Gene-Environment interactions in asthma: what we know today?
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7th Pneumonology Dept. and Asthma Centre, SOTIRIA” Hospital for Chest Diseases, Athens, Greece
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
Human Development and Health, Faculty of Medicine University of Southampton, Southampton General Hospital, Southampton, United Kingdom
Eleftherios Zervas   

7th Pneumonology Dept. and Asthma Centre, “SOTIRIA” Hospital for Chest Diseases, Mesogion Ave. 152, 11527 Athens, Greece
Pneumon 2012;25(1):83–98
Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: NHLBI/WHO workshop Report: National Institutes of Health, National Heart, Lung and Blood Institute. NIH publication No. 02-3659; updated 2009. Available on
Borish L, Culp JA. Asthma: a syndrome composed of heterogeneous diseases. Ann Allergy Asthma Immunol 2008;101:1-8.
Wenzel SE, Schwartz LB, Langmack EL et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001-1008.
Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006;368:804-813.
Samitas K, Vittorakis S, Chorianopoulos D, Oikonomidou E, Gaga M. Immunological Mechanisms in the Lung. Pneumon 2007; 20:274-278.
Wu X, Jin L, Xiong M. Mutual information for testing geneenvironment interaction. PLo S One 2009;4:e4578.
Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol 2010;126:453-465.
Holloway JW, Yang IA, Holgate ST. Genetics of allergic disease. J Allergy Clin Immunol 2010;125:S81-S94.
Pruss-Ustun A, Corvalan C. How much disease burden can be prevented by environmental interventions? Epidemiology 2007;18:167-178.
D’Amato G, Liccardi G, D’Amato M, Holgate S. Environmental risk factors and allergic bronchial asthma. Clin Exp Allergy 2005;35:1113-1124.
Umstead T, Phelps D, Floros J. Ground level ozone is both a regional and global problem. Pneumon 2011, 24:20-23.
Kunzli N, Kaiser R, Medina S et al. Public-health impact of outdoor and traffic-related air pollution: a European assessment. Lancet 2000;356:795-801.
Gilmour MI, Jaakkola MS, London SJ, Nel AE, Rogers CA. How exposure to environmental tobacco smoke, outdoor air pollutants, and increased pollen burdens influences the incidence of asthma. Environ Health Perspect 2006;114:627-633.
Jacquemin B, Sunyer J, Forsberg B et al. Association between modelled traffic-related air pollution and asthma score in the ECRHS. Eur Respir J 2009;34:834-842.
Bernstein JA, Alexis N, Bacchus H et al. The health effects of non-industrial indoor air pollution. J Allergy Clin Immunol 2008;121:585-591.
Baena-Cagnani CE, Gomez RM, Baena-Cagnani R, Canonica GW. Impact of environmental tobacco smoke and active tobacco smoking on the development and outcomes of asthma and rhinitis. Curr Opin Allergy Clin Immunol 2009;9:136-140.
Sturm JJ, Yeatts K, Loomis D. Effects of tobacco smoke exposure on asthma prevalence and medical care use in North Carolina middle school children. Am J Public Health 2004;94:308-313.
Yu M, Zheng X, Peake J, Joad JP, Pinkerton KE. Perinatal environmental tobacco smoke exposure alters the immune response and airway innervation in infant primates. J Allergy Clin Immunol 2008;122:640-647.
Bush RK. Indoor allergens, environmental avoidance, and allergic respiratory disease. Allergy Asthma Proc 2008;29:575-579.
Illi S, von ME, Lau S et al. Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study. Lancet 2006;368:763-770.
Sporik R, Squillace SP, Ingram JM et al. Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in children: a case-control study of three schools. Thorax 1999;54:675-680.
Custovic A, Taggart SC, Francis HC, Chapman MD, Woodcock A. Exposure to house dust mite allergens and the clinical activity of asthma. J Allergy Clin Immunol 1996;98:64-72.
Ohshima Y, Yamada A, Hiraoka M et al. Early sensitization to house dust mite is a major risk factor for subsequent development of bronchial asthma in Japanese infants with atopic dermatitis: results of a 4-year followup study. Ann Allergy Asthma Immunol 2002;89:265-270.
