Biomedical subjects

Xiaofeng Zhu

Publications and source records attributed to Xiaofeng Zhu.

At least 19 recordsLinked to original sources

PubMed2026

Chronic ethanol exposure alters the expression of genes associated with GPCR-related signaling in the olfactory bulb of male mice.

Chronic ethanol exposure, a key feature of alcohol use disorder (AUD), can affect the nervous system, but its molecular impact on the olfactory bulb remains unclear. In this study, an intermittent two-bottle voluntary drinking model was established in male mice, and transcriptome sequencing was performed on olfactory bulb tissues. DESeq2 analysis identified 188 differentially expressed genes, including 68 upregulated and 120 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway database (Reactome) analyses indicated that ethanol-responsive genes were predominantly enriched in receptor-mediated signaling pathways, particularly those linked to G protein-coupled receptor (GPCR) signaling. Protein-protein interaction analysis further identified eight core GPCR-related genes. Quantitative real-time PCR (qRT-PCR) validation revealed that Cxcl10, Grp, Pcp2, and Pdyn were markedly downregulated in the ethanol group. These results suggest that chronic ethanol exposure is associated with transcriptional alterations in the male mouse olfactory bulb and may selectively affect several GPCR-related signaling components. This study provides candidate molecular evidence for further investigation of ethanol-associated olfactory dysfunction.

Chronic ethanol exposure↗

PubMed2026

Partitioned blood pressure polygenic risk reveals differential genetic effects of tissue-specific enhancers and their interactions on cardiovascular disease.

Polygenic risk scores (PRS) compress genome-wide associations into a single predictor, but this aggregation obscures the distinct biological mechanisms through which genetic variation shapes complex traits. Here we introduce a framework that additively decomposes a trait's PRS, without loss of SNP heritability, into independent components defined by the tissue-specific and tissue-agnostic cis-regulatory elements (CREs) in which its variants act. Applied to blood pressure (BP) using ~0.5 million CREs across four BP-relevant tissues (adrenal gland, artery, heart, kidney), the framework reveals that regulatory effects are globally additive across tissues yet locally non-additive, and that the resulting partitioned scores carry pronounced, reproducible heterogeneity in their effects on BP and cardiovascular outcomes. We show this heterogeneity reflects gene-environment interactions, and trace one example to its mechanism: a kidney-CRE-partitioned score is protective against coronary artery disease and myocardial infarction through an interaction between ATP2B1 and antihypertensive medication. Explicitly modeling these interactions improves prediction and transferability, and tissue-focused partitioning increases power to resolve causal genes and reveals genes such as ADAMTS8 with antagonistic effects across BP components. Validated in an independent All of Us cohort, these findings recast the PRS from a blunt aggregate predictor into a mechanistic probe of context-dependent genetic architecture.

Journal Article↗

PubMed2006

Transferability of tag SNPs in genetic association studies in multiple populations.

A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.

Breast Neoplasms↗

PubMed2006

Analytical correction for multiple testing in admixture mapping.

Admixture mapping, using unrelated individuals from the admixture populations that result from recent mating between members of each parental population, is an efficient approach to localize disease-causing variants that differ in frequency between two or more historically separated populations. Recently, several methods have been proposed to test linkage between a susceptibility gene and a disease locus by using admixture-generated linkage disequilibrium (LD) for each of the genotyped markers. In a genome scan, admixture mapping usually tests 2,000 to 3,000 markers across the genome. Currently, either a very conservative Sidak (or Bonferroni) correction or a very time consuming simulation-based method is used to correct for the multiple tests and evaluate the overall p value. In this report, we propose a computationally efficient analytical approach for correction of the multiple tests and for calculating the overall p value for an admixture genome scan. Except for the Sidak (or Bonferroni) correction, our proposed method is the first analytical approach for correction of the multiple tests and for calculating the overall p value for a genome scan. Our simulation studies show that the proposed method gives correct overall type I error rates for genome scans in all cases, and is much more computationally efficient than simulation-based methods.

