FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 333:894-900 October 5, 1995 Number 14 Next

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma.

Methods We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE were measured. The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels.

Results Serum total IgE levels were strongly correlated (r = 0.65, P<0.01) in pairs of siblings concordant for bronchial hyperresponsiveness (defined as a >20 percent decrease in the forced expiratory volume in one second produced by histamine [threshold dose, <16 mg per milliliter]), suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels (r = 0.04, P>0.10). Analyses of pairs of siblings showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436 (P<0.001 for a histamine threshold value of 16 mg per milliliter).

Conclusions This study demonstrates that a trait for an elevated level of serum total IgE is coinherited with a trait for bronchial hyperresponsiveness and that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q. These findings are consistent with the existence of one or more genes on chromosome 5q31-q33 causing susceptibility to asthma.

Bronchial hyperresponsiveness is accompanied by bronchial inflammation and an allergic diathesis in patients with asthma.^{11,12,13,14,15,16,17,18,19} Even in children with no history or symptoms of atopy or asthma, bronchial hyperresponsiveness is strongly associated with elevated serum IgE levels.¹⁷ We and others have recently identified a major locus regulating serum IgE levels on chromosomes 5q31-q33.^20,21 This chromosomal region is rich in candidate genes, many of which regulate IgE production either directly or indirectly and affect the activation and proliferation of cells involved in inflammatory processes associated with bronchial hyperresponsiveness, allergy, and asthma.^{11,12,13,14,15,16,17,18,19,22,23,24,25,26,27,28} Thus, chromosome 5q31-q33 may also represent a candidate region for the genetic regulation of bronchial hyperresponsiveness.

Although population studies clearly show a very strong association between atopy and bronchial hyperresponsiveness,^17,18,19 they cannot identify patterns of inheritance or the number of genes involved, the magnitude of their effects, or in most cases, their location.²⁹ However, linkage analysis can facilitate the dissection of the genetics of complex diseases such as asthma.²⁹ To explain the close interrelation between bronchial hyperresponsiveness and atopy, we used family studies to investigate whether these traits are coinherited. Because a major gene regulating serum IgE has previously been mapped to chromosome 5q31-q33,^20,21 we also tested whether genetic susceptibility to bronchial hyperresponsiveness, provoked by histamine, was coinherited with markers from this region.

Methods

Ascertainment of Study Families

Since the early 1960s Beatrixoord, near Groningen, the Netherlands, has served as a rehabilitation facility and a regional referral center for patients with asthma and airways disease. Between 1962 and 1970, 1284 patients with obstructive airways disease were evaluated while their symptoms were clinically stable. Eighty-four families were selected by identifying in each case a proband with symptomatic asthma who was 45 years of age or younger and who had bronchial hyperresponsiveness to histamine at the time of the first study.³⁰

Clinical Assessment

The original evaluation of the probands included the performance of skin tests with common allergens, pulmonary-function testing, and testing of bronchial responsiveness with histamine.³¹ The probands were restudied approximately 25 years later, along with all their available children, grandchildren (six years of age and older), and spouses. Testing of relatives included a standard respiratory questionnaire (modified version of the British Medical Council questionnaire with additional questions on symptoms and therapy of allergy and asthma), pulmonary-function testing, measurement of bronchial responsiveness to inhaled histamine, skin tests, and measurement of serum total IgE.^30,31

The level of serum total IgE (expressed as international units per milliliter) was used as an index of atopy and measured by solid-phase immunoassay (Pharmacia Diagnostics, Uppsala, Sweden). The mean of duplicate samples was used. The test was repeated if the difference between duplicate samples exceeded 5 percent. Segregation analyses of log₁₀ serum total IgE levels suggested recessive inheritance of high IgE levels in this population.²¹ The mean IgE levels associated with the low IgE and high IgE phenotypes were 38 and 437 IU per milliliter, respectively.²¹ In the frequency distribution, a level of 100 IU per milliliter best distinguished the high- from the low-phenotype group; we therefore defined persons with elevated serum total IgE levels as those with levels above 100 IU per milliliter.

