Original Article
Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma
N Engl J Med 2008; 359:1985-1994November 6, 2008
- Abstract
Background
A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we examined a large, family-based data set that included extensive phenotypic and environmental data from the Epidemiological Study on the Genetics and Environment of Asthma.
Methods
We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects from 372 families for an association with asthma. We also tested for genetic heterogeneity according to the age at the onset of asthma and exposure to environmental tobacco smoke in early life.
Results
Eleven SNPs were significantly associated with asthma (P<0.01), of which three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Ordered-subset regression analysis led us to select an onset at 4 years of age or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (P<10−5 for four SNPs), whereas no association was found with late-onset asthma. With respect to exposure to environmental tobacco smoke in early life, we observed a significant association with early-onset asthma only in exposed subjects (P<5×10−5 for six SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (P=2.8×10−6; P=0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure).
Conclusions
This study shows that the increased risk of asthma conferred by 17q21 genetic variants is restricted to early-onset asthma and that the risk is further increased by early-life exposure to environmental tobacco smoke. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma.
Media in This Article
Figure 1
Ordered-Subset Regression Analysis of Asthma with Two Single-Nucleotide Polymorphisms (SNPs).Table 1
Characteristics of 1511 Genotyped Subjects from 372 Families.Article Activity
- Article
A consensus is emerging that asthma is not a single disease but rather a collection of separate entities with variable expression over the life span. Although various asthma phenotypes have been identified with the use of clinical criteria,1 little is known about their cause. The identification of their determinants is an important step toward understanding the physiopathology of asthma. One of the simplest criteria that can be used to differentiate asthma phenotypes is the age at onset. Longitudinal studies have shown that phenotypic features correlate with the age at the onset of asthma in children and adults2-5 and that asthma-associated phenotypes vary over time.
A genomewide association study of asthma in children identified genetic variants, called single-nucleotide polymorphisms (SNPs), on chromosome 17q21 that are associated with the risk of disease and that regulate the expression of at least one nearby gene, ORMDL3.6 This disease association has been replicated in several studies conducted mainly among children,7-10 but it is not known whether these variants influence the occurrence of asthma in an age-specific manner. More recently, these genetic variants have been shown to be associated with the expression of GSDML (also called GSDMB), a second gene from the region (Cookson W: personal communication), and with an increased risk of Crohn's disease.11
Environmental factors play a substantial role in the development of asthma, in some instances with the greatest effect at a specific developmental stage. Among these factors, environmental exposure to tobacco smoke in early life has been shown to interact with genetic susceptibility to asthma.12-17 In a genomewide linkage analysis conducted as part of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA),14 we showed that markers in the 17q21 region were linked to asthma susceptibility in the presence of exposure to environmental tobacco smoke.14
The large number of subjects in the EGEA family-based data set, which includes clinically ascertained cases of asthma in adults and children, makes it possible to test for associations with disease onset at a wide range of ages. The study also provides extensive data on environmental factors and asthma-related phenotypes. We used the EGEA data set to determine the association between 17q21 variants and the age at the onset of asthma and interaction between this association and exposure to environmental tobacco smoke in early life. We also tested for an association between these variants and major asthma-associated phenotypes related to atopy, inflammation, and lung function.
Methods
Study Population
The protocol for data collection in the EGEA has been described in detail previously.18 The sample included 1621 subjects in 388 nuclear families who were recruited through probands with asthma identified in seven clinical centers in five French cities. The ages of the subjects at the time of the study ranged from 7 to 65 years. Probands and their first-degree relatives responded to a questionnaire that was based on international standardized tools to diagnose asthma and to determine respiratory and allergic symptoms, treatments, and environmental exposures.18 Information on age at the onset of symptoms of asthma and exposure to tobacco smoke in early life was obtained from adults with asthma and from parents of children with asthma. The sample included 651 patients with asthma, with an age at onset ranging from less than 1 year to 57 years. Information about exposure to environmental tobacco smoke in early life was known for 98% of family members. We also examined four main asthma-related phenotypes — atopy (defined as at least one positive response to 11 allergens on a skin-prick test), total IgE levels, blood eosinophil counts, and the percentage of the predicted forced expiratory volume in 1 second (FEV1) — according to age, sex, and height (for details regarding phenotypes, see the Supplementary Appendix, available with the full text of this article at www.nejm.org). We obtained written informed consent from all study subjects or their parents.
Genotyping
DNA was available from 1543 of the 1621 subjects enrolled in the EGEA. We genotyped 38 SNPs located between 35.23 and 35.38 Mb on chromosome 17q21, including the key SNPs previously associated with asthma, along with other SNPs present in the region of strongest association (for details regarding genotyping, see the Supplementary Appendix).6 Genotyping was performed on an ABI7900HT Sequence Detection System with the use of TaqMan assays (Applied Biosystems). After applying quality-control procedures, we retained 36 SNPs genotyped in 1511 subjects from 372 families for analysis.
Statistical Analysis
We tested for an association between SNPs and asthma with a likelihood-based method,19,20 implemented in the Linkage and Association Modeling in Pedigrees (LAMP) program for analysis of families of arbitrary size and mode of selection (www.sph.umich.edu/csg/abecasis/lamp). This approach provides a powerful test of association with family structures similar to those of study families.20 The association was evaluated with the use of a likelihood-ratio test statistic, which compares the null hypothesis of an absence of association and linkage to the alternative of association and linkage. Asymptotically, the likelihood-ratio test statistic is distributed as a chi-square with 2 degrees of freedom under a general model for SNP effect and a chi-square with 1 degree of freedom when a specific genetic model is assumed.19,20 We evaluated the strength of the association (SNP effect size) under the best-fitting genetic model (recessive), using the ratio of estimates of penetrance for the homozygous risk-allele genotype to penetrance for other genotypes.
To investigate genetic heterogeneity according to the age at disease onset and to identify a cutoff point for classification into an early-onset group and a late-onset group, we performed ordered-subset regression. Subjects with asthma were ranked on the basis of increasing age at the first onset of symptoms, and logistic regression of asthma status on SNPs was performed in each ordered age-specific subset. We identified the subset for which the difference of the likelihood-ratio test statistics for association between the age-specific subsets and the total sample was maximal. The significance of the maximal difference in test statistics for association was assessed by permutation. Since this analysis provided evidence of heterogeneity according to the age at onset, we compared results in the early-onset group and the late-onset group by using LAMP and examining disease in one age-at-onset category, with all subjects in the other category being assigned an unknown disease status. To formally test for heterogeneity of the SNP effect according to the age at onset, we considered two independent samples of families, with all affected subjects in the offspring generation belonging to a single age-at-onset category.
