Predicting asthma phenotypes: characterization of IL1RL1 in asthma
Dijk, Fokelina Nicole
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Genetics of
onset of asthma
_
Chapter 2
Abstract
Purpose of review
Most asthma starts early in life. Defining phenotypes of asthma at this age is difficult as many preschool children have asthma-like respiratory symptoms. This review discusses progress in defining early wheez-ing phenotypes and describes genetic factors associated with the age of onset of asthma.
Recent findings
Latent class analyses confirmed transient and persistent wheezing phenotypes, and identified a novel in-termediate-onset wheezing phenotype that was strongly associated with atopy and asthma at age 8 years. However, no single cross-sectional or longitudinal definition of respiratory symptoms in childhood strongly predicts asthma later in life. Genome-wide association (GWA) studies have identified a locus on chromo-some 17q12–21 (encoding ORMDL3 and GSDMB) as a risk factor for predominantly childhood-onset asth-ma, but not for atopy, and overall not for adult-onset asthma. Other loci found by GWA studies appear to increase asthma risk both in children and adults. Atopy genes do not explain early-onset asthma.
Summary
Although most asthma starts early in life, no valid test is able to identify asthma at that age period. GWA studies have provided more insight into the unique and common genetic origins of adult-onset and childhood-onset asthma. The 17q12–21 locus is predominantly associated with childhood-onset asthma.
Abbreviations
ALSPAC - Avon Longitudinal Study of Parents and Children AHR - Airway hyperresponsiveness
AUC - Area under the curve
ETS - Environmental tobacco smoke ERS - European Respiratory Society GWA - Genome-wide association LD - Linkage disequilibrium
LLCA - Longitudinal latent class analysis OR - Odds ratio
Introduction
Asthma is a common chronic lower respiratory disease that results from the interactions between genes and environmental factors. It affects more than 300 million people worldwide and its prevalence is still increasing globally.1 Asthma is characterized by chronic airway inflammation associated with variable
airflow obstruction and airway hyperresponsiveness (AHR) leading to recurrent episodes of wheeze, cough, and shortness of breath.2 Different asthma phenotypes can be distinguished based on the
pres-ence, timing, and severity of symptoms (e.g., age of onset, nocturnal symptoms), atopy, responsiveness to triggers, and type of airway inflammation eosinophilic or neutrophilic). Recent findings indicate that ge-netic factors of childhood-onset asthma differ from those of adult-onset asthma. Therefore, this review will focus on recent progress made in defining phenotypes of early-onset asthma, and describe genetic factors associated with the age of onset of asthma.
Defining early-onset asthma
It is problematic to define when asthma starts, because there is no conclusive diagnostic test available at preschool age. Respiratory symptoms suggestive of asthma, such as wheeze, cough, and shortness of breath are highly prevalent in early childhood, yet not specific for asthma, and commonly occur during viral respiratory infections. In clinical practice, a history of recurrent wheezing episodes is frequently con-sidered as the onset of asthma in children, often defined retrospectively and, hence, inaccurately. Longitudinal studies revealed that wheezing in the first 6 years of life comprise distinct phenotypes, with dissimilar causes and outcomes. A 1995 seminal paper from the Tucson Children’s Respiratory Study introduced a longitudinal wheezing classification.3 The ‘early transient wheezing’ phenotype included
children with onset of wheezing during the first 3 years of life with no symptoms at age 6, the ‘persistent wheezing’ phenotype included children with wheezing during the first 3 years of life that continued until age 6, and the ‘late-onset wheezing’ phenotype included children with development of wheezing be-tween 3 and 6 years of age.
