Publications
49 results found
Zhang Y, Dean C, Chessum L, et al., 2014, Functional analysis of a novel ENU-induced PHD finger 11 (<i>Phf11)</i> mouse mutant, MAMMALIAN GENOME, Vol: 25, Pages: 573-582, ISSN: 0938-8990
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- Citations: 2
Loeser S, Zhang Y, Gregory L, et al., 2014, Novel insights into the <i>in vivo</i> function of <i>Ormdl3</i> - a gene associated with the onset of childhood asthma, IMMUNOLOGY, Vol: 143, Pages: 59-59, ISSN: 0019-2805
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- Citations: 3
Zhang Y, 2014, Genome Editing with ZFN, TALEN and CRISPR/Cas Systems:The Applications and Future Prospects, Advancements in Genetic Engineering, Vol: 03
Zhang Y, Moffatt MF, Cookson WOC, 2012, Genetic and genomic approaches to asthma: new insights for the origins, Current Opinion in Pulmonary Medicine, Vol: 18, Pages: 6-13, ISSN: 1070-5287
Purpose of review: The aim is to update current understanding of the genes identified by the recent genome-wide association studies (GWASs) of asthma and its associated traits. The review also discusses how to dissect the functional roles of novel genes in future research.Recent findings: More than 10 GWAS aimed at identifying the genes underlying asthma and relevant traits have been published in the past 3 years. The largest of these was from the GABRIEL consortium, which discovered that the IL18R1, IL33, SMAD3, ORMDL3, HLA-DQ and IL2RB loci were all significantly associated with asthma. Many novel asthma genes, including those previously identified by positional cloning, are expressed within the respiratory epithelium, emphasizing the importance of epithelial barriers in causing asthma . The genes controlling IgE levels have surprisingly little overlap with the genes mediating asthma susceptibility, suggesting that atopy is secondary to asthma rather than a primary driver of the disease. The next challenge will be the systematic analysis of the precise functions of these genes in the pathogenesis of asthma.Summary: GWAS have uncovered many novel genes underlying asthma and detailed functional dissection of their roles in asthma will point the way to new therapies for the disease.
Zhang Y, 2012, Applications of Gene Targeting in the Investigations of Human Airway Diseases, Cloning & Transgenesis, Vol: 02
Li F, Jiang L, Willis-Owen SA, et al., 2011, Vitamin D binding protein variants associate with asthma susceptibility in the Chinese han population, BMC Medical Genetics, Vol: 12, ISSN: 1471-2350
Background: Asthma is a genetically heterogeneous disease. Polymorphisms of genes encoding components ofthe vitamin D pathway have been reported to associate with the risk of asthma. We have previously demonstratedthat vitamin D status was associated with lung function in Chinese asthma patients. In this study, we testedwhether polymorphisms of genes encoding for vitamin D receptor (VDR), vitamin D 25-hydroxylase (CYP2R1) andvitamin D binding protein (GC) were associated with asthma in the Chinese Han population.Methods: We sequenced all 8 exons of VDR and all 5 exons of CYP2R1 in a Chinese case-control cohort of asthmaconsisting of 467 cases and 288 unrelated healthy controls. Two mutations were identified in these regions. Thesevariants were specified as rs2228570 in exon 2 of VDR and rs12794714 in exon 1 of CYP2R1. We also genotypedtwo common polymorphisms in GC gene (rs4588 and rs7041) by a PCR-restriction fragment length polymorphism(RFLP) method. We analyzed the association between these 4 polymorphisms and asthma susceptibility andasthma-related traits.Results: Polymorphic markers in VDR and CYP2R1 were not associated with asthma in the Chinese Han cohort.Importantly, variants in GC gene, which give rise to the two most common electrophoretic isoforms of the vitaminD binding protein, were associated with asthma susceptibility. Compared with isoform Gc1, Gc2 was significantlyassociated with the risk of asthma (OR = 1.35, 95% CI = 1.01-1.78 p = 0.006).Conclusions: The results provide supporting evidence for association between GC variants and asthmasusceptibility in the Chinese Han population.
