs -441C and -197C and haplotype TTT showed marginal association with asthma-related traits in Mexican subjects. SNP -441 genotype TT (P = .05) and haplotype TTT (P = .02) were associated with increased IgE levels in African Americans. CONCLUSION: We conclude that the PTGDR gene is not a significant risk factor for asthma among Puerto Ricans, Mexicans, or African Americans. CLINICAL IMPLICATIONS: Asthma candidate genes provide insights to pathophysiology and potentially new therapeutic targets, although the PTGDR gene was not found to be a significant risk factor for asthma in 3 populations.

Adolescent↗

PubMed2006

Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics.

Beta2-adrenergic receptor (beta2AR) gene polymorphisms have been reported to be associated with various asthma-related traits in different racial/ethnic populations. However, it is unknown whether beta2AR genetic variants are associated with asthma in African Americans. In this study, we have examined whether there is association between beta2AR genetic variants and asthma in African Americans. We have recruited 264 African American asthmatic subjects and 176 matched healthy controls participating in the Study of African Americans, Asthma, Genes and Environments (SAGE). We genotyped seven known and recently identified beta2AR SNP variants, then tested genotype and haplotype association of asthma-related traits with the beta2AR SNPs in our African American cohort with adjustment of confounding effect due to admixture background and environmental risk factors. We found a significant association of the SNP -47 (Arg-19Cys) polymorphism with DeltaFEF(25-75), a measure of bronchodilator drug responsiveness, in African American asthmatics after correction for multiple testing (P = 0.001). We did not observe association of the SNP +46 (Arg16Gly) variant with asthma disease diagnosis and asthma-related phenotypes. In contrast to previous results between the Arg16Gly variant and traits related to bronchodilator responsiveness, our results indicate that the Arg-19Cys polymorphism in beta upstream peptide may play an important role in bronchodilator drug responsiveness in African American subjects. Our findings highlight the importance of investigating genetic risk factors for asthma in different populations.

Adolescent↗

PubMed2006

Comparison of methods incorporating quantitative covariates into affected sib pair linkage analysis.

For complex traits, it may be possible to increase the power to detect linkage if one takes advantage of covariate information. Several statistics have been proposed that incorporate quantitative covariate information into affected sib pair (ASP) linkage analysis. However, it is not clear how these statistics perform under different gene-environment (G x E) interactions. We compare representative statistics to each other on simulated data under three biologically-plausible G x E models. We also compared their performance with a model-free method and with quantitative trait locus (QTL) linkage approaches. The statistics considered here are: (1) mixture model; (2) general conditional-logistic model (LODPAL); (3) multinomial logistic regression models (MLRM); (4) extension of the maximum-likelihood-binomial approach (MLB); (5) ordered-subset analysis (OSA); and (6) logistic regression modeling (COVLINK). In all three G x E models, most of these six statistics perform better when using the covariate C1 associated with a G x E interaction effect than when using the environmental risk factor C2 or the random noise covariate C3. Compared with a model-free method without covariates (S(all)), the mixture model performs the best when using C1, with the high-to-low OSA method also performing quite well. Generally, MLB is the least sensitive to covariate choice. However, most of these statistics do not provide better power than S(all). Thus, while inclusion of the "correct" covariate can lead to increased power, careful selection of appropriate covariates is vital for success.

Analysis of Variance↗

PubMed2005

Analysis of alcohol dependence phenotype in the COGA families using covariates to detect linkage.

Linkage analysis methods that incorporate etiological heterogeneity of complex diseases are likely to demonstrate greater power than traditional linkage analysis methods. Several such methods use covariates to discriminate between linked and unlinked pedigrees with respect to a certain disease locus. Here we apply several such methods including two mixture models, ordered subset analysis, and a conditional logistic model to genome scan data on the DSM-IV alcohol dependence phenotype on the Collaborative Studies on Genetics of Alcoholism families, and compare the results to traditional nonparametric linkage analysis. In general, there was little agreement among the various covariate-based linkage statistics. Linkage signals with empirical p-values less than 0.001 were detected on chromosomes 3, 4, 7, 10, and 12, with the highest peak occurring at the GABRB1 gene using the ecb21 covariate.