To investigate genetic heterogeneity according to early-life exposure to environmental tobacco smoke, we grouped families according to the exposure status of the offspring. All offspring in a given family were concordant with respect to exposure status in 91.2% of the families, and we assumed that the disease status of the parents and their early-life exposure to environmental tobacco smoke were unknown. The significance of the heterogeneity of association between sibships with tobacco exposure and those without such exposure was assessed with the use of the likelihood-ratio test from LAMP. P values were determined by random permutation of the exposure status of sibships among those having the same number of affected siblings; the distribution of the number of siblings was similar in sibships with exposure to tobacco smoke and those without such exposure (10,000 replicates). In the above analyses, we used phenotype and exposure information from the offspring's generation only. We performed a second test of association between early-onset asthma and 17q21 SNPs in parents who were exposed to environmental tobacco smoke early in life and in those who did not have such exposure, using Fisher's exact test. The association between 17q21 markers and asthma-related phenotypes was investigated by means of regression analysis with the use of Stata software, version 10.0 (see the Methods section in the Supplementary Appendix).
Results
17q21 Variants and Asthma
The characteristics of the 1511 genotyped subjects belonging to the 372 EGEA families are presented in Table 1Table 1
Characteristics of 1511 Genotyped Subjects from 372 Families.. When we analyzed the data without stratification according to the age at the onset of asthma, we found that 11 of the 17q21 SNPs were significantly associated with asthma (P<0.01). Of these SNPs, three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001) (Table 2Table 2
Association between 11 Single-Nucleotide Polymorphisms on Chromosome 17q21 and Asthma, Early-Onset Asthma, and Late-Onset Asthma., and Table 2 in the Supplementary Appendix). These three SNPs were among those with the most significant association (P≤2.5×10−8) in the initial genomewide association study.6 17q21 Variants and Age at Onset of Asthma
Ordered-subset regression analysis, performed for the 11 SNPs significantly associated with asthma, showed that the maximal difference in test statistics for association between the ordered age-specific subsets and the total sample was obtained at an age at onset of 4 years or younger, depending on the marker tested (Figure 1Figure 1
Ordered-Subset Regression Analysis of Asthma with Two Single-Nucleotide Polymorphisms (SNPs).). On the basis of 10,000 permutations, the maximal difference in test statistics for association was found to be significant for all 11 markers (empirical P values ranging from 1×10−4 for rs9303277 to 0.02 for rs4795405). We then used 4 years of age as the cutoff point to assign subjects to early-onset and late-onset subgroups.The early-onset subgroup included 235 subjects with asthma among 1270 subjects, and the late-onset subgroup included 395 subjects with asthma among 1282 subjects. The association between the SNPs and early-onset asthma was found to be much stronger than that for asthma as a whole (Table 2). We obtained P≤7×10−4 for the 11 SNPs and P<1×10−5 for 4 of the SNPs, with the strongest associations at rs9303277 (P=3.1×10−6) and rs8069176 (P=5.8×10−6). These results remained significant (P<1×10−3 for the four most strongly associated SNPs) after a conservative adjustment with the Bonferroni correction for the 108 tests conducted (36 SNPs tested in the early-onset subgroup, the late-onset subgroup, and the total group). In contrast, we found no significant association with asthma when the onset was after 4 years of age (Table 2). Tests for heterogeneity of the association with asthma between two independent family samples (152 families with early-onset asthma and 175 families with late-onset asthma) were significant for 10 of the 11 asthma-associated SNPs (Table 2).
Early Exposure to Tobacco Smoke
We next examined the influence of exposure to environmental tobacco smoke in early life. Initially, we used phenotype and exposure data for offspring only. There were 179 families in which all offspring had exposure to environmental tobacco smoke and 130 families in which all offspring did not have such exposure. Evidence for an association between early-onset asthma and all SNPs that previously showed an association with disease was highly significant in the smoke-exposed families (Table 3Table 3
Analysis of the Association between 11 Single-Nucleotide Polymorphisms (SNPs) on Chromosome 17q21 and Early-Onset Asthma, According to Status with Respect to Exposure to Environmental Tobacco Smoke in Early Life.). The strongest associations were observed at rs8069176 (P=2.8×10−6) and rs2305480 (P=8.7×10−6). Conversely, the associations were not significant in the unexposed families (P≥0.02) (Table 3). The patterns of heterogeneity of association according to exposure status were similar for all 11 SNPs and were significant on the basis of permutation tests for 8 SNPs (Table 3).When smoking exposure was not taken into account, the alleles associated with an increased risk of asthma were identical to those initially reported.6 Under the best-fitting recessive model (Table 3 in the Supplementary Appendix), the overall risk of early-onset asthma when smoking exposure was not taken into account was increased by a factor of 1.7 or more for subjects who were homozygous for the asthma-associated alleles, as compared with those with other genotypes, whereas the risk was increased by a factor of 2.3 or more for homozygous subjects with early-life exposure to environmental tobacco smoke. Moreover, for SNPs showing significant heterogeneity (P≤0.01) with respect to exposure to environmental tobacco smoke in early life, the ratio of the SNP effect on early-onset asthma was 1.9 or more in subjects with early exposure, as compared with those who did not have such exposure (Table 3).
We sought confirmation that the association between 17q21 variants and early-onset asthma was largely restricted to subjects who were exposed to environmental tobacco smoke by examining data from the parental generation (Table 4 in the Supplementary Appendix). The EGEA families included 475 parents with known asthma status who were exposed to tobacco smoke in early childhood (24 with early-onset asthma, 321 without asthma, and 130 with late-onset asthma) and 195 parents without early exposure (13 with early-onset asthma, 131 without asthma, and 51 with late-onset asthma). Among parents who were exposed to environmental tobacco smoke, early-onset asthma was significantly associated with four SNPs (P≤0.01). In contrast, there was no evidence of an association among parents without such exposure (P≥0.11).