In 2004, these wheezing phenotypes were further classified incorporating markers of atopy. ‘Transient wheezing’ was not associated with allergic sensitization and was associated with a slightly lower lung function, which was already present before any lower respiratory tract illness had occurred, probably caused by relatively narrow airways.3 ‘Nonatopic wheezing’ was associated with viral respiratory
infec-tions, without allergic sensitization.4 These children had normal lung function in infancy but slightly
lower lung function in later childhood, combined with increased AHR. ‘Atopic wheezing’ was recognized as the classical asthma phenotype, with normal lung function early in life but impairment later in life. Earlier onset of symptoms was associated with more severe asthma.3-5
Recently, two longitudinal birth cohort studies in the UK and the Netherlands analyzed annual reports of wheezing until age 8 and identified similar wheezing phenotype patterns using the unbiased, lon-gitudinal latent class analyses (LLCAs). A novel wheezing phenotype ‘intermediate-onset wheeze’ was identified, characterized by a low prevalence of wheeze until the age of 1.5 years with a rapidly increas-ing prevalence of symptoms thereafter.6 Persistent, late-onset, and intermediate-onset wheezing
phe-notypes were strongly associated with doctor-diagnosed asthma at age 8 years compared with never, transient early, and prolonged early wheezing phenotypes.6,7 Risk factors for persistence of wheeze were
As longitudinal phenotypes can only be categorized retrospectively, an European Respiratory Society task force proposed a cross-sectional classification of wheezing illness based on triggers: episodic viral wheeze (EVW) and multitrigger wheeze (MTW).8 It is often thought that MTW may precede asthma, yet
literature does not fully support this. Inconsistent clinical and pathological differences between these phenotypes have been reported9-11 and significant phenotypic switching between these wheezing
phe-notypes was observed.12 Therefore, this classification is of limited value when studying onset of asthma.13
When does asthma start?
In most patients, asthma has its origins in early childhood.14 A recent Danish study of high-risk children
showed that children with asthma at the age of 7 years already had increased AHR and lower lung func-tion as neonates. These lower lung funcfunc-tion levels progressively declined into childhood.15 Moreover,
characteristic pathological features of asthma in airway wall biopsies, such as eosinophilic inflammation and basement membrane thickening were observed in children with MTW at age 3, preceding symptoms of wheeze in toddlers.16,17 Finally, asthma at age 22 years was predicted by late-onset or persistent
wheez-ing at age 6, a decreased lung function, and AHR.18 There is still much uncertainty about the
relation-ship, similarities, and differences between childhood and adult asthma. Comparing the characteristics of childhood and adult asthma reveals similarities between risk factors, such as environmental tobacco smoke (ETS) exposure19,20, AHR, a family history of asthma6,7,18,21, the role of viral infections22, allergic
rhi-nitis23, atopic status, and eczema3,6,7,24,25,, but also differences (Table 1).26-30
Table 1. Clinical differences between childhood-onset and adulthood-onset asthma.
Susceptibility to childhood-asthma: answers from
genetic studies
Genetic factors were estimated to explain 34% of the variation in age of onset of asthma.31 Several
candidate gene studies have provided evidence for an age-specific genetic effect.32 Recently, novel
ge-nome-wide association (GWA) studies have allowed to disentangle childhood-onset and adult-onset asthma susceptibility in a hypothesis-free manner (Table 2 lists genetic terminology). Thus far, 14 GWA studies have been published revealing 27 loci with genome-wide significant risk variants for the develop-ment of asthma. Half of these studies were performed in childhood-onset asthma (Table 3).33-46
Table 2. Glossary table: genome-wide association study.