Holt RJ, Zhang Y, Binia A, et al., 2011, Allele-specific transcription of the asthma-associated PHD finger protein 11 gene (PHF11) modulated by octamer-binding transcription factor 1 (Oct-1)., Journal of Allergy and Clinical Immunology, Vol: 127, Pages: 1054-1062.e2, ISSN: 0091-6749
Asthma is a common, chronic inflammatory airway disease of major public health importance with multiple genetic determinants. Previously, we found by positional cloning that PHD finger protein 11 (PHF11) on chromosome 13q14 modifies serum immunoglobulin E (IgE) concentrations and asthma susceptibility. No coding variants in PHF11 were identified.ObjectiveHere we investigate the 3 single nucleotide polymorphisms (SNPs) in this gene most significantly associated with total serum IgE levels—rs3765526, rs9526569, and rs1046295—for a role in transcription factor binding.MethodsWe used electrophoretic mobility shift assays to examine the effect of the 3 SNPs on transcription factor binding in 3 cell lines relevant to asthma pathogenesis. Relative preferential expression of alleles was investigated by using the allelotyping method.ResultsElectrophoretic mobility shift assays show that rs1046295 modulates allele-specific binding by the octamer-binding transcription factor 1 (Oct-1). Analysis of the relative expression levels of the 2 alleles of this SNP in heterozygous individuals showed a modest, but highly significant (P = 6.5 × 10−16), preferential expression of the A allele consistent with a functional role for rs1046295.ConclusionThese results suggest a mechanism by which rs1046295 may act as a regulatory variant modulating transcription at this locus and altering asthma susceptibility.
Zhang Y, Cookson W, Moffatt M, 2009, Pharmacogenetics and Pharmacogenomics of Airway Diseases, Pharmacology and Therapeutics of Airway Disease, Editors: Barnes, Chung, Publisher: Taylor & Francis Group
I. Introduction Asthma and chronic obstructive pulmonary disease (COPD) are complex syndromes of airway inflammation. Asthma is a disease of the small airways of the lung. Intermittent narrowing of the respiratory bronchioles produces airway limitation and the symptoms of wheezing, chest tightness, and breathlessness. By contrast, in COPD the limitation of airflow is poorly reversible and usually gets progressively worse over time. The disease is primarily, but not exclusively, seen in smokers and former smokers. Environmental and genetic factors contribute to the etiology of both diseases. Cigarette smoking is the main risk factor for COPD, although less than 20% of chronic heavy smokers will develop symptoms of airway obstruction (1). Bronchodilators and corticosteroids are currently the most common medications used in the treatment of asthma and COPD.
GaoJ, Li W, Willis-Owen SA, et al., 2009, Polymorphisms of PHF11 and DPP10 are associated with asthma and related traits in a Chinese population., Respiration, Vol: 79, Pages: 17-24, ISSN: 1423-0356
Background: Initial studies by positional cloning have identified the genes encoding the plant homeodomain zinc finger protein 11 (PHF11) and dipeptidyl-peptidase 10 (DPP10) as asthma susceptibility genes. The variants in the two genes have been associated with asthma in several populations of European or Latin American origin. Objective: The aim of this study was to assess the common PHF11 and DPP10 polymorphisms for associations to asthma and asthma-related traits in a Han Chinese population. Methods: We genotyped six polymorphic markers in PHF11 and five polymorphic markers in DPP10 in a Han Chinese case-control cohort consisting of 408 asthma patients and 288 unrelated disease-free controls recruited from the Northern region of China. We analyzed the association between these markers and asthma as well as a number of intermediate, asthma-related traits. Linkage disequilibrium and haplotype patterns were also evaluated. Results: Significant associations were identified between two makers in PHF11 (rs1046295 and rs16659) and asthma susceptibility (odds ratio, OR = 1.32, 95% con fidence interval, CI = 1.06–1.65, p = 0.0096, for rs1046295, and OR = 1.41, 95% CI = 1.12–1.75, p = 0.0026, for rs16659). A strong association was observed between an SNP in DPP10 (rs10208402) and loge-transformed total IgE (p = 0.0003) and the percentage of peripheral blood eosinophils (p = 0.0023). A weak association between rs1430090 in DPP10 and forced expiratory volume in 1 s was also observed (p = 0.048). Haplotype analysis revealed two protective haplotypes in PHF11 against asthma. Conclusion: The results provide supporting evidence for genetic variants in PHF11 and DPP10 genes underlying asthma susceptibility and asthma-related quantitative traits in a Han Chinese population.
Yates L, McMurray F, Zhang Y, et al., 2009, ENU mutagenesis as a tool for understanding lung development and disease Biochemical Society Transactions 37: 838–842.
