Department of Biological Science
National University of Singapore
14 Science Drive 4
Allergy and Molecular Immunology Laboratory
Lee Hiok Kwee Functional Genomics Laboratories
Allergens and Hypersensitivity; Molecular Immunology and Molecular Mimicry, Aerobiology; Epidemiology and Genetics of Asthma and Atopy; Hypoallergenic Vaccines, Auto-allergens and Pan-allergens.
Our group is interested in understanding the basis of what constitutes an ‘allergen’. We have previously focused on delineating the molecular structure of major allergenic components from dust mites, cockroach, tropical pollen and spores, fungal allergens, as well as unique components from food proteins. This includes identifying, isolating, and cloning the allergenic components; analyzing the antigenic epitopes; and evaluating cross-reactivity between related allergens. We have also explored the use of multiple types of expression systems to produce large quantities of recombinant allergens for structural, biological and immunological studies, and for use in diagnosis and treatment of allergic diseases.
We are also interested in understanding the underlying basis of allergic diseases. We are currently taking a genetic approach to uncover the potential pathways and interactions influencing the pathogenesis and development of these complex diseases. This includes large-scale genome wide association studies, functional candidate gene evaluations, gene-gene (epistasis) and gene-environment studies.
Allergens for Diagnosis, Treatment and Control of Allergies
Type I allergic conditions such as allergic rhinitis, conjunctivitis and bronchial asthma, are a result of an exaggerated production of IgE antibodies against normally innocuous environmental or ingested allergens. In sensitized individuals, allergen exposure induces cross-linking of high-affinity FceRI receptor-bound IgE on effector cells and this would lead to the release of mediators that cause allergic symptoms. Although the mechanisms leading to allergic responses are been extensively elucidated, our understanding of the molecular structures triggering such allergic responses is incomplete. Our research work has focusedmon the high-throughput identification of allergens present in complex allergenic sources; the production, characterization and clinical evaluation of recombinant allergens together with their natural counterparts; and on the elucidation of the exact molecular structures based on molecular modeling, crystallization of the proteins or via Nuclear Magnetic Resonance (NMR) techniques.
The repertoire of antigens acting as allergens thus far covers a wide variety of structural and non-structural proteins, secreted and cytoplasmic proteins, as well as those with or without enzymatic activity, indicating that a vast variety of functionally different proteins are able to elicit IgE responses in atopic individuals. However, many of these allergens turn out to be cross-reactive molecules which belong to highly conserved protein families. From the current data, it seems that the allergen repertoire, although vast, is subject to a large redundancy with many cross-reactive molecules from diverse sources acting in a similar manner. This understanding could contribute to a relative reduction of the number of molecules needed for a highly sensitive and specific diagnosis of allergic conditions as well as for the development of component-resolved desensitization processes via immunotherapy.
We have developed a pipeline of related processes for the rapid identification of allergens; this includes the use of phage display, EST sequencing followed by full length cloning of allergenic components and the use of large scale proteomic identification, bioinformatics analysis and high-density arrays. The strategy has been demonstrated to be highly efficient. To date many different recombinant allergens (more than 200 from our laboratory alone) of various pollens, fungi, mites, insects, food components have been evaluated in more than 3000 allergic and control individuals from diverse environments. These studies demonstrated that recombinant allergens are highly specific and safe for clinical applications. Recombinant allergens offer a highly specific and safe diagnostic tool to elucidate patient- and disease-specific sensitization patterns which will be needed for the development of patient-tailored immunotherapeutic treatments.
Genetics of Asthma and Allergic Diseases
We initiated a genome-wide association study on atopy and allergic diseases in Singapore in collaboration with the Genome Institute of Singapore (GIS), and Department of Otolaryngology and Paediatrics, National University of Singapore, funded by the Singapore Immunology Network (SIgN). There are clear evidences to support the concept that allergic diseases are influenced by genetic predisposition and environmental factors. In the past decade, studies have shown linkages between certain phenotypes of allergic diseases with markers on >15 human chromosomes. However, variable results were obtained from many previous studies, possibly due to (1) differences in the susceptibility genes for atopy and allergic diseases in different populations; (2) the lack of sufficient statistical power; (3) insufficient coverage of candidate genes and genetic variations within candidate genes due to limited biological understanding of disease; and (4) developmental and environmental differences influencing variations in our susceptibility to these conditions. This proposed project will be carried out by a research team with multiple expertises in clinical allergy, molecular biology and immunology, population genetics, epidemiology, data-mining and integration. The main objectives include the ascertainment of a large clinically and epidemiologically well-characterized demographic-matched case-control cohort which will be recruited to provide sufficient statistical power for identification of major atopic susceptibility genes in our population.