The role of the 17q12–21 locus in childhood onset
Asthma In the first GWA study on asthma, the 17q12–21 IKZF3-ZPBP2-GSDMB-ORMDL3 region was identi-fied as an asthma susceptibility locus in childhood-onset asthma in a white population. This observation was extensively replicated34,40-42,44,47-52 and thus far only not confirmed in African–Americans.53 A remarkable
finding is that the 17q12–21 SNPs have a particularly strong association with (early) childhood-onset asth-ma. This was first shown in a French population wherein 17q12–21 risk alleles were strongly associated with asthma when retrospectively defined as starting before the age of 12, but not with asthma that started at a later age. Subsequently, a prospective Danish study confirmed that this ORMDL3/GSDMB locus conferred an increased risk of recurrent wheeze and asthma, but only in case of early-onset disease, that is, before the age of 3 years, but not in later-onset asthma. Furthermore, an association was observed with severe exac-erbations until age 6 years and AHR until age 4, but not with atopy.48 Other studies also indicated that the
17q12–21 locus is not an atopy-susceptibility locus.40,47,49,54,55 In addition, a recent study performed in the Avon
Longitudinal Study of Parents and Children (ALSPAC) cohort revealed a significant association between 17q12–21 SNPs and the persistent-onset and intermediate-onset wheezing phenotypes.55
A large-scale GWA meta-analysis of the GABRIEL (A Multidisciplinary Study to Identify the Genetic and En-vironmental Causes of Asthma in the European Community) consortium of European ancestry individuals classified asthmatic patients in two age-of-onset groups: before or after 16 years of age. Significant associ-ations of ORMDL3/GSDMB SNPs were restricted to childhood-onset asthma. The SNP with the strongest association had an odds ratio (OR) of 0.64 in the childhood-onset group, compared with an OR of 1.03 in individuals with a later onset (mean difference P value: 1.34x10-9).40 Two other studies reported a
signifi-cant association of the 17q12–21 locus with childhood-onset asthma, but not adult-onset asthma54 and
with severe childhood asthma.56 Furthermore, the effect of 17q12–21 SNPs on early-onset asthma seems to
stronger association between respiratory infections and asthma onset less than 4 years of age if they had early ETS exposure. Moreover, the latter effect was also present in childhood asthma that remits in adult-hood.58 In contrast, a complete restriction of the 17q12–21 variants to early-onset asthma was refuted in a study
of predominantly adult-onset severe asthma (mean age of onset 21 years). Yet a genome-wide significant as-sociation with this locus was reported.44 Furthermore, a study59 performed in US asthma patients reported a
similar OR for 17q12–21 risk variants in their early-onset (<4 years) and late onset (≥4 years) asthma group. The functionality of the genes at the 17q12–21 locus is not well understood. Asthma risk alleles at this lo-cus are strongly correlated over multiple genes and, therefore, it is difficult to discover the causal asthma variant(s). The asthma-associated 17q12–21 alleles were correlated with the transcript levels of predom-inantly two genes, ORM1-like 3 (Saccharomyces cerevisiae) (ORMDL3) and GSDMB, which indicates that both genes are coregulated.33,54,55,60,61 A functional SNP in this region affects the binding of the nuclear
CCCTC-binding factor and, thus, alters nucleosome occupancy leading to altered regulation of transcrip-tion.60 ORMDL3 encodes for a transmembrane protein anchored in the endoplasmic reticulum. Its
func-tion might be related to endoplasmatic reticulum-mediated calcium signaling with modulafunc-tion of an unfolded protein response.62,63 ORMDL3 may modify important pathways in the process of T-lymphocyte
activation.64 A recent study65 in mice demonstrated that ORMDL3 is an airway epithelial gene that is
acti-vated by Th2 cytokines and allergens. Furthermore, its function has been linked to sphingolipid homeo-stasis.66 GSDMB may play a role in apoptosis and tumorgenesis and is expressed in epithelial cells.67
In conclusion, although different definitions of early-onset and late-onset asthma have been used, it seems that the asthma-associated 17q12–21 polymorphisms are related to a nonatopic, more severe ear-ly-onset asthma phenotype, and associations with adult-onset asthma are less prominent.
Table 3. Published GWA studies and meta-analysis of GWA studies for childhood and adult asthma which obtained genetic associations at a genome-wide significant level, either in the original cohort, the replication cohort or in a combined analysis.
*Reported as mean (±SD) or range, mn=month, y=year, † Bold genes were genome wide significant (P≤5x10-8) in the original cohort, underlined genes were genome wide significant in the replication/combined analyses, normal printed genes showed nominal significance in original, replication or combined analyses, ‡ No association in African Ameri-can population, § Associated with total IgE levels, not with asthma, ∫ Only associated in AfriAmeri-can AmeriAmeri-cans.