Computational Biology↗

PubMed2006

A classical likelihood based approach for admixture mapping using EM algorithm.

Several disease-mapping methods have been proposed recently, which use the information generated by recent admixture of populations from historically distinct geographic origins. These methods include both classic likelihood and Bayesian approaches. In this study we directly maximize the likelihood function from the hidden Markov Model for admixture mapping using the EM algorithm, allowing for uncertainty in model parameters, such as the allele frequencies in the parental populations. We determined the robustness of the proposed method by examining the ancestral allele frequency estimate and individual marker-location specific ancestry when the data were generated by different population admixture models and no learning sample was used. The proposed method outperforms a widely used Bayesian MCMC strategy for data generated from various population admixture models. The multipoint information content for ancestry was derived based on the map provided by Smith et al. (2004) and the associated statistical power was calculated. We examined the distribution of admixture LD across the genome for both real and simulated data and established a threshold for genome wide significance applicable to admixture mapping studies. The software ADMIXPROGRAM for performing admixture mapping is available from authors.

Algorithms↗

PubMed2006

Minicircle-IFNgamma induces antiproliferative and antitumoral effects in human nasopharyngeal carcinoma.

PURPOSE: The aims of this work were to investigate the antitumor effect of IFNgamma gene transfer on human nasopharyngeal carcinoma (NPC) and to assess the potential of minicircle vector for antitumor gene therapy. EXPERIMENTAL DESIGN: We developed a recombinant minicircle vector carrying the human IFNgamma gene and evaluated the effects of minicircle-mediated IFNgamma gene transfer on NPC cell lines in vitro and on xenografts in vivo. RESULTS: Relative to p2PhiC31-IFNgamma, minicircle-mediated IFNgamma gene transfer in vitro resulted in 19- to 102-fold greater IFNgamma expression levels in transfected cells (293, NIH 3T3, CNE-1, CNE-2, and C666-1) and inhibited the growth of CNE-1, CNE-2, and C666-1 cells more efficiently, reducing relative growth rates to 7.1 +/- 1.6%, 2.7 +/- 1.0%, and 6.1 +/- 1.6%, respectively. Flow cytometry and caspase-3 activity assays suggested that the antiproliferative effects of IFNgamma gene transfer on NPC cell lines could be attributed to G(0)-G(1) arrest and apoptosis. Minicircle-mediated intratumoral IFNgamma expression in vivo was 11 to 14 times higher than p2PhiC31-IFNgamma in CNE-2- and C666-1-xenografted mice and lasted for 21 days. Compared with p2PhiC31-IFNgamma treatment, minicircle-IFNgamma treatment significantly increased survival and achieved inhibition rates of 77.5% and 83%, respectively. CONCLUSIONS: Our data indicate that IFNgamma gene transfer exerts antiproliferative effects on NPC cells in vitro and leads to a profound antitumor effect in vivo. Minicircle-IFNgamma is more efficient than corresponding conventional plasmids due to its capability of mediating long-lasting high levels of IFNgamma gene expression. Therefore, minicircle-mediated IFNgamma gene transfer is a promising novel approach in the treatment of NPC.

Animals↗

PubMed2006

Reconstructing genetic ancestry blocks in admixed individuals.

A chromosome in an individual of recently admixed ancestry resembles a mosaic of chromosomal segments, or ancestry blocks, each derived from a particular ancestral population. We consider the problem of inferring ancestry along the chromosomes in an admixed individual and thereby delineating the ancestry blocks. Using a simple population model, we infer gene-flow history in each individual. Compared with existing methods, which are based on a hidden Markov model, the Markov-hidden Markov model (MHMM) we propose has the advantage of accounting for the background linkage disequilibrium (LD) that exists in ancestral populations. When there are more than two ancestral groups, we allow each ancestral population to admix at a different time in history. We use simulations to illustrate the accuracy of the inferred ancestry as well as the importance of modeling the background LD; not accounting for background LD between markers may mislead us to false inferences about mixed ancestry in an indigenous population. The MHMM makes it possible to identify genomic blocks of a particular ancestry by use of any high-density single-nucleotide-polymorphism panel. One application of our method is to perform admixture mapping without genotyping special ancestry-informative-marker panels.