Biomedical Sciences: Cancer (Childhood Leukemia and Breast Cancer); Adipose Derived Stem Cell Biology and Tissue Engineering; Human Secreted Fluid Proteomics; and Biomarkers in Childhood Diseases (NUHS, KKH, Danone Research).
Genetics: Molecular Authenticity, Origins and Traceability of Bio-molecules (e.g., Food, Pharmaceutical Products and Commodities) (Eu Yang Sang); Timber Genetics and Biogeography (Certisource Timber Asia Pacific & Double Helix Tracking Technologies); Functional Genomic Characterization of Oil Palm Traits, Marker Assisted Breeding and Oil Palm Genomics (Sime Darby); Network Biology of Microalgae for Biofuels (ASEAN Algae Biofuels Network).
Kumar S, Ong SH, Ranganath S, Ong TC, Chew FT. A rule-based approach to robust clump splitting of environmental spores and pollen images. Pattern Recognition 2006; 39: 1088-98.
Leong DT, Khor WM, Chew FT, Lim TC, Hutmacher DW. Characterization of osteogenically induced adipose-derived precursor cells in 2- & 3-D environments. Cells Tissues Organs 2006; 182:1-11.
Hong MLW, Jiang N, Gopinath S, Chew FT. Proteomics technology and therapeutics. Clin Exp Pharmacol Physiol 2006; 33: 583-8.
Hindley J, Wünschmann S, Satinover SM, Woodfolk JA, Chew FT, Chapman MD, Pomés A. Bla g 6: a troponin C allergen from Blattella germanica with IgE binding calcium dependence. J Allergy Clin Immunol 2006; 117: 1389-95.
Chan SL, Ong ST, Ong SY, Chew FT, Mok YK. NMR structure based epitope mapping and modulation of dust mite group 13 allergen as a hypo-allergenic vaccine. J Immunol 2006; 176: 4852-60.
Batard T, Hrabina A, Bi XZ, Chabre H, Lemoine P, Couret MN, Faccenda D, Villet B, Harzic P, André F, Goh SY, André C, Chew FT, Moingeon P. Production and characterization of pharmaceutical-grade Dermatophagoides pteronyssinus and Dermatophagoides farinae house dust mites for allergy vaccines. Int Arch Allergy Immunol 2006; 140: 295-305.
Lam KKY, Loo AHB, Todd PA, Chew FT, Chou LM. Existence of intra-colonial paralogues of the ribosomal internal transcribed spacer (ITS) impedes studies of intra-colonial genetic variation in the scleractinian coral Diploastrea heliopora (Lamark 1816). Raffles Bulletin of Zoology 2006; 54: 421-5.
Kumar S, Ong SH, Ranganath S, Chew FT. A luminance- and contrast-invariant edge-similarity measure. IEEE Transactions on Pattern Analysis and Machine Intelligence 2006; 28: 2042-8.
Leong DTW, Abrham MC, Rath SN, Lim TC, Chew FT, Hutmacher DW. Investigating the effects of preinduction on human adipose derived precursor cells in an athymic rat model. Differentiation 2006; 74: 519-29.
Tan TN, Shek LPC, Goh DYT, Chew FT, Lee BW. Prevalence of asthma and comorbid allergy symptoms in Singaporean preschoolers. Asian Pacific J Allergy Immunol 2006; 24: 175-82.
Zuraimi MS, Tham KW, Chew FT, Ooi PL. Housing characteristics and young children's respiratory health in tropical Singapore. Healthy Building 2006, Lisbon Portugal, Proceedings of Healthy Buildings 2006, Vol. 1, ed. Fernandes EDO, da Silva MG and Pinto JR (2006): pages 161-4.