The SNPs that were most strongly associated with early-onset asthma were in strong linkage disequilibrium with one another, with pairwise linkage disequilibrium coefficient D′ between 0.87 and 1.0. We also observed weaker evidence of disease association with other markers from the region (Table 5 in the Supplementary Appendix) that were in moderate linkage disequilibrium with these SNPs (Figure 1 in the Supplementary Appendix). However, when a forward stepwise regression was applied, only the SNP with the most significant disease association (rs8069176) entered the model, suggesting that linkage disequilibrium between markers accounted for these observations.
Asthma-Related Phenotypes
Analysis of atopy, IgE levels, eosinophil counts, and FEV1 did not reveal any significant association with the SNPs that we investigated. The results of the analysis are shown in Table 6 in the Supplementary Appendix.
Discussion
Our study confirms the association between 17q21 markers and asthma and shows that these markers confer susceptibility specifically to early-onset asthma, thus supporting the hypothesis that asthma with an onset in early life may differ biologically from asthma with a later onset. This study also shows an interaction between 17q21 variants and exposure in early life to environmental tobacco smoke.
The self-reported year of asthma onset by adult subjects was found to have high accuracy in both a Swedish study21 of incident cases investigated after 10 years and the longitudinal European Community Respiratory Health Survey.22 In our study, we found high reproducibility (98%) of the reported age at onset with self-administered questionnaires used before enrolling the subjects in the survey and with the study questionnaires administered face-to-face. Hence, we conclude that erroneous recall of the age at the onset of asthma is unlikely to have significantly affected the results.
Ordered-subset regression analysis identified an age at onset of 4 years as the cutoff point for assigning subjects to an early-onset group and a late-onset group. We obtained a similar cutoff point on the basis of disease-status data from both parents and offspring or only offspring. This approach made it possible to avoid prespecification of an arbitrary threshold and may be suited to identifying homogeneous subsets for association studies. A cutoff age of 4 years is consistent with the early-childhood period of wheezing, as defined in longitudinal studies of patients with early-onset persistent wheezing.2,4,23-26 Early-onset persistent wheezing has been found to have a strong familial component and to be associated with atopy.25,26 We did not analyze the subphenotype of atopic asthma. Since 83% of offspring with asthma had atopy, the study did not have sufficient power to distinguish whether an association existed between variants at the 17q21 locus and either atopic or nonatopic asthma.
Exposure to environmental tobacco smoke may be subject to recall bias. Although an overall good reproducibility of the report of parental smoking in childhood was found in the EGEA, mothers of children with asthma underreported their smoking habits when questioned on their children's exposure to environmental tobacco smoke.27 This may have led to the misclassification of a few families as not having been exposed and, consequently, to a conservative test for heterogeneity. Our finding of a significant association between 17q21 variants and early-onset asthma in offspring who were exposed to environmental tobacco smoke is in general agreement with the results of our previous study, since the linkage peak was approximately 5 Mb from these variants and only sibling pairs with asthma who had been exposed to environmental tobacco smoke in early life shared a proportion of identical-by-descent marker alleles in excess to that expected under the null hypothesis of no linkage.14 We observed replication of the association in the parental generation; the association between 17q21 markers and early-onset asthma was significant only among parents who had been exposed to environmental tobacco smoke in early life. Potential underreporting of early-life exposure to environmental tobacco smoke by these parents27 may have resulted in a conservative test but would not have contributed to a false positive result.
The 17q21 markers associated with early-onset asthma confer an increased risk among homozygotes for the disease-associated allele that is of the same order of magnitude as the risk reported for these markers in the original genomewide association study.6 However, exposure to environmental tobacco smoke in early life is associated with an even greater risk. The magnitude of this risk is in the upper range of that reported for other early-life risk factors.28 The single group of disease-associated markers (in strong linkage disequilibrium with one another) at 35.23 to 35.34 Mb on chromosome 17q21 points to a relatively narrow region of interest that includes four genes. These are IKZF3 (one SNP), involved in the regulation of lymphocyte development29,30; ZPBP2, or zona pellucida–binding protein 2 (one SNP)31; GSDML (four SNPs), encoding one of the gasdermin proteins implicated in epithelial barrier function and skin differentiation32; and ORMDL3 (one SNP), which encodes transmembrane protein anchored in the endoplasmic reticulum.33 Three of the SNPs implicating these genes are nonsynonymous variants; the others reside outside of exons. The three nonsynonymous variants are a marker in exon 4 of ZPBP2 (rs11557467, I151S) and two markers in exon 8 of GSDML (rs2305480, P298S; and rs2305479, G291R). However, all of the disease-associated markers are strongly associated with transcript levels of ORMDL3, as reported previously.6,34 Subsequent investigations have shown that the same markers are also associated with transcript levels of GSDML, indicating that both ORMDL3 and GSDML are coregulated by cis-acting genetic variants (Cookson W: personal communication).
Although the functional role of ORMDL3 is unknown, recent work has suggested that it may have a role in viral respiratory infections.8 Passive exposure to tobacco smoke during fetal development and early life is associated with an increased incidence of viral infections in early childhood,35 and both early environmental exposure to tobacco smoke and early viral infections increase the risk of asthma.35,36 GSDML may be involved in the regulation of the growth and differentiation of epithelial cells.32 ADAM33, variants of which confer a risk of asthma, has a role in the epithelial mesenchymal trophic unit37 and influences lung function in early life.38 Our findings provide additional support that early-life events play a critical role in the pathogenesis of asthma.
In conclusion, we have shown that 17q21 variants are associated with the early onset of asthma and interact with exposure to environmental tobacco smoke in early life. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma. In addition, the data are consistent with the observation that since early-onset asthma and late-onset asthma have distinct genetic underpinnings, they are likely to result from distinct pathobiologic mechanisms.
Supported by INSERM, the French Ministry of Higher Education and Research, and the University of Evry and by grants from the French Agency for Environmental and Occupational Health Safety (Afsset-APR-SE-2004), the French National Agency for Research (ANR 05-SEST-020-02/05-9-97 and ANR 06-CEBS), and the European Commission as part of the Global Allergy and Asthma European Network (FOOD-CT-2004-506378) and the GABRIEL consortium (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community; HEALTH-LSH-2005-018996).