Alcoholism↗

PubMed2005

Population stratification confounds genetic association studies among Latinos.

In the United States, asthma prevalence and mortality are the highest among Puerto Ricans and the lowest among Mexicans. Case-control association studies are a powerful strategy for identifying genes of modest effect in complex diseases. However, studies of complex disorders in admixed populations such as Latinos may be confounded by population stratification. We used ancestry informative markers (AIMs) to identify and correct for population stratification among Mexican and Puerto Rican subjects participating in case-control studies of asthma. Three hundred and sixty-two subjects with asthma (Mexican: 181, Puerto Rican: 181) and 359 ethnically matched controls (Mexican: 181, Puerto Rican: 178) were genotyped for 44 AIMs. We observed a greater than expected degree of association between pairs of AIMs on different chromosomes in Mexicans (P < 0.00001) and Puerto Ricans (P < 0.00002) providing evidence for population substructure and/or recent admixture. To assess the effect of population stratification on association studies of asthma, we measured differences in genetic background of cases and controls by comparing allele frequencies of the 44 AIMs. Among Puerto Ricans but not in Mexicans, we observed a significant overall difference in allele frequencies between cases and controls (P = 0.0002); of 44 AIMs tested, 8 (18%) were significantly associated with asthma. However, after adjustment for individual ancestry, only two of these markers remained significantly associated with the disease. Our findings suggest that empirical assessment of the effects of stratification is critical to appropriately interpret the results of case-control studies in admixed populations.

Alleles↗

PubMed2005

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations.

Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which, cases and controls are matched by admixture, can be an appealing and a suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments. Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is a substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV(1), a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P=0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, beta(2) adrenergic receptor (beta(2)AR) and DeltaFEF(25-75), an asthma-related phenotype, as an example, we demonstrated population stratification was not a confounder in our genetic association. Our present work demonstrates that admixture-matched case-control strategies can efficiently control population stratification confounding in admixed populations.

Adolescent↗

PubMed2005

Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research.

Latinos are the largest minority population in the United States. Although usually classified as a single ethnic group by researchers, Latinos are heterogeneous from cultural, socioeconomic, and genetic perspectives. From a cultural and social perspective, Latinos represent a wide variety of national origins and ethnic and cultural groups, with a full spectrum of social class. From a genetic perspective, Latinos are descended from indigenous American, European, and African populations. We review the historical events that led to the formation of contemporary Latino populations and use results from recent genetic and clinical studies to illustrate the unique opportunity Latino groups offer for studying the interaction between racial, genetic, and environmental contributions to disease occurrence and drug response.

Asthma↗

PubMed2005

Comparison of three methods to estimate genetic ancestry and control for stratification in genetic association studies among admixed populations.

Population stratification may confound the results of genetic association studies among unrelated individuals from admixed populations. Several methods have been proposed to estimate the ancestral information in admixed populations and used to adjust the population stratification in genetic association tests. We evaluate the performances of three different methods: maximum likelihood estimation, ADMIXMAP and Structure through various simulated data sets and real data from Latino subjects participating in a genetic study of asthma. All three methods provide similar information on the accuracy of ancestral estimates and control type I error rate at an approximately similar rate. The most important factor in determining accuracy of the ancestry estimate and in minimizing type I error rate is the number of markers used to estimate ancestry. We demonstrate that approximately 100 ancestry informative markers (AIMs) are required to obtain estimates of ancestry that correlate with correlation coefficients more than 0.9 with the true individual ancestral proportions. In addition, after accounting for the ancestry information in association tests, the excess of type I error rate is controlled at the 5% level when 100 markers are used to estimate ancestry. However, since the effect of admixture on the type I error rate worsens with sample size, the accuracy of ancestry estimates also needs to increase to make the appropriate correction. Using data from the Latino subjects, we also apply these methods to an association study between body mass index and 44 AIMs. These simulations are meant to provide some practical guidelines for investigators conducting association studies in admixed populations.

Asthma↗

PubMed2005

CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma.