Genetics, Medical↗

PubMed2006

Diminished induction of skin fibrosis in mice with MCP-1 deficiency.

Scar and fibrosis are often the end result of mechanical injury and inflammatory diseases. One chemokine that is repeatedly linked to fibrotic responses is monocyte chemoattractant protein-1 (MCP-1). We utilized a murine fibrosis model that produces dermal lesions similar to scleroderma to evaluate collagen fibrillogenesis in the absence of MCP-1. Dermal fibrosis was induced by subcutaneous injection of bleomycin into the dorsal skin of MCP-1-/- and wild-type C57BL/6 mice. After 4 weeks of daily injections, bleomycin treatment led to thickened collagen bundles with robust inflammation in the lesional dermis of wild-type mice. In contrast, the lesional skin of MCP-1-/- mice exhibited a dermal architecture similar to phosphate-buffered saline (PBS)-injected control and normal skin, with few inflammatory cells. Ultrastructural analysis of the lesional dermis from bleomycin-injected wild-type mice revealed markedly abnormal arrangement of collagen fibrils, with normal large diameter collagen fibrils replaced by small collagen fibrils of 41.5 nm. In comparison, the dermis of bleomycin-injected MCP-1-/- mice displayed a uniform pattern of fibril diameters that was similar to normal skin (average diameter 76.7 nm). The findings implicate MCP-1 as a key determinant in the development of skin fibrosis induced by bleomycin, and suggest that MCP-1 may influence collagen fiber formation in vivo.

Animals↗

PubMed2006

Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans.

Admixed populations such as African Americans and Hispanic Americans present both challenges and opportunities in genetic epidemiologic research. Because of variation in admixture levels among individuals, case-control association studies may be subject to stratification bias. On the other hand, admixed populations also present special opportunities both for examining the role of genetic and environmental factors for observed racial/ethnic differences, and for possibly mapping alleles that contribute to such differences. Here we examined the distribution and relationship of individual admixture (IA) estimates with BMI and three measures of blood pressure in two admixed populations in the NHLBI Family Blood Pressure Program (FBPP): African Americans and Mexican Americans. For the African Americans, we observed modest but significant differences in average African IA among four recruitment sites. We observed a slight excess of African IA among hypertensives compared to normotensives, and a positive (non-significant) regression of African IA on blood pressure in untreated participants. Within Mexican Americans, we found no difference in average IA between hypertensives and normotensives, but a positive (marginally significant) regression of African IA on diastolic blood pressure. We also observed a significant positive regression of Caucasian IA (and negative regression of Native American IA) on BMI. Our results are suggestive of genetic differences between Africans and non-Africans that influence blood pressure, but such effects are likely to be modest compared to environmental ones. Excess obesity among Native Americans compared to whites is not consistent with a simple genetic explanation.

Adult↗

PubMed2006

A common genetic variant is associated with adult and childhood obesity.

Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.

Adult↗

PubMed2006

Crystal structure of mouse succinic semialdehyde reductase AKR7A5: structural basis for substrate specificity.