Dr. Vervloet reports receiving lecture fees from GlaxoSmithKline, Stallergenes, and Allerbio and consulting fees from AstraZeneca, GlaxoSmithKline, Allerbio, and UCB. No other potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa0806604) was published at www.nejm.org on October 15, 2008.
Source Information
From INSERM Unité 794, Paris (E.B., E.C., H.A., N.C., F.D.); Fondation Jean Dausset–Centre d'Etude du Polymorphisme Humain (CEPH), Paris (E.B., E.C., H.A., N.C., M.L., F.D.); Université d'Evry, Evry (E.B., H.A., N.C., F.D.); INSERM Unité 535, Villejuif (M.-H.D.); Université Paris–Sud 11, Villejuif (M.-H.D., N.L.M., F.K.); Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry (A.B., D.Z., M.L.); Hôpital Arnaud de Villeneuve, Montpellier (J.B.); Centre Hospitalier Lyon-Sud, Pierre Bénite (F.G.); Hôpital d'Enfants Armand Trousseau, Paris (J.J.); INSERM Unité 780, Villejuif (N.L.M., F.K.); Hôpital Necker, Paris (P.S.); INSERM Unité 823, Grenoble (V.S., I.P.); Hôpital Sainte-Marguerite, Marseille (D.V.); and Centre Hospitalier Universitaire de Grenoble, Grenoble (I.P.) — all in France.
Address reprint requests to Dr. Demenais at INSERM Unité 794, Fondation Jean Dausset–CEPH, 27 rue Juliette Dodu, 75010 Paris, France, or at florence.demenais@inserm.fr.
Appendix
The following investigators were members of the EGEA cooperative group: Coordination: F. Kauffmann, F. Demenais (genetics), I. Pin (clinical aspects). Respiratory Epidemiology: INSERM Unité 700, Paris: M. Korobaeff, F. Neukirch; INSERM Unité 707, Paris: I. Annesi-Maesano; INSERM Unité 780, Villejuif: F. Kauffmann, N. Le Moual, R. Nadif, M.P. Oryszczyn; INSERM Unité 823, Grenoble: V. Siroux. Genetics: INSERM Unité 393, Paris: J. Feingold; INSERM Unité 535, Villejuif: M.H. Dizier; INSERM Unité 794, Paris: E. Bouzigon, F. Demenais; Centre National de Génotypage, Evry: I. Gut, M. Lathrop. Clinical Centers: Grenoble: I. Pin, C. Pison; Lyon: D. Ecochard, F. Gormand, Y. Pacheco; Marseille: D. Charpin, D. Vervloet; Montpellier: J. Bousquet; Paris-Cochin: A. Lockhart, R. Matran; Paris-Necker: E. Paty, P. Scheinmann; Paris-Trousseau: A. Grimfeld, J. Just. Data and Quality Management: INSERM Unité 155, Paris: J. Hochez; INSERM Unité 780, Villejuif: N. Le Moual, C. Ravault; INSERM Unité 794, Paris: N. Chateigner; Grenoble: J. Ferran.
- References
References
1
Wenzel SE . Asthma: defining of the persistent adult phenotypes. Lancet 2006;368:804-813
CrossRef | Web of Science | Medline2
Martinez FD ,Wright AL ,Taussig LM ,Holberg CJ ,Halonen M ,Morgan WJ . Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-138
Full Text | Web of Science | Medline3
Sears MR ,Greene JM ,Willan AR , et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349:1414-1422
Full Text | Web of Science | Medline4
Morgan WJ ,Stern DA ,Sherrill DL , et al. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 2005;172:1253-1258
CrossRef | Web of Science | Medline5
Lowe LA ,Simpson A ,Woodcock A ,Morris J ,Murray CS ,Custovic A . Wheeze phenotypes and lung function in preschool children. Am J Respir Crit Care Med 2005;171:231-237
CrossRef | Web of Science | Medline6
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
CrossRef | Web of Science | Medline7
Galanter J ,Choudhry S ,Eng C , et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med 2008;177:1194-1200
CrossRef | Web of Science | Medline8
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
CrossRef | Web of Science | Medline9
Madore AM ,Tremblay K ,Hudson TJ ,Laprise C . Replication of an association between 17q21 SNPs and asthma in a French-Canadian familial collection. Hum Genet 2008;123:93-95
CrossRef | Web of Science | Medline10
Tavendale R ,Macgregor DF ,Mukhopadhyay S ,Palmer CN . A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol 2008;121:860-863
CrossRef | Web of Science | Medline11
Barrett JC ,Hansoul S ,Nicolae DL , et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008;40:955-962
CrossRef | Web of Science | Medline12
Choudhry S ,Avila PC ,Nazario S , et al. CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma. Am J Respir Crit Care Med 2005;172:173-182
CrossRef | Web of Science | Medline13
Colilla S ,Nicolae D ,Pluzhnikov A , et al. Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol 2003;111:840-846
CrossRef | Web of Science | Medline14
Dizier MH ,Bouzigon E ,Guilloud-Bataille M , et al. Evidence for gene × smoking exposure interactions in a genome-wide linkage screen of asthma and bronchial hyper-responsiveness in EGEA families. Eur J Hum Genet 2007;15:810-815
CrossRef | Web of Science | Medline15
Kabesch M ,Hoefler C ,Carr D ,Leupold W ,Weiland SK ,von Mutius E . Glutathione S transferase deficiency and passive smoking increase childhood asthma. Thorax 2004;59:569-573
CrossRef | Web of Science | Medline16
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
CrossRef | Web of Science | Medline17
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
Web of Science | Medline18
Kauffmann F ,Dizier MH ,Pin I , et al. Epidemiological study of the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy: phenotype issues. Am J Respir Crit Care Med 1997;156:S123-S129