#Studies: MAGICS: German Multicenter Asthma Genetics in Childhood Study, ISAAC Phase II: International Study of Asthma and Allergies in Childhood cohort, phase II, CAMP: Childhood Asthma Management Program, GACRS: Genet-ics of Asthma in Costa Rica Study, BAMSE: Swedish birth cohort study Barn Allergi Milieu Stockholm Epidemiologi, PACT: Pediatric Asthma Controller Trial.
Other asthma genes found by genome-wide
association studies: age-studies
Eleven asthma genes were identified in seven GWA studies performed in populations with childhood-on-set asthma. The GABRIEL GWA study found, next to the childhood-onchildhood-on-set asthma ORMDL3/GSDMB lo-cus, also more prominent effects in childhood-onset asthma for the IL1RL1/IL18R1 and IL33 genes.40 In
contrast, HLA-DQ variants were slightly more strongly associated among the later-onset individuals, but none of these differences was significant. In childhood-onset asthma, an association with cAMP-specific 3’,5’-cyclic phosphodiesterase 4D (PDE4D)34 and DENN/MADD Domain containing 1B (DENND1B)35 gene
poly-morphisms was identified in US white populations. PDE4D was reported to be important in signaling pathways and airway smooth muscle contraction68, whereas DENND1B encodes for a protein that may
interact with tumor necrosis factor-a. It is expressed by natural killer and dendritic cells, which have a critical role in the inflammatory pathogenesis of asthma.35,63 A subsequent analysis of DENND1B
vari-ants with age of onset of asthma was performed in children of European and African ancestry, all with asthma diagnosed before age 6. This yielded contradictory results, with opposite alleles being associated in children with asthma symptoms at older age, compared with younger age, and also different alleles associated in populations of African ancestry compared with European ancestry. The latter might be due to differences in underlying genetic architecture between populations.35
In Japanese childhood-onset (<15 years) asthma patients, the genes Major histocompatibility complex, class II, DP (HLA-DP) and Solute Carrier Family 30 member 8 (SLC30A8) emerged as genome-wide significant vari-ants.36 The HLA-DP gene product is a cell surface receptor for foreign or self-antigens, with a function
in immune-related diseases. The gene seems to have a protective role in Th1-derived diseases such as diabetes type 1 and rheumatoid arthritis, which suggests that it regulates Th1/Th2 balance.69,70 SLC30A8
is associated with type 2 diabetes, and its link to asthma may lie in its localization in epithelial cells and epithelial integrity.71
In the Isle of Wight study, SNPs and haplotypes at chromosome 1p33-p32.31 were associated with asthma
and asthma severity in children with asthma at age 10 using a pooled GWA study approach.37 This region
contained the ATP Synthase Mitochondrial F1 Complex Assembly Factor 1 (ATPAF1), C1ORF223, and KIAA0494 genes. In replication cohorts, wherein asthma was diagnosed during childhood, significant trends for as-sociation were identified in this linkage disequilibrium block in several ethnic groups, except in Hispanic populations. In an Australian study43 of adults and children, SNPs at the IL-6 receptor gene IL6R1 and on
chromosome 11q13.5 were identified as asthma susceptibly variants in individuals of European ancestry of whom 53.9% had childhood-onset asthma, defined as onset 16 years of age or less (26.1% >16 years, 20% unknown). No significant difference in strength of association of these risk alleles with age of onset was found.
Other asthma GWA studies have identified important asthma susceptibility genes, yet included both adults and children with often an unknown age of asthma onset (Table 3), thus not allowing conclusions as to differential effects according to age of onset of asthma.