Bronchial responsiveness was tested in family members according to the method of de Vries et al.³² because this method was used to assess the probands between 1962 and 1970. To test bronchial responsiveness, the subjects first inhaled a diluent for 30 seconds of normal breathing and then inhaled doses of histamine that were doubled every 5 minutes (from 0.5 mg per milliliter to 32 mg per milliliter). The test was stopped when the forced expiratory volume in one second (FEV₁) fell by 20 percent or more, or the highest concentration of histamine (32 mg per milliliter) was reached. For subjects with less than a 20 percent decrement in FEV₁ at the highest concentration of histamine, a threshold value of 64 mg of histamine per milliliter was arbitrarily assigned. The lowest concentration of histamine that induced a decline in the FEV₁ of at least 20 percent was termed the threshold value. Subjects were classified as positive or negative for bronchial hyperresponsiveness on the basis of their histamine threshold value (with positive status defined by a value of either <16 or <32 mg per milliliter). Bronchial hyperresponsiveness was also expressed as the provocation concentration of histamine causing a 20 percent decrease in the FEV₁ (PC₂₀) and was estimated by extrapolation from the dose–response curve.

Molecular Methods

DNA was extracted from peripheral leukocytes from members of the 84 families, as described previously (no DNA was available from 8 additional families that have been studied previously).^21,31 Genomic DNA was diluted to a concentration of 200 µg per milliliter for amplification. Simple-sequence-repeat loci³³ were selected from the Genome Data Base (Welch Library, Johns Hopkins University, Baltimore) and included those used to demonstrate linkage to a major locus regulating serum total IgE.²¹ The products were amplified by the polymerase chain reaction³⁴ and sized according to previously described methods.²¹ The samples were handled as described by Weber and May³³ with minor modifications. One or two simple-sequence-repeat loci were loaded on each gel. Genotypes were determined from two independent readings of each autoradiograph by persons who were unaware of the families' clinical characteristics.

Linkage Analyses

Linkage analysis is an analytic method to test for cosegregation at meiosis of a chromosomal region determining a trait or disorder. In the absence of a genetic model for the inheritance of bronchial hyperresponsiveness, and assuming that multiple genes on different chromosomes regulate this trait, we used a nonparametric approach to test for linkage. Linkage analyses were performed with methods involving affected pairs of siblings (Sibpal, Sage, Louisiana State University, New Orleans),³⁵ an established approach for the investigation of the genetic basis of complex traits, such as bronchial hyperresponsiveness, atopy, and asthma. Affected pairs of siblings are usually tested first, since a proportion of unaffected pairs of siblings may be gene carriers who do not express the trait. In contrast to lod-score methods, in this method the model for inheritance (dominant, recessive, and so on) does not need to be specified. Thus, the clinical characteristics of the parents are not used in testing for linkage; the pertinent observation is how often two affected offspring share copies of the same parental marker allele.³⁶ If the same copy of a marker allele is observed in different offspring, the alleles are said to be inherited in a manner that is termed "identical by descent." Linkage is suggested when affected pairs of siblings are identical by descent for a marker allele significantly more often than expected by chance (50 percent). The transmission of a specific marker allele with a disease gene in different offspring suggests that the marker locus is linked with the disease or located close enough to it on the same chromosome that they cosegregate during meiosis. The disease trait can then be mapped because the chromosomal location of the marker is known.

We also analyzed bronchial hyperresponsiveness as a quantitative trait using a regressive approach to identify the relation between siblings for the actual PC₂₀ values and the proportion of marker alleles identical by descent.³⁵ As with least-squares regression analysis, this method uses the regression of the squared difference in the actual PC₂₀ value on the estimated proportion of alleles identical by descent from all pairs of siblings from all families to test for linkage.

Statistical Analysis

All clinical and genotype data were managed with Paradox on an IBM personal computer (IBM, Research Triangle Park, N.C.). Pearson correlation coefficients and chi-square tests were performed with SAS software (SAS Institute, Cary, N.C.). All P values are two-tailed except those for analyses of affected pairs of siblings, in which a one-tailed test was used because we were testing only for an increased sharing of alleles.

If the serum total IgE level is assumed to be strongly correlated with susceptibility to bronchial hyperresponsiveness,^{11,12,13,14,15,16,17,18,19} and each is largely determined by genetic background,^{2,3,4,5,6,7,8,9,10,20,21} then these traits should be inherited independently at meiosis if the genes responsible are located on different chromosomes. To test the hypothesis that genes determining serum IgE level and susceptibility to bronchial hyperresponsiveness are coinherited (cosegregate at meiosis), we examined whether there was a correlation in serum total IgE values between pairs of siblings who were concordant for bronchial hyperresponsiveness or for the absence of bronchial hyperresponsiveness and whether there was a correlation in log₁₀ PC₂₀ FEV₁ values between pairs of siblings who were concordant for elevated serum total IgE values (log₁₀ value, >2). If these traits are not genetically linked (segregate independently at meiosis), then siblings concordant for one trait would not be expected to be concordant for the second trait.