Zuraimi MS, Tham KW, Chew FT, Ooi PL, Bornehag CG, Sundell J. Association between child care center characteristics with respiratory health and allergies among young children in the tropics. Healthy Building 2006, Lisbon, Portugal, Proceedings of Healthy Buildings 2006, Vol. 1, ed. Fernandes EDO, da Silva MG and Pinto JR (2006): 169-74.
Leong DTW, Gupta A, Bai HF, Wan Q, Yoong LF, Too HP, Chew FT, Hutmacher DW. Absolute quantification of gene expression in biomaterials using real time PCR. Biomaterials 2007; 28: 203-10.
Tham KW, Zuraimi MS, Koh D, Chew FT, Ooi PL. Associations between home dampness and presence of molds with asthma and allergic symptoms among young children in the tropics. Pediatr Allergy Immunol 2007; 18: 418-24.
Kidon MI, Chew FT. Component specific IgE in the diagnosis of allergic disease in childhood: more of the same or something more? Isreal Med Assoc J 2007; 9: 476–8.
Gao YF, Wang DY, Ong TC, Tay SL, Yap KH, Chew FT. Identification and characterization of a novel allergen from Blomia tropicalis, Blo t 21. J Allergy Clin Immunol 2007; 120: 105-12.
Zuraimi MS, Tham KW, Chew FT, Ooi PL. Indoor air quality and respiratory symptoms among children in tropical childcare centers employing different ventilation strategies. Indoor Air 2007; 17: 317-27.
Zhou L, Beuerman RW, Huang L, Barathi A, Foo YH, Li SF, Chew FT, Tan D. Proteomic analysis of rabbit tear fluid: Defensin levels after an experimental corneal wound are correlated to wound closure. Proteomics 2007; 7: 3194-206.
Koo SH, Ong TC, Chong KT, Lee CGL, Chew FT, Lee EJD. Multiplexed genotyping of ABC transporter polymorphisms with the Bioplex suspension array. Biol Proced Online 2007; 9: 18-30.
Chew FT. Identification of the major components of the dust mite proteome and the full repertoire of its allergens. In: Allergy Clin Immunol International - 'Cellular and Molecular Targets in Allergy and Clinical Immunology', Hogrefe & Huber Publishers, 2007.
Zuraimi MS, Tham KW, Koh D, Chew FT, Ooi PL. Home exposures to environmental tobacco smoke (ETS) and allergies among young children in Singapore. Int Arch Allergy Immunol 2008; 146: 57-65.
Chan SL, Ong TC, Gao YF, Tiong YS, Wang DY, Chew FT, Mok YK. NMR structure and IgE epitopes of Blo t 5, a major dust mite allergen. J Immunol 2008; 181: 2586-96.
Zuraimi MS, Ong TC, Tham KW, Chew FT. Indoor allergens in childcare centres in Singapore: concentrations, distribution & determinants. Pediatr Allergy Immunol 2008; 19: 746-55.
Lim SJ, Tong JC, Chew FT, Tammi MT. The value of position-specific scoring matrices for assessment of protein allergenicity. BMC Bioinformatics 2008; 9: S21.
Tan YW, Chan SL, Ong TC, Yit LY, Tiong YS, Chew FT, Sivaraman J, Mok YK. Structures of two major allergens, Bla g 4 and Per a 4, from cockroaches and their IgE binding epitopes. J Biol Chem 2009; 284: 3148-57.
Wong KN, Tan WL, Chew FT. Identification and characterization of microsatellite loci in Intsia palembanica (Merbau), a valuable tropical timber species. Mol Ecol Res 2009; 9: 360-4. (previously Mol Ecol Notes).
Lim CSH, Lim SL, Chew FT, Ong TC, Deharveng L. Collembola are unlikely to cause human dermatitis. J Insect Science 9: No. 76.
Tong, JC, FT Chew, SJ Lim, HC Muh, S Pardha, MT Tammi. Allergen Atlas: A comprehensive knowledge center and analysis resource for allergen information. Bioinformatics 2009; 25: 979-80.
Zhou L, Beuerman RW, Ang LPK, Chan CM, Li SFY, Chew FT, Tan DTH. Elevation of human alpha-defensins and S100 calcium binding protein A8 and A9 in tear fluid of pterygium patients. Invest Ophathalmol Vis Sci 2009; 50: 2077-86.