Web of Science | Medline19
Li M ,Boehnke M ,Abecasis GR . Joint modeling of linkage and association: identifying SNPs responsible for a linkage signal. Am J Hum Genet 2005;76:934-949
CrossRef | Web of Science | Medline20
Li M ,Boehnke M ,Abecasis GR . Efficient study designs for test of genetic association using sibship data and unrelated cases and controls. Am J Hum Genet 2006;78:778-792
CrossRef | Web of Science | Medline21
Toren K ,Palmqvist M ,Lowhagen O ,Balder B ,Tunsater A . Self-reported asthma was biased in relation to disease severity while reported year of asthma onset was accurate. J Clin Epidemiol 2006;59:90-93
CrossRef | Web of Science | Medline22
Pattaro C ,Locatelli F ,Sunyer J ,de Marco R . Using the age at onset may increase the reliability of longitudinal asthma assessment. J Clin Epidemiol 2007;60:704-711
CrossRef | Web of Science | Medline23
Zeiger RS ,Dawson C ,Weiss S . Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 1999;103:376-387
CrossRef | Web of Science | Medline24
Kurukulaaratchy RJ ,Fenn MH ,Waterhouse LM ,Matthews SM ,Holgate ST ,Arshad SH . Characterization of wheezing phenotypes in the first 10 years of life. Clin Exp Allergy 2003;33:573-578
CrossRef | Web of Science | Medline25
Kurukulaaratchy RJ ,Matthews S ,Arshad SH . Does environment mediate earlier onset of the persistent childhood asthma phenotype? Pediatrics 2004;113:345-350
CrossRef | Web of Science | Medline26
Stein RT ,Martinez FD . Asthma phenotypes in childhood: lessons from an epidemiological approach. Paediatr Respir Rev 2004;5:155-161
CrossRef | Medline27
Siroux V ,Guilbert P ,Le Moual N ,Oryszczyn MP ,Kauffmann F . Influence of asthma on the validity of reported lifelong environmental tobacco smoke in the EGEA study. Eur J Epidemiol 2004;19:841-849
CrossRef | Web of Science | Medline28
Salam MT ,Li YF ,Langholz B ,Gilliland FD . Early-life environmental risk factors for asthma: findings from the Children's Health Study. Environ Health Perspect 2004;112:760-765
CrossRef | Web of Science | Medline29
Wang JH ,Avitahl N ,Cariappa A , et al. Aiolos regulates B cell activation and maturation to effector state. Immunity 1998;9:543-553
CrossRef | Web of Science | Medline30
Schmitt C ,Tonnelle C ,Dalloul A ,Chabannon C ,Debre P ,Rebollo A . Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation. Apoptosis 2002;7:277-284
CrossRef | Web of Science | Medline31
Katoh M ,Katoh M . Identification and characterization of human ZPBP-like gene in silico. Int J Mol Med 2003;12:399-404
Web of Science | Medline32
Tamura M ,Tanaka S ,Fujii T , et al. Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. Genomics 2007;89:618-629
CrossRef | Web of Science | Medline33
Hjelmqvist L, Tuson M, Marfany G, Herrero E, Balcells S, Gonzàlez-Duarte R. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol 2002;3(6):research0027.1-0027.16.
34
Dixon AL ,Liang L ,Moffatt MF , et al. A genome-wide association study of global gene expression. Nat Genet 2007;39:1202-1207
CrossRef | Web of Science | Medline35
DiFranza JR ,Aligne CA ,Weitzman M . Prenatal and postnatal environmental tobacco smoke exposure and children's health. Pediatrics 2004;113:1007-1015
Web of Science | Medline36
Hashimoto S ,Matsumoto K ,Gon Y ,Ichiwata T ,Takahashi N ,Kobayashi T . Viral infection in asthma. Allergol Int 2008;57:21-31
CrossRef | Medline37
Holgate ST ,Davies DE ,Powell RM ,Howarth PH ,Haitchi HM ,Holloway JW . Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms. Eur Respir J 2007;29:793-803
CrossRef | Web of Science | Medline38
Simpson A ,Maniatis N ,Jury F , et al. Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function. Am J Respir Crit Care Med 2005;172:55-60
CrossRef | Web of Science | Medline
- Citing Articles (69)
Citing Articles
1
L. Cameron. (2012) The LTE4-P2Y12 pathway in asthma. Clinical & Experimental Allergy 42:2, 176-179
CrossRef2
E V Bräuner, S Loft, O Raaschou-Nielsen, U Vogel, P S Andersen, M Sørensen. (2012) Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze. Genes and Immunity 13:1, 94-97
CrossRef3
A. S. Karunas, B. B. Yunusbaev, Yu. Yu. Fedorova, G. F. Gimalova, N. N. Ramazanova, L. L. Gur’eva, L. A. Mukhtarova, Sh. Z. Zagidullin, E. I. Etkina, E. K. Khusnutdinova. (2011) Genome-wide association study of bronchial asthma in the Volga-Urals region of Russia. Molecular Biology 45:6, 911-920
CrossRef4
Jennifer Goldman, Mara L Becker, Bridgette Jones, Mark Clements, J Steven Leeder. (2011) Development of biomarkers to optimize pediatric patient management: what makes children different?. Biomarkers in Medicine 5:6, 781-794
CrossRef5
Valérie Siroux, Judith Garcia-Aymerich. (2011) The investigation of asthma phenotypes. Current Opinion in Allergy and Clinical Immunology 11:5, 393-399
CrossRef6
Barbara Hrdlickova, Lydie Izakovicova Holla. (2011) Relationship between the 17q21 locus and adult asthma in a Czech population. Human Immunology 72:10, 921-925
CrossRef7
Audrey Poon, Augusto A. Litonjua, Catherine Laprise. (2011) Relevance and implication of genetic determinants to asthma pathophysiology. Current Opinion in Allergy and Clinical Immunology 11:5, 407-413
CrossRef8