BACKGROUND: A recent family-based genomewide screen revealed linkage between the 5q31 region and the diagnosis of asthma, but only in those exposed to environmental tobacco smoke (ETS). Among the candidate genes in this region is CD14. METHODS: To determine whether polymorphisms in the CD14 gene are related to this gene-by-environment interaction in Latinos, we used both family-based and cross-sectional cohort analysis to test for interactions between CD14 genotypes/haplotypes, exposure to ETS, and asthma-related phenotypes in 659 Mexican and Puerto Rican families. RESULTS: We identified 21 single nucleotide polymorphisms (SNPs) in the CD14 gene by sequencing 72 Puerto Ricans, Mexicans, and African Americans with asthma. Three SNPs, -810, -159, and +1437, were further genotyped in families with asthma. Among all subjects with asthma exposed to ETS, without regard to ethnicity, CD14 +1437 genotypes were associated with asthma severity. SNP +1437 GG or GC genotypes were significantly associated with lower baseline FEV1 using both family-based (p = 0.0009) and cross-sectional cohort (p = 0.03) analyses. Subjects with asthma with the GG or GC genotypes who were exposed to ETS had mean baseline FEV1 (% predicted) values 8.6% lower than subjects not exposed to ETS (p = 0.03). As previously observed in whites, we found an interaction between plasma IgE levels, SNP -159 genotypes, and ETS exposure (p = 0.0002). The lowest IgE levels were in those subjects with the TT genotype and who were exposed to ETS regardless of ethnicity. CONCLUSIONS: Our data suggest a gene-by-environment interaction between CD14 genotypes and ETS, which affects pulmonary function and IgE levels among Latinos with asthma.

Adolescent↗

PubMed2004

Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions.

Age-related maculopathy (ARM), or age-related macular degeneration, is one of the most common causes of visual impairment in the elderly population of developed nations. In a combined analysis of two previous genomewide scans that included 391 families, containing up to 452 affected sib pairs, we found linkage evidence in four regions: 1q31, 9p13, 10q26, and 17q25. We now have added a third set of families and have performed an integrated analysis incorporating 530 families and up to 736 affected sib pairs. Under three diagnostic models, we have conducted linkage analyses using parametric (heterogeneity LOD [HLOD] scores under an autosomal dominant model) and nonparametric (Sall statistic) methods. There is ongoing evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. If we treat the third set of families as a replication set, then two regions (10q26 and 17q25) are replicated, with LOD scores >1.0. If we pool all our data together, then four regions (1q31, 2q14.3, 10q26, and 17q25) show HLOD or Sall scores > or =2.0. Within the 1q31 region, we observed an HLOD of 2.72 (genomewide P=.061) under our least stringent diagnostic model, whereas the 17q25 region contained a maximal HLOD of 3.53 (genomewide P=.007) under our intermediate diagnostic model. We have evaluated our results with respect to the findings from several new independent genomewide linkage studies and also have completed ordered subset analyses (OSAs) with apolipoprotein E alleles, smoking history, and age at onset as stratifying covariates. The OSAs generate the interesting hypothesis that the effect of smoking on the risk of ARM is accentuated by a gene in the 10q26 region--a region implicated by four other studies.

Chromosomes, Human, Pair 1↗

PubMed2004

Distribution of genome-wide linkage disequilibrium based on microsatellite loci in the Samoan population.

Whole genome-wide scanning for susceptibility loci based on linkage disequilibrium (LD) has been proposed as a powerful strategy for mapping common complex diseases, especially in isolated populations. We recruited 389 individuals from 175 families in the US territory of American Samoa, and 96 unrelated individuals from American Samoa and the independent country of Samoa in order to examine background LD by using a 10 centimorgan (cM) map containing 381 autosomal and 18 X-linked microsatellite markers. We tested the relationship between LD and recombination fraction by fitting a regression model. We estimated a slope of -0.021 (SE 0.00354; p<0.0001). Based on our results, LD in the Samoan population decays steadily as the recombination fraction between autosomal markers increases. The patterns of LD observed in the Samoan population are quite similar to those previously observed in Palau but markedly contrast with those observed in a non-isolated Caucasian sample, where there is essentially no marker-to-marker LD. Our analyses support the hypothesis of a recent bottleneck, which is consistent with the known demographic history of the Samoan population. Furthermore, population substructure tests support the hypothesis that self-identified Samoans represent one homogenous genetic population.