Solberg LC, Valdar W, Gauguier D, et al., 2006, A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice, MAMMALIAN GENOME, Vol: 17, Pages: 129-146, ISSN: 0938-8990
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- Citations: 85
Hysi P, Kabesch M, Moffatt MF, et al., 2005, NOD1 variation, immunoglobulin E and asthma, Human Molecular Genetics, Vol: 14, Pages: 935-941, ISSN: 1460-2083
Asthma is a familial inflammatory disease of the airways of the lung. Microbial exposures in childhood protectagainst asthma through unknown mechanisms. The innate immune system is able to identify microbial componentsthrough a variety of pattern-recognition receptors (PRRs). NOD1 is an intracellular PRR that initiatesinflammation in response to bacterial diaminopimelic acid (iE-DAP). The NOD1 gene is on chromosome 7p14, ina region that has been genetically linked to asthma. We carried out a systematic search for polymorphism in thegene. We found an insertion–deletion polymorphism (ND1 1 32656) near the beginning of intron IX thataccounted for 7% of the variation in IgE in two panels of families (P < 0.0005 in each). Allele*2 (the insertion)was associated with high IgE levels. The same allele was strongly associated with asthma in an independentstudy of 600 asthmatic children and 1194 super-normal controls [odds ratio (OR) 6.3; 95% confidence interval(CI) 1.4–28.3, dominant model]. Differential binding of the two ND1 1 32656 alleles was observed to a proteinfrom nuclei of the Calu 3 epithelial cell line. In an accompanying study, the deletion allele (ND1 1 32656*1)was found to be associated with inflammatory bowel disease. The results indicate that intracellular recognitionof specific bacterial products affects the presence of childhood asthma.
Allen M, Heinzmann A, Noguchi E, et al., 2003, Positional cloning of a novel gene influencing asthma from Chromosome 2q14, NATURE GENETICS, Vol: 35, Pages: 258-263, ISSN: 1061-4036
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- Citations: 247
Zhang Y, Leaves NI, Anderson GG, et al., 2003, Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma, Nature Genetics, Vol: 34, Pages: 181-186, ISSN: 1061-4036
Atopic or immunoglobulin E (IgE)-mediated diseases include the common disorders of asthma, atopic dermatitis and allergic rhinitis1. Chromosome 13q14 shows consistent linkage to atopy and the total serum IgE concentration2,3,4,5,6. We previously identified association between total serum IgE levels and a novel 13q14 microsatellite (USAT24G1; ref. 7) and have now localized the underlying quantitative-trait locus (QTL) in a comprehensive single-nucleotide polymorphism (SNP) map. We found replicated association to IgE levels that was attributed to several alleles in a single gene, PHF11. We also found association with these variants to severe clinical asthma. The gene product (PHF11) contains two PHD zinc fingers and probably regulates transcription. Distinctive splice variants were expressed in immune tissues and cells.
Anderson GG, Leaves NI, Bhattacharyya S, et al., 2002, Positive association to IgE levels and a physical map of the 13q14 atopy locus., Eur J Hum Genet, Vol: 10, Pages: 266-270, ISSN: 1018-4813
Linkage of atopy and associated traits to a locus on chromosome 13q14 has been identified by several studies in diverse populations. We have previously shown the putative atopy gene to be contained within an interval of approximately 5 Mb flanked by D13S328 and D13S1269 and centred on D13S273. We have now extended this work using a top-down approach to physical mapping. A YAC contig was constructed covering the D13S328 and D13S1269 interval. Thirty-one ESTs were mapped to the contig. We constructed a BAC and PAC contig flanking D13S273 by approximately 750 kb in either direction. The interval contained 27 of the 31 ESTS from the YAC contig. Seven previously unknown microsatellites were recovered and then typed in two subject panels. A positive association between the total serum Immunoglobulin E concentration and the novel USAT24G1 microsatellite was discovered (P(corrected)<0.005) and replicated in a second panel of families. The discovery of a region of positive association within the BAC/PAC contig will permit identification of the atopy gene from this locus.
Anderson GG, Leaves NI, Bhattacharyya S, et al., 2002, Positive association to IgE levels and a physical map of the 13q14 atopy locus, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 10, Pages: 266-270, ISSN: 1018-4813
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- Citations: 22
Zhang Y, Cookson W, 2002, Case study of QTL analysis in a mouse model of asthma., Quantitative Trait Loci: Methods and Protocols, Editors: Camp, Cox, Publisher: Springer, Pages: 253-279, ISBN: 978-0-89603-927-8
Asthma is the most common childhood disease. It is characterized by inflammation of the small airways of the lung that produces intermittent narrowing of the respiratory bronchioles, airflow limitation, and the symptoms of wheezing, chest tightness, and breathless ness. The most common form is allergic asthma, also known as atopic asthma. The atopic state is distinguished by the strength of the immunoglobulin E (IgE) response to commonly inhaled proteins, known as allergens.
Abecasis GR, Noguchi E, Heinzmann A, et al., 2001, Extent and Distribution of Linkage Disequilibrium in Three Genomic Regions., American Journal of Human Genetics, Vol: 68, Pages: 191-197, ISSN: 0002-9297
The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.
Zhang Y, Lefort J, Kearsey J, et al., 1999, A genome-wide screen for asthma-associated quantitative trait loci in a mouse model of allergic asthma, Hum Mol Genet 8: 601-605, Pages: 8:601-605, ISSN: 0964-6906
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