Francine M. Ducharme, Maja Krajinovic. (2011) Steroid responsiveness and wheezing phenotypes. Paediatric Respiratory Reviews 12:3, 170-176
CrossRef9
Dara G Torgerson, Elizabeth J Ampleford, Grace Y Chiu, W James Gauderman, Christopher R Gignoux, Penelope E Graves, Blanca E Himes, Albert M Levin, Rasika A Mathias, Dana B Hancock, James W Baurley, Celeste Eng, Debra A Stern, Juan C Celedón, Nicholas Rafaels, Daniel Capurso, David V Conti, Lindsey A Roth, Manuel Soto-Quiros, Alkis Togias, Xingnan Li, Rachel A Myers, Isabelle Romieu, David J Van Den Berg, Donglei Hu, Nadia N Hansel, Ryan D Hernandez, Elliott Israel, Muhammad T Salam, Joshua Galanter, Pedro C Avila, Lydiana Avila, Jose R Rodriquez-Santana, Rocio Chapela, William Rodriguez-Cintron, Gregory B Diette, N Franklin Adkinson, Rebekah A Abel, Kevin D Ross, Min Shi, Mezbah U Faruque, Georgia M Dunston, Harold R Watson, Vito J Mantese, Serpil C Ezurum, Liming Liang, Ingo Ruczinski, Jean G Ford, Scott Huntsman, Kian Fan Chung, Hita Vora, Xia Li, William J Calhoun, Mario Castro, Juan J Sienra-Monge, Blanca del Rio-Navarro, Klaus A Deichmann, Andrea Heinzmann, Sally E Wenzel, William W Busse, James E Gern, Robert F Lemanske, Terri H Beaty, Eugene R Bleecker, Benjamin A Raby, Deborah A Meyers, Stephanie J London, Frank D Gilliland, Esteban G Burchard, Fernando D Martinez, Scott T Weiss, L Keoki Williams, Kathleen C Barnes, Carole Ober, Dan L Nicolae. (2011) Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nature Genetics 43:9, 887-892
CrossRef10
Carole Ober, Tsung-Chieh Yao. (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunological Reviews 242:1, 10-30
CrossRef11
Jinho Yu, Mi-Jin Kang, Byoung-Ju Kim, Ji-Won Kwon, Young-Hwa Song, Won-Ah Choi, Yee-Jin Shin, Soo-Jong Hong. (2011) Polymorphisms in GSDMA and GSDMB are associated with asthma susceptibility, atopy and BHR. Pediatric Pulmonology 46:7, 701-708
CrossRef12
Francine Kauffmann, Raphaëlle Varraso. (2011) The epidemiology of cough. Pulmonary Pharmacology & Therapeutics 24:3, 289-294
CrossRef13
Anna Lluis, Michaela Schedel, Jing Liu, Sabina Illi, Martin Depner, Erika von Mutius, Michael Kabesch, Bianca Schaub. (2011) Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion. Journal of Allergy and Clinical Immunology 127:6, 1587-1594.e6
CrossRef14
Ma'en Obeidat, Ian P. Hall. (2011) Genetics of complex respiratory diseases: implications for pathophysiology and pharmacology studies. British Journal of Pharmacology 163:1, 96-105
CrossRef15
J. Bousquet, J. Anto, C. Auffray, M. Akdis, A. Cambon-Thomsen, T. Keil, T. Haahtela, B. N. Lambrecht, D. S. Postma, J. Sunyer, R. Valenta, C. A. Akdis, I. Annesi-Maesano, A. Arno, C. Bachert, F. Ballester, X. Basagana, U. Baumgartner, C. Bindslev-Jensen, B. Brunekreef, K. H. Carlsen, L. Chatzi, R. Crameri, E. Eveno, F. Forastiere, J. Garcia-Aymerich, S. Guerra, H. Hammad, J. Heinrich, D. Hirsch, B. Jacquemin, F. Kauffmann, M. Kerkhof, M. Kogevinas, G. H. Koppelman, M. L. Kowalski, S. Lau, K. C. Lodrup-Carlsen, M. Lopez-Botet, J. Lotvall, C. Lupinek, D. Maier, M. J. Makela, F. D. Martinez, J. Mestres, I. Momas, M. C. Nawijn, A. Neubauer, S. Oddie, S. Palkonen, I. Pin, C. Pison, F. Rancé, S. Reitamo, E. Rial-Sebbag, M. Salapatas, V. Siroux, D. Smagghe, M. Torrent, E. Toskala, P. van Cauwenberge, A. J. M. van Oosterhout, R. Varraso, L. von Hertzen, M. Wickman, C. Wijmenga, M. Worm, J. Wright, T. Zuberbier. (2011) MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 66:5, 596-604
CrossRef16
LOUBNA AKHABIR, ANDREW J. SANDFORD. (2011) Genome-wide association studies for discovery of genes involved in asthma. Respirology 16:3, 396-406
CrossRef17
Max A. Seibold, David A. Schwartz. (2011) The Lung: The Natural Boundary Between Nature and Nurture. Annual Review of Physiology 73:1, 457-478
CrossRef18
Carole Ober, Donata Vercelli. (2011) Gene–environment interactions in human disease: nuisance or opportunity?. Trends in Genetics 27:3, 107-115
CrossRef19
Shah Samir, Yeung Colin, Spentzas Thomas. (2011) Impact of environmental tobacco smoke on children admitted with status asthmaticus in the pediatric intensive care unit. Pediatric Pulmonology 46:3, 224-229
CrossRef20
Giuseppe Verlato, Oscar Bortolami, Simone Accordini, Mario Olivieri, Veronica Cappa, Massimiliano Bugiani, Angelo Corsico, Pietro Pirina, Simona Villani, Roberto de Marco. (2011) Asthma in Childhood Reduces Smoking Initiation in Subsequent Teens Among Males. Journal of Adolescent Health 48:3, 253-258
CrossRef21
Carlos E. Baena-Cagnani, Héctor A. Badellino. (2011) Diagnosis of Allergy and Asthma in Childhood. Current Allergy and Asthma Reports 11:1, 71-77
CrossRef22
Marco Folci, Francesca Meda, M. Eric Gershwin, Carlo Selmi. (2011) Cutting-Edge Issues in Primary Biliary Cirrhosis. Clinical Reviews in Allergy & Immunology
CrossRef23
Shin-Hwa Lee, Jong-Sook Park, Choon-Sik Park. (2011) The Search for Genetic Variants and Epigenetics Related to Asthma. Allergy, Asthma and Immunology Research 3:4, 236
CrossRef24
Mayumi Tamari, Kaori Tomita, Tomomitsu Hirota. (2011) Genome-Wide Association Studies of Asthma. Allergology International 60:3, 247-252
CrossRef25