Chromosomes, Human, X↗

PubMed2004

Clinical and pathological correlation of the microdeletion of Y chromosome for the 30 patients with azoospermia and severe oligoasthenospermia.

AIM: To review the accumulated 30 patients with different area of Y chromosome microdeletions, focusing on their correlation with the clinical and pathological findings. METHODS: A total of 334 consecutive infertile men with azoospermia (218 patients) and severe oligoasthenospermia (116 patients) were screened. Complete physical and endocrinological examinations, general chromosome study and multiplex polymerase chain reaction assay to evaluate the Y chromosome microdeletion were performed. Ten patients received testicular biopsy. Then the clinical and pathological findings were analyzed with reference to the areas of Y chromosome microdeletion. RESULTS: There is a decline of the percentage of sperm appearing in semen in the group that the gene deletion region from AZFc to AZFb. The clinical evidence of the impairment (decreased testicular size and elevated serum FSH) is also relevantly aggravated in this group. However, the pathology of testicular biopsy specimen was poorly correlated with the different deletion areas of the Y chromosome, which may be due to the limited number of specimens. CONCLUSION: The clinical correlation of spermatogenic impairment to the different AZF deletion regions may provide the information for the infertile couples in pre-treatment counseling.

Adult↗

PubMed2003

Initial otolaryngological manifestations of severe acute respiratory syndrome in Taiwan.

OBJECTIVE: To provide a clue for screening severe acute respiratory syndrome (SARS), a highly transmissible disease with health care workers at particular risk, in the early stage from an otolaryngological perspective. DESIGN: Prospective study. SETTING: Community hospital. PATIENTS: Between April 17 and April 26, 2003, 32 consecutive patients with SARS were encountered. Investigation consisted of local examination of ear, nose, and throat fields; palpation of the nuchal areas; and plain chest radiography. Analyses of throat swab samples using reverse transcription-polymerase chain reaction were conducted. RESULTS: Clinical manifestations included fever in 31 patients (97%), followed by cough, dyspnea, chill, headache, sore throat, diarrhea, rhinorrhea, and otalgia. Neither the pharyngeal wall nor the tonsillar area demonstrated hyperemia. There was no lymphadenopathy in the neck. Plain chest radiographs revealed consolidation in 25 (78%) of 32 patients. Results of reverse transcription-polymerase chain reaction analysis targeting the novel coronavirus present in throat swab samples were positive in 19 (66%) of 29 patients tested. Twenty-eight patients required supplemental oxygen, and 14 patients were intubated with mechanical ventilation. Twenty-eight patients survived and 4 patients died. CONCLUSIONS: When presented with a patient with flulike symptoms such as fever and/or cough, but no pharyngeal hyperemia or neck lymphadenopathy, physicians should be alerted to the possibility of SARS. In contrast, evidence of inflammatory signs in the otolaryngological field may explain the flulike symptoms, and serve as a differential diagnostic tool between influenza and SARS.

Adolescent↗

PubMed2003

Effects of dietary arginine supplementation on antibody production and antioxidant enzyme activity in burned mice.