Tovey ER, Almqvist C, Li Q, Crisafulli D, Marks GB. Nonlinear relationship of mite allergen exposure to mite sensitization and asthma in a birth cohort. J Allergy Clin Immunol 2008;122:114- 118.
Bertelsen RJ, Carlsen KC, Carlsen KH et al. Childhood asthma and early life exposure to indoor allergens, endotoxin and beta(1,3)-glucans. Clin Exp Allergy 2010;40:307-316.
Brussee JE, Smit HA, van Strien RT et al. Allergen exposure in infancy and the development of sensitization, wheeze, and asthma at 4 years. J Allergy Clin Immunol 2005;115:946-952.
D’Amato G. Environmental urban factors (air pollution and allergens) and the rising trends in allergic respiratory diseases. Allergy 2002;57(Suppl)72:30-33.
Kihlstrom A, Lilja G, Pershagen G, Hedlin G. Exposure to birch pollen in infancy and development of atopic disease in childhood. J Allergy Clin Immunol 2002;110:78-84.
Denning DW, O’Driscoll BR, Hogaboam CM, Bowyer P, Niven RM. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J 2006;27:615-626.
Zureik M, Neukirch C, Leynaert B et al. Sensitisation to airborne moulds and severity of asthma: cross sectional study from European Community respiratory health survey. BMJ 2002;325:411-414.
Perzanowski MS, Sporik R, Squillace SP et al. Association of sensitization to Alternaria allergens with asthma among school-age children. J Allergy Clin Immunol 1998;101:626-632.
Rosenthal LA, Avila PC, Heymann PW et al. Viral respiratory tract infections and asthma: the course ahead. J Allergy Clin Immunol 2010;125:1212-1217.
Jackson DJ, Gangnon RE, Evans MD et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am.J.Respir.Crit Care Med 2008;178:667-672.
Kusel MM, de Klerk NH, Kebadze T et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007;119:1105-1110.
Hylkema MN, Sterk PJ, de Boer WI, Postma DS. Tobacco use in relation to COPD and asthma. Eur Respir J 2007;29:438-445.
Rovina N, Gratziou C. Asthma and smoking. Pneumon 2006; 19:202-215.
Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma phenotype? J Appl Physiol 2010;108:729-734.
Arvaniti F, Priftis KN, Panagiotakos DB. Dietary habits and asthma: a review. Allergy Asthma Proc 2010;31:e1-10.
Allen S, Britton JR, Leonardi-Bee JA. Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis. Thorax 2009;64:610-619.
Zervas E, Gaga M. Work-related and occupational asthma. In: Palange P., Simonds A., eds. ERS Handbook, Respiratory Medicine.: ERS; 2010:268-272.
Tarlo SM, Balmes J, Balkissoon R et al. Diagnosis and management of work-related asthma: American College Of Chest Physicians Consensus Statement. Chest 2008;134:1S-41S.
Koppelman GH, Los H, Postma DS. Genetic and environment in asthma: the answer of twin studies. Eur Respir J 1999;13:2-4.
Nieminen MM, Kaprio J, Koskenvuo M. A population-based study of bronchial asthma in adult twin pairs. Chest 1991;100:70-75.
Duffy DL, Martin NG, Battistutta D, Hopper JL, Mathews JD. Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis 1990;142:1351-1358.
Deichmann KA, Starke B, Schlenther S et al. Linkage and association studies of atopy and the chromosome 11q13 region. J Med Genet 1999;36:379-382.
Dawn TM, Barrett JH. Genetic linkage studies. Lancet 2005; 366:1036-1044.
Wills-Karp M, Ewart SL. Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 2004;5:376-387.
Bouzigon E, Forabosco P, Koppelman GH et al. Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy. Eur J Hum Genet 2010;18:700-706.
Howard TD, Meyers DA, Bleecker ER. Mapping susceptibility genes for allergic diseases. Chest 2003;123:363S-368S.
Van EP, Little RD, Dupuis J et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426-430.
Allen M, Heinzmann A, Noguchi E et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 2003;35:258-263.
Gohlke H, Illig T, Bahnweg M et al. Association of the interleukin-1 receptor antagonist gene with asthma. Am J Respir Crit Care Med 2004;169:1217-1223.