In conclusion, it is difficult to put forward a solid opinion about distinct genetic origins of childhood-on-set and adult-onchildhood-on-set asthma. Most studies made no formal comparison between the two age groups. Fur-thermore, age of onset is subject to recall bias because it was often defined in a retrospective manner.72
Until now, only the childhood-onset associated ORMDL3/GSDMB region has been replicated when age of onset was taken into account and this has not been observed so strongly for other GWA loci.
Genome-wide association studies of age of onset asthma
and wheezing phenotypes
Until now, only one GWA study reported on the association between asthma and age of onset in childhood as an outcome measurement. This study included 573 US non-Hispanic white children with a mean±SD age of asthma onset of 3.1±2.5 years38 and replicated in three independent cohorts with European,
Amer-ican, and Latin American children (age of onset 2.5±2.3, 3.1±2.4, and 3.3±2.7 years, respectively). Two SNPs on chromosome 3 and 11 were associated with earlier onset of asthma using a survival analysis. The com-bined effect of the associated SNPs led to a mean age of onset of 3.4 in children having 0 risk alleles, compared with a mean age of onset of 2.5 years (P<0.0001) in children having at least one risk allele. Both SNPs were not located in any known gene, but one of them was close to the IL-5 receptor a gene (IL5RA). This receptor is selectively expressed in the bronchial muscle and shows an eosinophil-independent role in AHR.38 Recently, a GWA study39 performed in the ALSPAC cohort investigated whether the combined
signal of asthma risk SNPs was predictive of childhood-onset asthma (<8 years). Asthma-associated SNPs from the GABRIEL GWA study (excluding ALSPAC) were used to construct a genetic prediction score. Children were classified into six LLCA-derived wheezing phenotypes6: persistent, late-onset,
inter-mediate-onset, prolonged early, transient early, and never/infrequent wheezing. Despite weak discrimi-nation (area under the receiver operating characteristic curve scores≤0.60), an association was examined
between the top 46 ranked SNPs (including mostly 17q12–21 SNPs) and two symptom-based phenotypes, early-onset persistent wheeze and intermediate-onset wheeze. Interestingly, doctor-diagnosed asthma was associated with the lower ranked SNPs, which could indicate that early-onset persistent wheeze and intermediate-onset wheeze are better predicted by the 17q12–21 locus than doctor-diagnosed asthma. However, the clinical relevance of prediction scores in the determination of disease risk is poor.39,40,43
Genome-wide association studies of asthma and atopy:
a comparison
Atopy is a strong risk factor for childhood asthma. Therefore, it is of interest to compare atopy genesthat regulate total or specific IgE production, and blood eosinophils to asthma susceptibility SNPs (Table 4). 73-80,81,82 Remarkably, published data suggest that early childhood asthma is not explained by atopic genetic
susceptibility, as atopy genes thus far discovered through GWA studies are not detected as asthma sus-ceptibility genes. This observation is paralleled by studies that showed no association between allergen exposure and asthma83,84, and reports that avoidance of allergens did not lead to a reduction in asthma
development.85 The causal model in which allergic sensitization directly leads to an increased risk of
asth-ma should, therefore, be re-considered.86
Conclusion
Although most asthma starts early in life, there is no valid test to diagnose asthma in the first years of life. GWA studies have provided more insight into the specific and common genetic origins of adult-onset and childhood-onset asthma. The 17q12–21 asthma locus is important for childhood-onset, nonatopic, more severe asthma. Other asthma risk loci do not have a strong relation with age of onset. Finally, atopy risk alleles do not explain genetic susceptibility to asthma. Future genetic studies are needed to systematical-ly compare age of onset of asthma in large groups of patients including interactions with environmental factors, especially in critical periods, and additionally implementing the role of epigenetic mechanism. Studies that assess the effects of asthma risk SNPs on gene expression (expression quantitative trait loci) can guide further functional studies that will provide more insight into asthma pathogenesis.87 Finally, in
this way, early detection of asthma using genetic markers interacting with personal and environmental factors might become feasible.
Key points
• Novel longitudinal symptom based wheezing phenotypes have been discovered by the use of latent class analyses.