This study investigated the effect of arginine (Arg) supplementation on specific antibody production and antioxidant enzyme activities in burned mice vaccinated with detoxified Pseudomonas exotoxin A linked with the outer membrane proteins I and F, named PEIF. Also, the survival rate of burned mice complicated with Pseudomonas aeruginosa was evaluated. Experiment 1: Thirty BALB/c mice were assigned to two groups. One group was fed a control diet with casein as the protein source, while the other group was supplemented with 2% Arg in addition to casein. The two groups were isonitrogenous. The mice were immunized twice with PEIF, and the production of specific antibodies against PEIF was measured every week. After 8 weeks, all mice received a 30% body surface area burn injury. Mice were sacrificed 24h after the burn. The antioxidant enzyme activities and lipid peroxides in the tissues as well as the specific antibody production were analyzed. Experiment 2: Twenty-eight mice were divided into two groups and vaccinated as described in experiment 1. After the burn the mice were infected with P. aeruginosa, and the survival rate was observed for 8 days. The results demonstrated that antioxidant enzyme activities and lipid peroxides in tissues were significantly lower in the Arg group than in the control group after the burn. The production of specific antibodies against P. aeruginosa significantly increased in the Arg group at 4 and 7 weeks after immunization, and 24h after the burn. The survival rates of vaccinated burned mice after bacterial infection did not significantly differ between the two groups. These results suggest that vaccinating mice with Arg supplementation may enhance humoral immunity and attenuate the oxidative stress induced by burn injury. However, Arg supplementation did not improve survival in vaccinated mice complicated with P. aeruginosa infection.

Animals↗

PubMed2002

Effects of arginine supplementation on antioxidant enzyme activity and macrophage response in burned mice.

This study investigated the effect of arginine (Arg) supplementation on antioxidant enzyme activities and macrophage response in burned mice. Experiment 1: 60 male BALB/c mice were assigned to two groups. One group was fed a control diet with casein as the protein source, the other group was supplemented with 2% Arg in addition to casein. The two groups were isonitrogenous. After 4 weeks, all mice received a 30% body surface area burn injury. The antioxidant enzyme activities and lipid peroxides in the tissues were analyzed. Experiment 2: 20 mice were divided into two groups and burn injury was induced after feeding for 4 weeks as described in experiment 1. Twenty-four hours after the burn, tumor necrosis factor-alpha (TNF-alpha) secreted by cultured peritoneal macrophages was measured. The results show that antioxidant enzyme activities and lipid peroxides in tissues tended to be lower in the Arg group than in the control group after the burn. Production of TNF-alpha by peritoneal macrophages after stimulation with lipopolysacchride (LPS) was significantly elevated in the Arg group, whereas no response was observed in the control group. These results suggest that dietary Arg supplementation attenuates the oxidative stress induced by burn injury, and a better macrophage response was observed when Arg was administered.

Animals↗

PubMed2002

Clustering and heritability of insulin resistance in Chinese and Japanese hypertensive families: a Stanford-Asian Pacific Program in Hypertension and Insulin Resistance sibling study.

The clustering between hypertension and other metabolic abnormalities related to insulin resistance syndrome (IRS) has been investigated in cross-sectional and prospective studies. Offspring studies have revealed that the clustering characteristics of IRS have familial components. However, it is not known whether the clustering also occurs in siblings (sibs) with different levels of blood pressure (BP). In addition, the genetic susceptibility accounting for the clustering in hypertensive families has not been determined. Siblings with Japanese or Chinese ancestry and having either similar BP levels (concordant sibs) or different BP levels (discordant sibs) were recruited. The delta method and variance component model were applied to analyze the differences in metabolic variables between hypertension (HTN) and low BP (LBP) sibs, and to compute the polygenic heritabilities for these metabolic variables and insulin sensitivity. After adjustment for age, gender and body mass index (BMI), HTN (n=393) sibs had higher levels of triglyceride (p < 0.0001), VLDL-cholesterol (p<0.0001), fasting insulin (p < 0.05), and homeostasis model assessment of insulin resistance (HOMAir) (p < 0.05) than LBP sibs (n = 389), but there were no differences in fasting glucose or high density lipoprotein (HDL)-cholesterol. The HTN sibs also had higher plasma glucose and insulin levels at 2 h after 75 g oral glucose loading (p<0.001 and p<0.01, respectively). The heritability estimates for fasting glucose, fasting insulin and HOMAir were 0.58, 0.43 and 0.46, respectively; for triglyceride, HDL-cholesterol, and BMI they were 0.60, 0.63 and 0.54, respectively. In hypertensive families, sibs with extreme levels of BP have significant differences in IRS-associated metabolic variables. The clustering characteristics and the significance of heritability estimation for these metabolic variables indicate that IRS is familial in nature and heritable in Chinese and Japanese hypertensive families.

Adult↗