Zuraimi MS, Fang L, Tan TK, Chew FT, Tham KW. Airborne fungi in low and high allergic prevalence child care centres. Atmospheric Environment 2009; 43: 2391-2400.
Chew GL, Reardon AM, Correa JC, Young M, Acosta L, Mellins R, Chew FT, Perzanowski, M. Mite sensitization among Latina women in New York, where domestic mite allergen levels are typically low. Indoor Air 2009; 19: 193-7.
Ong ST, Chew FT. Reconstructing the repertoire of mite allergens by recombinant DNA technology. In: Allergy Frontiers: From Epigenetics to Future therapies, edited by Steve Holgate, Lanny Rossenwasser and Ruby Pawankar, Volume 6 (Section: Future perspectives) 2009; pp. 49-64.
Ramani A, Chew FT. Validation of pooled genotyping on the Affymetrix 500k and SNP6.0 genotyping platforms using the polynomial-based probe-specific correction. BMC Genetics 2009; 10: No. 82.
Batard T, Chabre H, Gouyon B, Nony E, Hrabina M, Jain K, Couret MN, Brochier V, Beauvallet C, Chew FT, Moingeon P. Application of proteomics for the characterization of biological allergen extracts. Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M. 2009; 96: 55-60.
Kumar S, Ong SH, Ranganath S, Chew FT. Invariant texture classification for biomedical cell specimens via non-linear polar map filtering. Computer Vision and Image Understanding 2010; 114: 44-53.
Parate PN, Wang DY, Chew FT. Linkage disequilibrium pattern of polymorphisms from asthma candidate genes from chromosome 5q31-q33 in the Singapore Chinese population. Ann Hum Genetics 2010; 74: 137-45.
Andiappan AK, Ramani A, Parate PN, Wang DY, Chew FT. Evaluating the transferability of Hapmap SNPs to a Singapore Chinese population. BMC Genetics 2010; 11: No. 36.
Lwin ZM, Guo CH, Salim A, Yip GWC, Jiang N, Chew FT, Thike AA, Tan PH, Bay BH. Clinicopathological significance of calreticulin in breast invasive ductal carcinoma. Mod Pathol 2010; 23: 1559-66.
Zuraimi MS, Tham KW, Chew FT, Ooi PL, Koh D. Home air conditioning, traffic exposure and asthma and allergic symptoms among preschool children. Pediatr Allergy Immunol 2011; 22 (1 pt 2): e112–e118.
Platts-Mills TAE, Lee BW, Arruda KL, Chew FT. Allergens as risk factors for allergic disease. In: World Allergy Organization's (WAO) White Book on Allergy 2011, pg 79-84. (Book Chapter).
Kidon MI, Chiang WC, Liew WK, Ong TC, Tiong YS, Wong KN, Angus AC, Ong ST, Gao YF, Reginald K, Bi ZX, Shang HS, Chew FT. Mite component-specific IgE repertoire and phenotypes of allergic disease in childhood: the tropical perspective. Paediatr Allergy Immunol 2011; 22: 202–210.
Jiang N, Koh GSM, Kham SKY, Lim JYS, Hany A, Chew FT, Yeoh AEJ. BIM is a prognostic biomarker to early prednisolone response in acute lymphoblastic leukemia (ALL). Exp Haematol 2011; 3: 321-329.
Andiappan AK, Yeo WS, Parate PN, Ramani A, Suri BK, Wang DY, Chew FT. Variation in Uteroglobin-Related Protein 1 (UGRP1) gene is associated with allergic rhinitis in Singapore Chinese. BMC Med Genetics 2011; 12(1): No. 39.
Lowe A, Wong KN, Tiong YS, Iyerh S, Chew FT. A DNA method to verify the integrity of timber supply chains: confirming the legal sourcing of merbau timber from logging concession to sawmill. Silvae Genetica 2010; 59: 263-8.
Jiang N, Kham SKY, Koh GSM, Lim JYS, Hany A, Chew FT, Yeoh AEJ. Identification of prognostic protein biomarkers in childhood acute lymphoblastic leukemia (ALL). J Proteomics 2011; 74: 843-57.