• GWA studies have revealed that 17q12-21 is predominantly a childhood-onset asthma locus, with modified effects through ETS exposure.
• Two loci have been associated with age of onset in childhood asthma, one locus being close to the IL5RA gene.
• Genetic susceptibility to asthma cannot be explained by atopic risk alleles.
• Genetic profiles of childhood and adult asthma, with the combination of environmental risk factors and associated biomarkers may improve the early detection of asthma.
Table 4. Published GWA studies and meta-analysis of GWA studies for atopy and asthma related phenotypes which obtained genetic associations at a genome-wide significant level, either in the original cohort, the replication cohort or in a combined analysis.
*Reported as mean (±SD) or range, mn=month, y=year, † Bold genes were genome wide significant (P≤5x10-8) in the original cohort, underlined genes were genome wide significant in the replication/combined analyses, normal printed genes showed nominal significance in original, replication or combined analyses, ‡Only associated with grass sensiti-zation, not allergic rhinitis. §Study: COAST: The Childhood Origins of Asthma.
References
1. Masoli M, Fabian D, Holt S, et al. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469–478.
2. Papadopoulos NG, Arakawa H, Carlsen KH, et al. International consensus on (ICON) pediatric asthma. Allergy. 2012;67:976–997.
3. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332:133–138.
4. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354:541–45.
5. Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons from an epidemiological approach. Paediatr Respir Rev. 2004;5:155–61.
6. Henderson J, Granell R, Heron J, et al. Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax. 2008;63:974–80.
7. Savenije OE, Granell R, Caudri D, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol. 2011;127:1505–12e14.
8. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008;32:1096–110.
9. Sonnappa S, Bastardo CM, Wade A, et al. Symptom-pattern phenotype and pulmonary function in preschool wheezers. J Allergy Clin Immunol. 2010;126:519–526.e1–7.
10. Kotaniemi-Syrjanen A, Pelkonen AS, Malmstrom K, et al. Symptom-based classification of wheeze: how does it work in infants? J Allergy Clin Immunol. 2011;128:1111–1112.e1–2.
11. Sonnappa S, Bastardo CM, Saglani S, et al. Relationship between past airway pathology and current lung function in preschool wheezers. Eur Respir J. 2011;38:1431–436.
12. Schultz A, Devadason SG, Savenije OE, et al. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr. 2010;99:56–60.
13. Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol. 2012;130:325–31.
14. Turner SW, Palmer LJ, Rye PJ, et al. The relationship between infant airway function, childhood airway responsiveness, and asthma. Am J Respir Crit Care Med. 2004;169:921–27.
15. Bisgaard H, Jensen SM, Bonnelykke K. Interaction between asthma and lung function growth in early life. Am J Respir Crit Care Med. 2012;185:1183–189.
16. Saglani S, Payne DN, Zhu J, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007;176:858–864.
17. Pohunek P, Warner JO, Turzikova J, et al. Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol. 2005;16:43–51.
18. Stern DA, Morgan WJ, Halonen M, et al. Wheezing and bronchial hyperresponsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008;372:1058–1064.
19. Mitchell EA, Beasley R, Keil U, et al. The association between tobacco and the risk of asthma, rhinoconjunctivitis and eczema in children and adolescents: analyses from Phase Three of the ISAAC programme. Thorax. 2012;67:941–949.
20. Leuenberger P, Schwartz J, Ackermann-Liebrich U, et al. Passive smoking exposure in adults and chronic respiratory symptoms (SAPALDIA Study). Swiss Study on Air Pollution and Lung Diseases in Adults, SAPALDIA Team. Am J Respir Crit Care Med 1994;150:1222–1228.
21. Porsbjerg C, von Linstow ML, Ulrik CS, et al. Risk factors for onset of asthma: a 12-year prospective follow-up study. Chest. 2006;129:309–316.