Noguchi E, Yokouchi Y, Zhang J et al. Positional identification of an asthma susceptibility gene on human chromosome 5q33. Am J Respir Crit Care Med 2005;172:183-188.
Walley AJ, Chavanas S, Moffatt MF et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001; 29:175-178.
Koppelman GH, Meyers DA, Howard TD et al. Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness. Am J Respir Crit Care Med 2009;180:929-935.
Nicolae D, Cox NJ, Lester LA et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005;76:349-357.
Laitinen T, Polvi A, Rydman P et al. Characterization of a common susceptibility locus for asthma-related traits. Science 2004;304:300-304.
Zhang Y, Leaves NI, Anderson GG et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003;34:181- 186.
Oguma T, Palmer LJ, Birben E et al. Role of prostanoid DP receptor variants in susceptibility to asthma. N Engl J Med 2004;351:1752-1763.
Barton SJ, Koppelman GH, Vonk JM et al. PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline. J Allergy Clin Immunol 2009;123:1391-1400.
Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002;3:391-397.
March ME, Sleiman PM, Hakonarson H. The genetics of asthma and allergic disorders. Discov Med 2011;11:35-45.
Zhang G, Hayden CM, Khoo SK et al. Beta2-Adrenoceptor polymorphisms and asthma phenotypes: interactions with passive smoking. Eur Respir J 2007;30:48-55.
Hawkins GA, Tantisira K, Meyers DA et al. Sequence, haplotype, and association analysis of ADR beta2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med 2006;174:1101- 1109.
Guerra S, Graves PE, Morgan WJ et al. Relation of beta2- adrenoceptor polymorphisms at codons 16 and 27 to persistence of asthma symptoms after the onset of puberty. Chest 2005;128:609-617.
Amirzargar AA, Movahedi M, Rezaei N et al. Polymorphisms in IL4 and iLARA confer susceptibility to asthma. J Investig Allergol Clin Immunol 2009;19:433-438.
Pykalainen M, Kinos R, Valkonen S et al. Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes. J Allergy Clin Immunol 2005;115:80-87.
Beghe B, Barton S, Rorke S et al. Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 2003;33:1111-1117.
Nakao F, Ihara K, Kusuhara K et al. Association of IFN-gamma and IFN regulatory factor 1 polymorphisms with childhood atopic asthma. J Allergy Clin Immunol 2001;107:499-504.
Sandford AJ, Chagani T, Zhu S et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000;106:135-140.
Zhu S, Chan-Yeung M, Becker AB et al. Polymorphisms of the IL-4, TNF-alpha, and Fcepsilon RIbeta genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med 2000;161:1655-1659.
Beghe B, Hall IP, Parker SG et al. Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease. Allergy 2010;65:474-481.
Black S, Teixeira AS, Loh AX et al. Contribution of functional variation in the IL13 gene to allergy, hay fever and asthma in the NSHD longitudinal 1946 birth cohort. Allergy 2009;64:1172-1178.
Hunninghake GM, Soto-Quiros ME, Avila L et al. Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood. J Allergy Clin Immunol 2007;120:84-90.
Hizawa N, Maeda Y, Konno S et al. Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility. Clin Exp Allergy 2006;36:872-876.
Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005;6:95- 108.
Akhabir L, Sandford AJ. Genome-wide Association Studies for Discovery of Genes Involved in Asthma. Respirology 2011; 16:396-406.
Moffatt MF, Kabesch M, Liang L et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007;448:470-473.
Bisgaard H, Bonnelykke K, Sleiman PM et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med 2009;179:179-185.
Bouzigon E, Corda E, Aschard H et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med 2008;359:1985-1994.
Ferreira MA, McRae AF, Medland SE et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur J Hum Genet 2011;19:458-464.
Leung TF, Sy HY, Ng MC et al. Asthma and atopy are associated with chromosome 17q21 markers in Chinese children. Allergy 2009;64:621-628.
Madore AM, Tremblay K, Hudson TJ, Laprise C. Replication of an association between 17q21 SNPs and asthma in a FrenchCanadian familial collection. Hum Genet 2008;123:93-95.
Wu H, Romieu I, Sienra-Monge JJ et al. Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy 2009;64:629-635.
Gudbjartsson DF, Bjornsdottir US, Halapi E et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009;41:342-347.