The aldo-keto reductases make up a superfamily of enzymes which can reduce a variety of aldehydes and ketones to their corresponding alcohols. Within each family are distinct preferences for certain substrates, presumably reflecting their role within the cell. The original member of the AKR7A subfamily was purified from liver as an aflatoxin dialdehyde reductase AKR7A1. However, recent additions to the family have revealed that even closely related enzymes have clear substrate preferences with AKR7A2, AKR7A4, and AKR7A5 showing much higher affinities for succinic semialdehyde (SSA) than does AKR7A1. To investigate the structural basis of this specificity, the crystal structure of mouse AKR7A5 has been determined to better than 2.5 A resolution. The structure is of the ternary complex of the enzyme with NADP+ and tartrate as an inhibitor. This structure has the same overall fold as the previously determined structure of AKR7A1; however, there are a number of differences in loops around the active site that contribute to observed differences in the substrate specificity between the AKR7A enzymes. Several differences are the result of bulky hydrophobic residues found in AKR7A5, namely, Met44, Trp77, and Trp224, which significantly restrict the size and modify the architecture of the substrate-binding pocket, producing a tighter or less flexible binding site for SSA than in AKR7A1. Site-directed mutagenesis was used to introduce Met44, Trp77, and Trp224 individually into AKR7A1, to test if they improved the affinity of the enzyme for SSA. Each mutation showed improved affinity for SSA, with Trp77Met having the largest effect. This confirms the role of these amino acids as substrate determinants for SSA.

Alcohol Oxidoreductases↗

PubMed2006

A combinatorial searching method for detecting a set of interacting loci associated with complex traits.

Complex diseases are presumed to be the results of the interaction of several genes and environmental factors, with each gene only having a small effect on the disease. Mapping complex disease genes therefore becomes one of the greatest challenges facing geneticists. Most current approaches of association studies essentially evaluate one marker or one gene (haplotype approach) at a time. These approaches ignore the possibility that effects of multilocus functional genetic units may play a larger role than a single-locus effect in determining trait variability. In this article, we propose a Combinatorial Searching Method (CSM) to detect a set of interacting loci (may be unlinked) that predicts the complex trait. In the application of the CSM, a simple filter is used to filter all the possible locus-sets and retain the candidate locus-sets, then a new objective function based on the cross-validation and partitions of the multi-locus genotypes is proposed to evaluate the retained locus-sets. The locus-set with the largest value of the objective function is the final locus-set and a permutation procedure is performed to evaluate the overall p-value of the test for association between the final locus-set and the trait. The performance of the method is evaluated by simulation studies as well as by being applied to a real data set. The simulation studies show that the CSM has reasonable power to detect high-order interactions. When the CSM is applied to a real data set to detect the locus-set (among the 13 loci in the ACE gene) that predicts systolic blood pressure (SBP) or diastolic blood pressure (DBP), we found that a four-locus gene-gene interaction model best predicts SBP with an overall p-value = 0.033, and similarly a two-locus gene-gene interaction model best predicts DBP with an overall p-value = 0.045.

Blood Pressure↗

PubMed2006

Sequential gene expression profiling in lung transplant recipients with chronic rejection.

STUDY OBJECTIVES: Chronic allograft rejection is the leading cause of morbidity and mortality for long-term survivors of lung transplantation. Previous studies have implicated only isolated genes in the development of chronic rejection and have not examined multiple pathways in an individual concurrently. Using microarray technology, we identified and compared gene expression profiling in lung transplant recipients with and without chronic rejection, and follow sequential expression of genes differentially expressed between the two groups. DESIGN: Prospective, cohort study. SETTING: Single lung transplant center. PATIENTS OR PARTICIPANTS: Eleven transplant recipients with chronic rejection were matched with 9 control transplant recipients. INTERVENTIONS: All recipients underwent surveillance bronchoscopies at predetermined times to rule out infection and/or acute rejection. Gene expression profiling was obtained from hybridizing BAL fluid cell RNA to a 96-gene microarray. MEASUREMENTS AND RESULTS: Fifteen genes were found to be significantly differentially expressed between the two patient groups, and they are involved in inflammatory, fibrotic, and apoptotic pathways. Temporal expression of the significant genes demonstrated a change in their levels at the onset of chronic rejection, with normalization to prerejection levels as rejection continued. CONCLUSIONS: We conclude that microarray technology is valuable in studying the mechanism of chronic lung rejection, and the expression of genes in multiple pathways is elevated in patients with chronic lung rejection.