22. Sigurs N, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax. 2010;65:1045–1052.
23. Shaaban R, Zureik M, Soussan D, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372:1049–1057.
24. Gergen PJ, Arbes SJ Jr, Calatroni A, et al. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. 2009;124:447–453.
25. Arbes SJ Jr, Gergen PJ, Vaughn B, Zeldin DC. Asthma cases attributable to atopy: results from the Third National Health and Nutrition Examination Survey. J Allergy Clin Immunol 2007;120:1139–1145.
26. Gelfand EW. Is asthma in childhood different from asthma in adults? Why do we need special approaches to asthma in children? Allergy Asthma Proc. 2008;29:99–102.
27. Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113:101–108.
28. Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129:974–82e13.
29. Paull K, Covar R, Jain N, et al. Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999-2002. Pediatr Pulmonol. 2005;39:311–317.
30. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med. 1968;278:1355–1360.
31. Thomsen SF, Duffy DL, Kyvik KO, Backer V. Genetic influence on the age at onset of asthma: a twin study. J Allergy Clin Immunol. 2010;126:626–630.
32. Bottema RW, Reijmerink NE, Koppelman GH, et al. Phenotype definition, age,and gender in the genetics of asthma and atopy. Immunol Allergy Clin North Am. 2005;25:621–639.
33. 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.
34. 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.
35. Sleiman PM, Flory J, Imielinski M, et al. Variants of DENND1B associated with asthma in children. N Engl J Med 2010;362:36–44.
36. Noguchi E, Sakamoto H, Hirota T, et al. Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations. PLoS Genet. 2011;7:e1002170.
37. 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.e11.
38. Forno E, Lasky-Su J, Himes B, et al. Genome-wide association study of the age of onset of childhood asthma. J Allergy Clin Immunol. 2012;130:83–90.e4.
39. Spycher BD, Henderson J, Granell R, et al. Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort. J Allergy Clin Immunol. 2012;130:503–509.e1-7.
40. Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363:1211–1221.
41. Torgerson DG, Ampleford EJ, Chiu GY, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet. 2011;43:887–892.
42. Hirota T, Takahashi A, Kubo M, et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet 2011;43:893–896.
43. Ferreira MA, Matheson MC, Duffy DL, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet. 2011;378:1006–1014.
44. Wan YI, Shrine NR, Soler Artigas M, et al. Genome-wide association study to identify genetic determinants of severe asthma. Thorax. 2012;67:762–768.
45. Ramasamy A, Kuokkanen M, Vedantam S, et al. Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA. PLoS One. 2012;7:e44008.
46. Myers RA, Himes BE, Gignoux CR, et al. Further replication studies of the EVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans. J Allergy Clin Immunol. 2012;130:1294–1301.
47. 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.
48. 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.
49. Sleiman PM, Annaiah K, Imielinski M, et al. ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. J Allergy Clin Immunol. 2008;122:1225–1227.
50. 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.
51. Hirota T, Harada M, Sakashita M, et al. Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population. J Allergy Clin Immunol. 2008;121:769–770.
52. Yang FF, Huang Y, Li QB, et al. Single nucleotide polymorphisms in the ORM1-like 3 gene associated with childhood asthma in a Chinese population. Genet Mol Res. 2012;11:4646–4653.
53. 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.e4.
54. Halapi E, Gudbjartsson DF, Jonsdottir GM, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet. 2010;18:902–908.
55. Granell R, Henderson AJ, Timpson N, et al. Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes. J Allergy Clin Immunol. 2013;131:685-94.
56. Khorasani N, Bhavsar PK, et al. Chromosome 17q21 SNP and severe asthma. J Hum Genet. 2011;56:97–98.
57. van der Valk RJ, Duijts L, Kerkhof M, et al. Interaction of a 17q12 variant with both fetal and infant smoke exposure in the development of childhood asthmalike symptoms. Allergy. 2012;67:767–774.
58. Smit LA, Bouzigon E, Pin I, et al. 17q21 variants modify the association between early respiratory infections and asthma. Eur Respir J. 2010;36:57–64.