Moffatt MF, Gut IG, Demenais F et al. A large-scale, consortiumbased genomewide association study of asthma. N Engl J Med 2010;363:1211-1221.
Reijmerink NE, Bottema RW, Kerkhof M et al. TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy. Allergy 2010;65:199-207.
Wu H, Romieu I, Shi M et al. Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans. J Allergy Clin Immunol 2010;125:321-327.
Li X, Howard TD, Zheng SL et al. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol 2010;125:328-335.
Weidinger S, Gieger C, Rodriguez E et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet 2008;4:e1000166.
Himes BE, Hunninghake GM, Baurley JW et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 2009;84:581-593.
Melen E, Himes BE, Brehm JM et al. Analyses of shared genetic factors between asthma and obesity in children. J Allergy Clin Immunol 2010;126:631-637.
Kim SH, Oh HB, Lee KW et al. HLA DRB1*15-DPB1*05 haplotype: a susceptible gene marker for isocyanate-induced occupational asthma? Allergy 2006;61:891-894.
Sleiman PM, Flory J, Imielinski M et al. Variants of DENND1B associated with asthma in children. N Engl J Med 2010;362:36- 44.
Ober C, Tan Z, Sun Y et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N Engl J Med 2008;358:1682-1691.
Schauberger EM, Ewart SL, Arshad SH et al. Identification of ATPAF1 as a novel candidate gene for asthma in children. J Allergy Clin Immunol 2011; 128:753-760.
Mathias RA, Grant AV, Rafaels N et al. A genome-wide association study on African-ancestry populations for asthma. J Allergy Clin Immunol 2010;125:336-346.
Simpson A, Custovic A. Prevention of allergic sensitization by environmental control. Curr Allergy Asthma Rep 2009;9:363- 369.
Castro-Giner F, Kauffmann F, de CR, Kogevinas M. Geneenvironment interactions in asthma. Occup Environ Med 2006; 63:776-786.
London SJ, Romieu I. Gene by environment interaction in asthma. Annu Rev Public Health 2009;30:55-80.
von ME. Gene-environment interactions in asthma. J Allergy Clin Immunol 2009;123:3-11.
Steiropoulos P, Ito K. Genes and severe asthma. Pneumon 2011;24:321-329.
Winterton DL, Kaufman J, Keener CV et al. Genetic polymorphisms as biomarkers of sensitivity to inhaled sulfur dioxide in subjects with asthma. Ann Allergy Asthma Immunol 2001;86:232-238.
David GL, Romieu I, Sienra-Monge JJ et al. Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. Am J Respir Crit Care Med 2003;168:1199-1204.
Castro-Giner F, Kunzli N, Jacquemin B et al. Traffic-related air pollution, oxidative stress genes, and asthma (ECHRS). Environ Health Perspect 2009;117:1919-1924.
Lee YL, Lin YC, Lee YC et al. Glutathione S-transferase P1 gene polymorphism and air pollution as interactive risk factors for childhood asthma. Clin Exp Allergy 2004;34:1707-1713.
Lee YL, McConnell R, Berhane K, Gilliland FD. Ambient ozone modifies the effect of tumor necrosis factor G-308A on bronchitic symptoms among children with asthma. Allergy 2009;64:1342-1348.
Melen E, Nyberg F, Lindgren CM et al. Interactions between glutathione S-transferase P1, tumor necrosis factor, and trafficrelated air pollution for development of childhood allergic disease. Environ Health Perspect 2008;116:1077-1084.
Islam T, Berhane K, McConnell R et al. Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children. Thorax 2009;64:197-202.
Islam T, McConnell R, Gauderman WJ et al. Ozone, oxidant defense genes, and risk of asthma during adolescence. Am J Respir Crit Care Med 2008;177:388-395.
Wenten M, Gauderman WJ, Berhane K et al. Functional variants in the catalase and myeloperoxidase genes, ambient air pollution, and respiratory-related school absences: an example of epistasis in gene-environment interactions. Am J Epidemiol 2009;170:1494-1501.
Blumenthal M, Marcus-Bagley D, Awdeh Z et al. HLA-DR2, [HLA-B7, SC31, DR2], and [HLA-B8, SC01, DR3] haplotypes distinguish subjects with asthma from those with rhinitis only in ragweed pollen allergy. J Immunol 1992;148:411-416.