Adult↗

PubMed2006

Common variants in the ENPP1 gene are not reproducibly associated with diabetes or obesity.

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78-0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.

Asian People↗

PubMed2005

A genome-wide linkage and association study using COGA data.

BACKGROUND: Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. METHODS: Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleotide polymorphisms (SNPs). Family based genome-wide association test was also conducted using the SNPs. RESULTS: Nonparametric linkage analysis revealed weak linkage evidence on chromosome 7, and association analysis identified SNP tsc0515272 on chromosome 3 as significantly associated with alcoholism. CONCLUSION: Linkage analysis may require large sample sizes and high quality genotyping and marker maps to adequately improve power, while association analysis could hold more promise in efforts to identify variants responsible for complex traits.

Alcoholism↗

PubMed2005

Identifying genetic variation affecting a complex trait in simulated data: a comparison of meta-analysis with pooled data analysis.

We explored the power and consistency to detect linkage and association with meta-analysis and pooled data analysis using Genetic Analysis Workshop 14 simulated data. The first 10 replicates from Aipotu population were used. Significant linkage and association was found at all 4 regions containing the major loci for Kofendrerd Personality Disorder (KPD) using both combined analyses although no significant linkage and association was found at all these regions in a single replicate. The linkage results from both analyses are consistent in terms of the significance level of linkage test and the estimate of locus location. After correction for multiple-testing, significant associations were detected for the same 8 single-nucleotide polymorphisms (SNP) in both analyses. There were another 2 SNPs for which significant associations with KPD were found only by pooled data analysis. Our study showed that, under homogeneous condition, the results from meta-analysis and pooled data analysis are similar in both linkage and association studies and the loss of power is limited using meta-analysis. Thus, meta-analysis can provide an overall evaluation of linkage and association when the original raw data is not available for combining.

Computer Simulation↗

PubMed2005

Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension.

BACKGROUND: The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes. METHOD AND RESULTS: This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7+/-20.7 versus 129.4+/-17.4 mm Hg; P=0.029) and adjusted (132.5+/-1.6 versus 128.9+/-0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8+/-1.9 versus 121.4+/-0.7 mm Hg; P=0.03). CONCLUSIONS: The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

Adult↗

PubMed2005

Refinement of the DFNA41 locus and candidate genes analysis.

We previously mapped the 41rst gene locus (DFNA41) for autosomal dominant hearing loss on chromosome 12q24-qter in a large multi-generational Chinese family. We determined that DFNA41 is located in a 15 cM region, proximal to the marker D12S1609. A maximum two point LOD score of 6.56 at theta = 0.0 was obtained with marker D12S343. In the current study, screening of eight candidate genes within the DFNA41 interval did not reveal the mutation causing deafness in this family. Eight highly informative single nucleotide polymorphisms (SNPs) in the region of D12S343 were selected for linkage and association study. Because the pedigree studied here is a large family with many founders, we applied the transmission/disequilibrium (TDT) test. To account for the dependence of small families and the relatively small sample size, simulations were performed to obtain P-values. For three nearby SNPs spanning a 7 kb interval, we found significant evidence of linkage and association. The highest Z score of linkage and association of 3.6 (P < or = 0.0001) was obtained for SNP rs1566667. Haplotype analysis revealed that affected individuals were heterozygous for one core SNP (rs1027560-rs1027557-rs1566667-rs1463865-rs2078105) CAGTC haplotype, confirming location and autosomal dominant inheritance of the DFNA41 locus. Examination of pairwise LD calculation identified a major haplotype block defined by the four most centromeric SNPs. This study represents a significant refinement of the DFNA41 locus and should facilitate positional cloning of the disease gene.

Centromere↗