Andiappan AK, Wang DY, Ramani A, Parate PN, Suri BK, Low HQ, Li Y, Zhao WT, Castagnoli P, Liu JJ, Chew FT. Genomewide association study in a Singapore Chinese population validates 2 novel loci on chromosomes 19p13.2 locus and 10q24.1 locus as associated with atopy and allergic rhinitis. PLoS One 2011; 6(5): e19719.
Andiappan AK, Parate PN, Ramani A, Suri BK, Wang DY, Chew FT. Genetic variation in BDNF associated with asthma and allergic rhinitis. Cytokine 2011; 56: 218-23
Sander I, Rozynek P, Rihs HP, van Kampen V, Chew FT, Lee WS, Kotschy-Lang N, Merget R, Brüning T, Raulf-Heimsoth M. Multiple wheat flour allergens and cross-reactive carbohydrate determinants bind IgE in baker's asthma. Allergy 2011; 66: 1208-15
Ong TC, Lim SH, Chen XW, Mohd Dali SD, Tan HTW, Lee BW, Chew FT. Fern spore and pollen airspora profile of Singapore. Aerobiologia 2012; 28: 135-51
Tan KW, Kumar S, Chew FT, Mok YK. Cloning, expression, purification, crystallization and preliminary X-ray diffraction studies of a major group 7 allergen, Der f 7, from the dust mite Dermatophagoides farinae. Acta Crystallographica F 2011; 67: 1612-5.
Ramani A, Andiappan AK, Parate PN, Suri BK, Wang DY, Chew FT. Genome-wide association study identifies PERLD1 as asthma candidate gene. BMC Med Genetics 2011; 12(1): No. 170.
Lwin ZM, Yip GWC, Chew FT, Bay BH. Down-regulation of ER60 protease inhibits cellular proliferation by inducing G1/S arrest in breast cancer in vitro. Anat Rec 2012; 295: 410-6.
Andiappan AK, Foo JN, Choy MW, Chen HJ, Common JEA, Tang MBY, van Bever HP, Giam YC, Suri BK, Ramani A, Parate PN, Lane BE, Wang DY, Chew FT*, Liu JJ*. Validation of GWAS loci for atopic dermatitis in a Singapore Chinese population. J Invest Dermatol 2012; 132: 1505-7.
Leong DTW, Abraham MC, Gupta A, Lim TC, Chew FT, Hutmacher DW. ATF5, a possible regulator of osteogenic differentiation in human adipose-derived stem cells. J Cell Biochem2012 113: 2744-53.
Nilsson D, Andiappan AK, Halldén C, Wang DY, Säll T, Chew FT, Cardell O. Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study.BMC Med Genetics2012; 13: No. 66.
Tan KW, Ong TC, Gao YF, Tiong LYS, Wong KN, Chew FT, Mok YK. NMR structure and IgE epitopes of Blo t 21, a major Blomia tropicalis allergen. J Biol Chem2012; 287:34776-85.
Tan KW, Jobichen C, Ong TC, Gao YF, Tiong YS, Wong KN, Chew FT, Sivaraman J, Mok YK. Crystal structure of Der f 7, a dust mite allergen from Dermatophagoides farinae. PLoS One 2012; 7(9): e44850.
Tsai CH, Tung KY, Su MW, Chiang BL, Chew FT, Kuo NW, Leo LY. Interleukin-13 genetic variants, household carpet use and childhood asthma. PLoS One 2013; 8(1): e51970.
Nilsson D, Andiappan AK, Halldén C, Chew FT, Säll T, Wang DY, Cardell O. Poor reproducibility of allergic rhinitis SNP associations. PLoS One 2013; 8(1): e53975.
Andiappan AK, Wang DY, Ramani A, Suri BK, Lee B, Rotzschke O, Liu JJ, Chew FT. Replication of genome-wide association study loci for allergic rhinitis and house dust mite sensitization in an Asian population of ethnic Chinese in Singapore. J Allergy Clin Immunol (in press).
Neoh BK, Teh HF, Ng TLM, Tiong SH, Mohd Amiron E, Mohamed M, Chew FT, Kulaveerasingam H, Appleton DR. Profiling of metabolites in oil palm mesocarp at different stages of oil biosynthesis. J Agric Food Chem (in press).