Soriano JB, Ercilla G, Sunyer J et al. HLA class II genes in soybean epidemic asthma patients. Am J Respir Crit Care Med 1997;156:1394-1398.
Blumenthal MN, Langefeld CD, Barnes KC et al. A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity. J Allergy Clin Immunol 2006;117:79- 85.
Llanes E, Quiralte J, Lopez E et al. Analysis of polymorphisms in olive pollen allergy: IL13, IL4RA, IL5 and ADRB2 genes. Int Arch Allergy Immunol 2009;148:228-238.
Di SC, Charron D, Deichmann K, Buono C, Ruffilli A. Atopic asthma and TNF-308 alleles: linkage disequilibrium and association analyses. Hum Immunol 2003;64:359-365.
Wang Z, Chen C, Niu T et al. Association of asthma with beta(2)- adrenergic receptor gene polymorphism and cigarette smoking. Am J Respir Crit Care Med 2001;163:1404-1409.
Rouse RL, Boudreaux MJ, Penn AL. In utero environmental tobacco smoke exposure alters gene expression in lungs of adult BALB/c mice. Environ Health Perspect 2007;115:1757- 1766.
Gilliland FD, Li YF, Dubeau L et al. Effects of glutathione Stransferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children. Am J Respir Crit Care Med 2002;166:457-463.
Rogers AJ, Brasch-Andersen C, Ionita-Laza I et al. The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma. Clin Exp Allergy 2009;39:1721-1729.
Ramadas RA, Sadeghnejad A, Karmaus W et al. Interleukin-1R antagonist gene and pre-natal smoke exposure are associated with childhood asthma. Eur Respir J 2007;29:502-508.
Sadeghnejad A, Karmaus W, Arshad SH et al. IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study. Respir Res 2008;9:2.
Reijmerink NE, Kerkhof M, Koppelman GH et al. Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness. Allergy 2009;64:898- 904.
Jaakkola JJ, Nafstad P, Magnus P. Environmental tobacco smoke, parental atopy, and childhood asthma. Environ Health Perspect 2001;109:579-582.
Colilla S, Nicolae D, Pluzhnikov A et al. Evidence for geneenvironment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol 2003;111:840-846.
Palmer CN, Doney AS, Lee SP et al. Glutathione S-transferase M1 and P1 genotype, passive smoking, and peak expiratory flow in asthma. Pediatrics 2006;118:710-716.
Panasevich S, Lindgren C, Kere J et al. Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing. Clin Exp Allergy 2010;40:458-467.
Li YF, Tseng PJ, Lin CC et al. NAD(P)H: Quinone oxidoreductase 1, glutathione S-transferase M1, environmental tobacco smoke exposure, and childhood asthma. Mutat Res 2009;678:53-58.
Meyers DA, Postma DS, Stine OC et al. Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure. J Allergy Clin Immunol 2005;115:1169-1175.
Werner M, Topp R, Wimmer K et al. TLR4 gene variants modify endotoxin effects on asthma. J Allergy Clin Immunol 2003;112:323- 330.
Zambelli-Weiner A, Ehrlich E, Stockton ML et al. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J Allergy Clin Immunol 2005;115:1203-1209.
Simpson A, John SL, Jury F et al. Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am J Respir Crit Care Med 2006;174:386-392.
Keskin O, Birben E, Sackesen C et al. The effect of CD14-c159T genotypes on the cytokine response to endotoxin by peripheral blood mononuclear cells from asthmatic children. Ann Allergy Asthma Immunol 2006;97:321-328.
Tsai CH, Tung KY, Chen CH, Lee YL. Tumour necrosis factor G308A polymorphism modifies the effect of home dampness on childhood asthma. Occup Environ Med 2011; 68:771-776.
Arshad SH. Does exposure to indoor allergens contribute to the development of asthma and allergy? Curr Allergy Asthma Rep 2010;10:49-55.
Kim YK, Oh HB, Oh SY et al. HLA-DRB1*07 may have a susceptibility and DRB1*04 a protective effect upon the development of a sensitization to house dust mite Dermatophagoides pteronyssinus. Clin Exp Allergy 2001;31:110-115.