59. Flory JH, Sleiman PM, Christie JD, et al. 17q12–21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. J Allergy Clin Immunol. 2009;124:605–607.
60. Verlaan DJ, Berlivet S, Hunninghake GM, et al. Allele-specific chromatin remodeling in the ZPBP2/ GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet. 2009;85:377–393.
61. Berlivet S, Moussette S, Ouimet M, et al. Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12–q21 in lymphoblastoid cell lines. Hum Genet. 2012;131:1161–1171.
62. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, et al. The asthma associated ORMDL3 gene product regulates endoplasmic reticulummediated calcium signaling and cellular stress. Hum Mol Genet. 2010;19:111–121.
63. Akhabir L, Sandford AJ. Genome-wide association studies for discovery of genes involved in asthma. Respirology. 2011;16:396–406.
64. Carreras-Sureda A, Cantero-Recasens G, Rubio-Moscardo F, et al. ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Hum Mol Genet. 2013;22:519–530.
65. Miller M, Tam AB, Cho JY, et al. ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proc Natl Acad Sci U S A 2012;109:16648–16653.
66. Breslow DK, Collins SR, Bodenmiller B, et al. Orm family proteins mediate sphingolipid homeostasis. Nature. 2010;463:1048–1053.
67. Komiyama H, Aoki A, Tanaka S, et al. Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB). Genes Genet Syst 2010;85:75–83.Hansen G, Jin S, Umetsu DT, Conti M. Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc Natl Acad Sci U S A. 2000;97:6751–6756.
68. Varney MD, Valdes AM, Carlson JA, et al. HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2010;59:2055–2062.
69. Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis: a genomewide study. N Engl J Med 2007;357:1199–1209.
70. Sladek R, Rocheleau G, Rung J, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445:881–885.
71. Burgess JA, Walters EH, Byrnes GB, et al. Who remembers whether they had asthma as children? J Asthma. 2006;43:727–730.
72. 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.
73. 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.
74. 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.
75. Esparza-Gordillo J, Weidinger S, Folster-Holst R, et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet. 2009;41:596–601.
76. Rothenberg ME, Spergel JM, Sherrill JD, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. 2010;42:289–291.
77. Wan YI, Strachan DP, Evans DM, et al. A genome-wide association study to identify genetic determinants of atopy in subjects from the United Kingdom. J Allergy Clin Immunol. 2011;127:223– 231;231.e1–3.
78. Ramasamy A, Curjuric I, Coin LJ, et al. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J Allergy Clin Immunol. 2011;128:996–1005.
79. Paternoster L, Standl M, Chen CM, et al. Meta-analysis of genome-wideassociation studies identifies three new risk loci for atopic dermatitis. Nat Genet 2011;44:187–192.
80. Granada M, Wilk JB, Tuzova M, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol 2012;129:840–845.e21.
81. Hirota T, Takahashi A, Kubo M, et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet. 2012;44:1222–1226.
82. Lau S, Illi S, Sommerfeld C, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 2000;356:1392–1397.
83. Lodrup Carlsen KC, Roll S, Carlsen KH, et al. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PLoS One. 2012;7:e43214.
84. Gehring U, de Jongste JC, Kerkhof M, et al. The 8-year follow-up of the PIAMA intervention study assessing the effect of mite-impermeable mattress covers. Allergy 2012;67:248–256.
85. Guerra S, Martinez FD. Is allergy an asthmatic disease? Arch Bronconeumol. 2011;47:479–481.
86. Hao K, Bosse´ Y, Nickle DC, et al. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet. 2012;8:e1003029.
Olga E.M. Savenije, Jestinah M. Mahachie John, Raquel Granell, Marjan Kerkhof, F. Nicole Dijk, Johan C. de Jongste, Henriëtte A. Smit, Bert Brunekreef, Dirkje S. Postma, Kristel Van Steen, John Henderson, and Gerard H. Koppelman