Ernesto Prado Montes de Oca. (2011) Human Polymorphisms as Clinical Predictors in Leprosy. Journal of Tropical Medicine 2011, 1-14
CrossRef26
Aristea Binia, Nadia Khorasani, Pankaj K Bhavsar, Ian Adcock, Chris E Brightling, K Fan Chung, William O C Cookson, Miriam F Moffatt. (2011) Chromosome 17q21 SNP and severe asthma. Journal of Human Genetics 56:1, 97-98
CrossRef27
Mousheng Xu, Kelan G Tantisira, Ann Wu, Augusto A Litonjua, Jen-hwa Chu, Blanca E Himes, Amy Damask, Scott T Weiss. (2011) Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers. BMC Medical Genetics 12:1, 90
CrossRef28
QiuRong Fang, Hailing Zhao, Aihua Wang, Yaoqin Gong, Qiji Liu. (2011) Association of genetic variants in chromosome 17q21 and adult-onset asthma in a Chinese Han population. BMC Medical Genetics 12:1, 133
CrossRef29
Petter Lundborg, Anders Stenberg. (2010) Nature, nurture and socioeconomic policy—What can we learn from molecular genetics?. Economics & Human Biology 8:3, 320-330
CrossRef30
Daniel T Swarr, Hakon Hakonarson. (2010) Unraveling the complex genetic underpinnings of asthma and allergic disorders. Current Opinion in Allergy and Clinical Immunology 10:5, 434-442
CrossRef31
Kathleen C Barnes. (2010) Genomewide association studies in allergy and the influence of ethnicity. Current Opinion in Allergy and Clinical Immunology 10:5, 427-433
CrossRef32
Tilman E. Klassert, Juan J. Sánchez, Teresa A. Almeida, Luz Candenas, Francisco Pinto, Orlando Acosta, Mariano Hernández. (2010) Common variants of the neuropeptide expressing tachykinin genes and susceptibility to asthma: A case–control study. Journal of Neuroimmunology 227:1-2, 202-207
CrossRef33
Moffatt, Miriam F., Gut, Ivo G., Demenais, Florence, Strachan, David P., Bouzigon, Emmanuelle, Heath, Simon, von Mutius, Erika, Farrall, Martin, Lathrop, Mark, Cookson, William O.C.M., . (2010) A Large-Scale, Consortium-Based Genomewide Association Study of Asthma. New England Journal of Medicine 363:13, 1211-1221
Full Text34
Eva Halapi, Daniel F Gudbjartsson, Gudrun M Jonsdottir, Unnur S Bjornsdottir, Gudmar Thorleifsson, Hafdis Helgadottir, Carolyn Williams, Gerard H Koppelman, Andrea Heinzmann, H Marike Boezen, Aslaug Jonasdottir, Thorarinn Blondal, Sigurjon A Gudjonsson, Adalbjorg Jonasdottir, Theodora Thorlacius, Amanda P Henry, Janine Altmueller, Marcus Krueger, Hyoung Doo Shin, Soo-Taek Uh, Hyun Sub Cheong, Brynja Jonsdottir, Bjorn R Ludviksson, Dora Ludviksdottir, David Gislason, Choon-Sik Park, Klaus Deichmann, Philip J Thompson, Matthias Wjst, Ian P Hall, Dirkje S Postma, Thorarinn Gislason, Augustine Kong, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Kari Stefansson. (2010) A sequence variant on 17q21 is associated with age at onset and severity of asthma. European Journal of Human Genetics 18:8, 902-908
CrossRef35
Hans Bisgaard, Klaus Bønnelykke. (2010) Long-term studies of the natural history of asthma in childhood. Journal of Allergy and Clinical Immunology 126:2, 187-197
CrossRef36
Gideon M Hirschfield, Xiangdong Liu, Younghun Han, Ivan P Gorlov, Yan Lu, Chun Xu, Yue Lu, Wei Chen, Brian D Juran, Catalina Coltescu, Andrew L Mason, Piotr Milkiewicz, Robert P Myers, Joseph A Odin, Velimir A Luketic, Danute Speiciene, Catherine Vincent, Cynthia Levy, Peter K Gregersen, Jinyi Zhang, E Jenny Heathcote, Konstantinos N Lazaridis, Christopher I Amos, Katherine A Siminovitch. (2010) Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nature Genetics 42:8, 655-657
CrossRef37
Xuejun Qin, Elizabeth R. Hauser, Silke Schmidt. (2010) Ordered subset analysis for case-control studies. Genetic Epidemiology 34:5, 407-417
CrossRef38
Andrew Bush. (2010) The problem of preschool wheeze: new developments, new questions. Acta medica Lituanica 17:1, 40-50
CrossRef39
Patrick MA Sleiman, Hakon Hakonarson. (2010) Recent advances in the genetics and genomics of asthma and related traits. Current Opinion in Pediatrics 22:3, 307-312
CrossRef40
Emmanuelle Bouzigon, Paola Forabosco, Gerard H Koppelman, William O C M Cookson, Marie-Hélène Dizier, David L Duffy, David M Evans, Manuel A R Ferreira, Juha Kere, Tarja Laitinen, Giovanni Malerba, Deborah A Meyers, Miriam Moffatt, Nicholas G Martin, Mandy Y Ng, Pier Franco Pignatti, Mathias Wjst, Francine Kauffmann, Florence Demenais, Cathryn M Lewis. (2010) Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy. European Journal of Human Genetics 18:6, 700-706
CrossRef41
Donata Vercelli. (2010) Gene–environment interactions in asthma and allergy: the end of the beginning?. Current Opinion in Allergy and Clinical Immunology 10:2, 145-148
CrossRef42
Stavros Garantziotis, David A. Schwartz. (2010) Ecogenomics of Respiratory Diseases of Public Health Significance. Annual Review of Public Health 31:1, 37-51
CrossRef43
Vojko Berce, Uroš Potočnik. (2010) Functional polymorphism in CTLA4 gene influences the response to therapy with inhaled corticosteroids in Slovenian children with atopic asthma. Biomarkers 15:2, 158-166
CrossRef44
David K. Breslow, Sean R. Collins, Bernd Bodenmiller, Ruedi Aebersold, Kai Simons, Andrej Shevchenko, Christer S. Ejsing, Jonathan S. Weissman. (2010) Orm family proteins mediate sphingolipid homeostasis. Nature 463:7284, 1048-1053