Rajagopalan G, Tilahun AY, Iijima K et al. HLA-DR polymorphism modulates response to house dust mites in a transgenic mouse model of airway inflammation. Tissue Antigens 2011; 77:589- 592.
Holloway JW, Doull I, Begishvili B et al. Lack of evidence of a significant association between HLA-DR, DQ and DP genotypes and atopy in families with HDM allergy. Clin Exp Allergy 1996;26:1142-1149.
Torres-Galvan MJ, Quiralte J, Blanco C et al. Linkage of house dust mite allergy with the HLA region. Ann Allergy Asthma Immunol 1999;82:198-203.
Moffatt MF, Schou C, Faux JA et al. Association between quantitative traits underlying asthma and the HLA-DRB1 locus in a family-based population sample. Eur J Hum Genet 2001;9:341-346.
Parapanissiou E, Papastavrou T, Deligiannidis A et al. HLA antigens in Greek children with allergic bronchial asthma. Tissue Antigens 2005;65:481-484.
Pampuch A, Kowal K, Bodzenta-Lukaszyk A et al. The -675 4G/5G plasminogen activator inhibitor-1 promoter polymorphism in house dust mite-sensitive allergic asthma patients. Allergy 2006;61:234-238.
Kowal K, Bodzenta-Lukaszyk A, Pampuch A et al. Analysis of -675 4 g/5 G SERPINE1 and C-159T CD14 polymorphisms in house dust mite-allergic asthma patients. J Investig Allergol Clin Immunol 2008;18:284-292.
Sharma S, Raby BA, Hunninghake GM et al. Variants in TGFB1, dust mite exposure, and disease severity in children with asthma. Am J Respir Crit Care Med 2009;179:356-362.
Acevedo N, Vergara C, Gusmao L et al. The C-509T promoter polymorphism of the transforming growth factor beta-1 gene is associated with levels of total and specific IgE in a Colombian population. Int Arch Allergy Immunol 2010;151:237-246.
Shin HD, Kim LH, Park BL et al. Association of interleukin 18 (IL18) polymorphisms with specific IgE levels to mite allergens among asthmatic patients. Allergy 2005;60:900-906.
Wang TN, Chen WY, Huang YF et al. The synergistic effects of the IL-9 gene and environmental exposures on asthmatic Taiwanese families as determined by the transmission/disequilibrium test. Int J Immunogenet 2006;33:105-110.
Martinez B, Barrios K, Vergara C et al. A NOS1 gene polymorphism associated with asthma and specific immunoglobulin E response to mite allergens in a Colombian population. Int Arch Allergy Immunol 2007;144:105-113.
Hunninghake GM, Soto-Quiros ME, Lasky-Su J et al. Dust mite exposure modifies the effect of functional IL10 polymorphisms on allergy and asthma exacerbations. J Allergy Clin Immunol 2008;122:93-98.
Konno S, Takahashi D, Hizawa N et al. Genetic impact of a butyrophilin-like 2 (BTNL2) gene variation on specific IgE responsiveness to Dermatophagoides farinae (Der f) in Japanese. Allergol Int 2009;58:29-35.
Hizawa N, Freidhoff LR, Ehrlich E et al. Genetic influences of chromosomes 5q31-q33 and 11q13 on specific IgE responsiveness to common inhaled allergens among African American families. Collaborative Study on the Genetics of Asthma (CSGA). J Allergy Clin Immunol 1998;102:449-453.
Gao P, Grigoryev DN, Rafaels NM et al. CD14, a key candidate gene associated with a specific immune response to cockroach. Clin Exp Allergy 2010;40:1353-1364.
Donfack J, Tsalenko A, Hoki DM et al. HLA-DRB1*01 alleles are associated with sensitization to cockroach allergens. J Allergy Clin Immunol 2000;105:960-966.
Kalpaklioglu AF, Turan M. Possible association between cockroach allergy and HLA class II antigens. Ann Allergy Asthma Immunol 2002;89:155-158.
Weiss LA, Lester LA, Gern JE et al. Variation in ITGB3 is associated with asthma and sensitization to mold allergen in four populations. Am J Respir Crit Care Med 2005;172:67-73.
Knutsen AP, Vijay HM, Kariuki B et al. Association of IL-4RA single nucleotide polymorphisms, HLA-DR and HLA-DQ in children with Alternaria-sensitive moderate-severe asthma. Clin Mol Allergy 2010;8:5.
Wu AC, Lasky-Su J, Rogers CA, Klanderman BJ, Litonjua AA. Fungal exposure modulates the effect of polymorphisms of chitinases on emergency department visits and hospitalizations. Am J Respir Crit Care Med 2010;182:884-889.
Vicencio AG, Chupp GL, Tsirilakis K et al. CHIT1 mutations: genetic risk factor for severe asthma with fungal sensitization? Pediatrics 2010;126:e982-e985.
Bottema RW, Reijmerink NE, Kerkhof M et al. Interleukin 13, CD14, pet and tobacco smoke influence atopy in three Dutch cohorts: the allergenic study. Eur Respir J 2008;32:593-602.
Schuttelaar ML, Kerkhof M, Jonkman MF et al. Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure. Allergy 2009;64:1758- 1765.
Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000;406:782-787.
Yang IA, Fong KM, Holgate ST, Holloway JW. The role of Toll-like receptors and related receptors of the innate immune system in asthma. Curr Opin Allergy Clin Immunol 2006;6:23-28.
Raby BA, Klimecki WT, Laprise C et al. Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am J Respir Crit Care Med 2002;166:1449-1456.
Smit LA, Bongers SI, Ruven HJ et al. Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study. Clin Exp Allergy 2007;37:1602-1608.
Yang IA, Barton SJ, Rorke S et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun 2004;5:41-45.
Bjornvold M, Munthe-Kaas MC, Egeland T et al. A TLR2 polymorphism is associated with type 1 diabetes and allergic asthma. Genes Immun 2009;10:181-187.
Bottema RW, Kerkhof M, Reijmerink NE et al. Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood. J Allergy Clin Immunol 2010;126:338-346.
Eder W, Klimecki W, Yu L et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004;113:482-488.
Qian FH, Zhang Q, Zhou LF et al. Polymorphisms in the toll-like receptor 2 subfamily and risk of asthma: a case-control analysis in a Chinese population. J Investig Allergol Clin Immunol 2010;20:340-346.
Smit LA, Siroux V, Bouzigon E et al. CD14 and toll-like receptor gene polymorphisms, country living, and asthma in adults. Am J Respir Crit Care Med 2009;179:363-368.
Hoffjan S, Stemmler S, Parwez Q et al. Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Med Genet 2005;6:34.
Kormann MS, Depner M, Hartl D et al. Toll-like receptor heterodimer variants protect from childhood asthma. J Allergy Clin Immunol 2008;122:86-92.
Tantisira K, Klimecki WT, Lazarus R et al. Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun 2004;5:343-346.
Moller-Larsen S, Nyegaard M, Haagerup A et al. Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax 2008;63:1064-1069.
Lazarus R, Klimecki WT, Raby BA et al. Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics 2003;81:85-91.
Heinzmann A, Brugger M, Bierbaum S et al. Joint influences of Acidic-Mammalian-Chitinase with Interleukin-4 and Toll-like receptor-10 with Interleukin-13 in the genetics of asthma. Pediatr Allergy Immunol 2010;21:e679-e686.
Lazarus R, Raby BA, Lange C et al. TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples. Am J Respir Crit Care Med 2004;170:594-600.
Custovic A, Rothers J, Stern D et al. Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies. J Allergy Clin Immunol 2011;127:390-397.
Hoffjan S, Nicolae D, Ostrovnaya I et al. Gene-environment interaction effects on the development of immune responses in the 1st year of life. Am J Hum Genet 2005;76:696-704.
Kirkbride HJ, Bolscher JG, Nazmi K et al. Genetic polymorphism of MUC7: allele frequencies and association with asthma. Eur J Hum Genet 2001;9:347-354.
Rousseau K, Vinall LE, Butterworth SL et al. MUC7 haplotype analysis: results from a longitudinal birth cohort support protective effect of the MUC7*5 allele on respiratory function. Ann Hum Genet 2006;70:417-427.