CrossRef45
Donata Vercelli. (2010) Genetics and biology of asthma 2010: La' ci darem la mano…. Journal of Allergy and Clinical Immunology 125:2, 347-348
CrossRef46
M. Kabesch. (2010) Asthmagenetik 2010. Monatsschrift Kinderheilkunde 158:2, 129-136
CrossRef47
Sleiman, Patrick M.A., Flory, James, Imielinski, Marcin, Bradfield, Jonathan P., Annaiah, Kiran, Willis-Owen, Saffron A.G., Wang, Kai, Rafaels, Nicholas M., Michel, Sven, Bonnelykke, Klaus, Zhang, Haitao, Kim, Cecilia E., Frackelton, Edward C., Glessner, Joseph T., Hou, Cuiping, Otieno, F. George, Santa, Erin, Thomas, Kelly, Smith, Ryan M., Glaberson, Wendy R., Garris, Maria, Chiavacci, Rosetta M., Beaty, Terri H., Ruczinski, Ingo, Orange, Jordan M., Allen, Julian, Spergel, Jonathan M., Grundmeier, Robert, Mathias, Rasika A., Christie, Jason D., von Mutius, Erika, Cookson, William O.C., Kabesch, Michael, Moffatt, Miriam F., Grunstein, Michael M., Barnes, Kathleen C., Devoto, Marcella, Magnusson, Mark, Li, Hongzhe, Grant, Struan F.A., Bisgaard, Hans, Hakonarson, Hakon, . (2010) Variants of DENND1B Associated with Asthma in Children. New England Journal of Medicine 362:1, 36-44
Full Text48
Harold J Farber. (2010) Optimizing maintenance therapy in pediatric asthma. Current Opinion in Pulmonary Medicine 16:1, 25-30
CrossRef49
G. Cantero-Recasens, C. Fandos, F. Rubio-Moscardo, M. A. Valverde, R. Vicente. (2010) The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Human Molecular Genetics 19:1, 111-121
CrossRef50
Dae Jin Song. (2010) Environmental tobacco smoke and childhood asthma. Korean Journal of Pediatrics 53:2, 121
CrossRef51
Alan D. Woolf, Megan Sandel. 2009. Susceptibility of Children to Environmental Xenobiotics. .
CrossRef52
Merritt L Fajt, Sally E Wenzel. (2009) Asthma phenotypes in adults and clinical implications. Expert Review of Respiratory Medicine 3:6, 607-625
CrossRef53
Jean-François Bach. (2009) The biological individual – The respective contributions of genetics, environment and chance. Comptes Rendus Biologies 332:12, 1065-1068
CrossRef54
Steve Handoyo, Lanny J. Rosenwasser. (2009) Asthma phenotypes. Current Allergy and Asthma Reports 9:6, 439-445
CrossRef55
Guicheng Zhang, Jack Goldblatt, Peter Lesouëf. (2009) The era of genome-wide association studies: opportunities and challenges for asthma genetics. Journal of Human Genetics 54:11, 624-628
CrossRef56
Daniel Arnold, Bridgette L. Jones. (2009) Personalized medicine: A pediatric perspective. Current Allergy and Asthma Reports 9:6, 426-432
CrossRef57
James H. Flory, Patrick M. Sleiman, Jason D. Christie, Kiran Annaiah, Jonathan Bradfield, Cecilia E. Kim, Joseph Glessner, Marcin Imielinski, Hongzhe Li, Edward C. Frackelton, Hou Cuiping, George Otieno, Kelly Thomas, Ryan Smith, Wendy Glaberson, Maria Garris, Rosetta Chiavacci, Julian Allen, Jonathan Spergel, Robert Grundmeier, Michael Grunstein, Michael Magnusson, Struan F.A. Grant, Klaus Bønnelykke, Hans Bisgaard, Hakon Hakonarson. (2009) 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. Journal of Allergy and Clinical Immunology 124:3, 605-607
CrossRef58
Johan Van Limbergen, David C. Wilson, Jack Satsangi. (2009) The Genetics of Crohn's Disease. Annual Review of Genomics and Human Genetics 10:1, 89-116
CrossRef59
Kyle A. Nelson. (2009) Pharmacogenomics of Acute Asthma: The β2-Adrenergic Receptor Gene as a Model for Future Therapy. Clinical Pediatric Emergency Medicine 10:2, 95-102
CrossRef60
Martin R. Stämpfli, Gary P. Anderson. (2009) How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nature Reviews Immunology 9:5, 377-384
CrossRef61
Hardy, John, Singleton, Andrew, . (2009) Genomewide Association Studies and Human Disease. New England Journal of Medicine 360:17, 1759-1768
Full Text62
Carlos E Baena-Cagnani, R Maximiliano Gómez, Rodrigo Baena-Cagnani, G Walter Canonica. (2009) Impact of environmental tobacco smoke and active tobacco smoking on the development and outcomes of asthma and rhinitis. Current Opinion in Allergy and Clinical Immunology 9:2, 136-140
CrossRef63
(2009) Smoking Exposure, 17q21 Variants, and Early-Onset Asthma. New England Journal of Medicine 360:12, 1255-1256
Full Text64
William Cookson, Liming Liang, Gonçalo Abecasis, Miriam Moffatt, Mark Lathrop. (2009) Mapping complex disease traits with global gene expression. Nature Reviews Genetics 10:3, 184-194
CrossRef65
Nobuyuki Hizawa. (2009) Genetic Backgrounds of Asthma and COPD. Allergology International 58:3, 315-322
CrossRef66
Eva Halapi, Unnur Steina Bjornsdottir. (2009) Overview on the current status of asthma genetics. The Clinical Respiratory Journal 3:1, 2-7
CrossRef67
Stanley J. Szefler. (2009) Advances in pediatric asthma in 2008: Where do we go now?. Journal of Allergy and Clinical Immunology 123:1, 28-34
CrossRef68
Donata Vercelli. (2009) Gene-environment interactions: The road less traveled by in asthma genetics. Journal of Allergy and Clinical Immunology 123:1, 26-27
CrossRef69
Holloway, John W., Koppelman, Gerard H., . (2008) 17q21 Variants and Asthma — Questions and Answers. New England Journal of Medicine 359:19, 2043-2045
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