Laitinen T, Daly MJ, Rioux JD et al. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genomewide scan in a founder population. Nat Genet 2001;28:87-91.
van Heel DA, Ghosh S, Butler M et al. Synergistic enhancement of Toll-like receptor responses by NOD1 activation. Eur J Immunol 2005;35:2471-2476.
Weidinger S, Klopp N, Rummler L et al. Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 2005;116:177-184.
Radon K. The two sides of the “endotoxin coin”. Occup Environ Med 2006;63:73-78.
Bignon JS, Aron Y, Ju LY et al. HLA class II alleles in isocyanateinduced asthma. Am J Respir Crit Care Med 1994;149:71-75.
Balboni A, Baricordi OR, Fabbri LM et al. Association between toluene diisocyanate-induced asthma and DQB1 markers: a possible role for aspartic acid at position 57. Eur Respir J 1996;9:207-210.
Mapp CE, Beghe B, Balboni A et al. Association between HLA genes and susceptibility to toluene diisocyanate-induced asthma. Clin Exp Allergy 2000;30:651-656.
Rihs HP, Barbalho-Krolls T, Huber H, Baur X. No evidence for the influence of HLA class II in alleles in isocyanate-induced asthma. Am J Ind Med 1997;32:522-527.
Bernstein JA, Munson J, Lummus ZL, Balakrishnan K, Leikauf G. T-cell receptor V beta gene segment expression in diisocyanate-induced occupational asthma. J Allergy Clin Immunol 1997;99:245-250.
Beghe B, Padoan M, Moss CT et al. Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma. Allergy 2004;59:61-64.
Piirila P, Wikman H, Luukkonen R et al. Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure. Pharmacogenetics 2001;11:437-445.
Wikman H, Piirila P, Rosenberg C et al. N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics 2002;12:227-233.
Mapp CE, Fryer AA, De MN et al. Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates. J Allergy Clin Immunol 2002;109:867-872.
Kim SH, Cho BY, Park CS et al. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy 2009;39:203-212.
Horne C, Quintana PJ, Keown PA, Dimich-Ward H, Chan-Yeung M. Distribution of DRB1 and DQB1 HLA class II alleles in occupational asthma due to western red cedar. Eur Respir J 2000;15:911-914.
Young RP, Barker RD, Pile KD, Cookson WO, Taylor AJ. The association of HLA-DR3 with specific IgE to inhaled acid anhydrides. Am J Respir Crit Care Med 1995;151:219-221.
Jones MG, Nielsen J, Welch J et al. Association of HLA-DQ5 and HLA-DR1 with sensitization to organic acid anhydrides. Clin Exp Allergy 2004;34:812-816.
Riedler J, Braun-Fahrlander C, Eder W et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129-1133.
Von Ehrenstein OS, Von ME, Illi S et al. Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy 2000;30:187-193.
Braun-Fahrlander C, Riedler J, Herz U et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869-877.
Lauener RP, Birchler T, Adamski J et al. Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 2002;360:465-466.
Eder W, Klimecki W, Yu L et al. Association between exposure to farming, allergies and genetic variation in CARD4/NOD1. Allergy 2006;61:1117-1124.
Bieli C, Eder W, Frei R et al. A polymorphism in CD14 modifies the effect of farm milk consumption on allergic diseases and CD14 gene expression. J Allergy Clin Immunol 2007;120:1308- 1315.
Ege MJ, Strachan DP, Cookson WO et al. Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. J Allergy Clin Immunol 2011;127:138-144.
Kabesch M, Hoefler C, Carr D et al. Glutathione S transferase deficiency and passive smoking increase childhood asthma. Thorax 2004;59:569-573.
Yang Q, Khoury MJ. Evolving methods in genetic epidemiology. III. Gene-environment interaction in epidemiologic research. Epidemiol Rev 1997;19:33-43.
Ottman R. An epidemiologic approach to gene-environment interaction. Genet Epidemiol 1990;7:177-185.
Colhoun HM, McKeigue PM, Davey SG. Problems of reporting genetic associations with complex outcomes. Lancet 2003;361:865-872.
Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 2001;358:1356-1360.
Yang IA, Holloway JW. Asthma: advancing gene-environment studies. Clin Exp Allergy 2007;37:1264-1266.