Results

Relation between the Inheritance of Bronchial Hyperresponsiveness and Serum Total IgE Levels

Table 1 lists the clinical and physiologic data on the first-degree (children) and second-degree (grandchildren) offspring included in our analyses, the 84 probands and their spouses, and the spouses of 29 of the probands' children. There were no half-siblings. Only 19.5 percent of the spouses, including those of the probands' offspring, met the criteria for bronchial hyperresponsiveness (PC₂₀, <32 mg of inhaled histamine per milliliter), whereas 33.6 percent of the first-degree offspring and 35.7 percent of the second-degree offspring were classified as having bronchial hyperresponsiveness. Only six kindreds had at least one affected pair of siblings whose spouses were also hyperresponsive to histamine.

View this table: [in this window] [in a new window]   Table 1. Clinical and Physiologic Characteristics of the Probands, Their First- and Second-Degree Offspring, and Their Spouses.

 
Serum total IgE levels were correlated in 35 pairs of siblings (the offspring of the probands) who were concordant for bronchial hyperresponsiveness (histamine threshold value, <32 mg per milliliter) (r = 0.40, P<0.05) (Figure 1A), suggesting that these traits are coinherited. When a more conservative definition of bronchial hyperresponsiveness was used (histamine threshold value, <16 mg per milliliter), serum total IgE values were correlated in 15 pairs of siblings who met this criterion (r = 0.65, P<0.01) (Figure 1B). Eleven of these 15 pairs of siblings (73 percent) had elevated IgE levels (>100 IU per milliliter, or a log₁₀ value >2). Among these 15 pairs of siblings, only 7 subjects did not report symptoms of asthma. The PC₂₀ values for pairs of siblings with elevated IgE levels are shown in Figure 2. Bronchial hyperresponsiveness was not correlated with IgE levels (r = 0.04, P>0.10).

View larger version (4K): [in this window] [in a new window]   Figure 1. Relation of Serum Total IgE Values in pairs of Siblings Concordant for Bronchial Hyperresponsiveness to Histamine Producing a 20 Percent Decrease in FEV1. The siblings are the offspring of the probands (children and grandchildren). In Panel A, analysis of serum total IgE levels (log10 values) in 35 pairs of siblings with bronchial hyperresponsiveness (histamine threshold value, 32 mg per milliliter) shows a significant correlation (r = 0.40, P<0.05), suggesting that these traits may cosegregate at meiosis. In Panel B, analysis of serum total IgE levels in 15 pairs of siblings with bronchial hyperresponsiveness (histamine threshold value, 16 mg per milliliter) shows a significant correlation (r = 0.65, P<0.01) despite the use of a more conservative definition of bronchial hyperresponsiveness. When these pairs of siblings were subdivided on the basis of IgE values, the majority had elevated levels (log10 value, >2). All of these pairs of siblings share one or more parental alleles for D5S436 or D5S658. The asterisks indicate two sets of overlying values.

 

View larger version (2K): [in this window] [in a new window]   Figure 2. Relation of PC20 Values in 72 Pairs of Siblings Concordant for Elevated Serum Total IgE Levels (Log10 Value, >2). The study subjects were the children and grandchildren of the probands. In subjects who had no significant response to the inhalation of 32 mg of histamine per milliliter (the highest concentration tested), a PC20 value of 64 mg per milliliter was arbitrarily assigned. Bronchial hyperresponsiveness was not correlated with IgE levels (r = 0.04, P>0.10). The asterisks indicate two sets of overlying values, the daggers three sets, and the double dagger four sets.

 
Linkage Analyses

Table 2 shows the results of linkage analyses in the pairs of siblings with bronchial hyperresponsiveness (histamine threshold value, <32 mg per milliliter). These loci are listed in the order in which they currently appear on genetic maps (in which the beginning of the list indicates the most centromeric location)³⁷ of chromosome 5q31-q33 covering a region of approximately 18 cM (Figure 3). There was statistically significant evidence of linkage with D5S436 and several markers located nearby. The markers were considered informative when maternal and paternal alleles could be distinguished in the offspring. Markers D5S658 and D5S436, spanning a distance of approximately 3 million base pairs on chromosome 5q, were informative in 35 pairs of siblings with bronchial hyperresponsiveness. D5S658 and D5S436 showed evidence of linkage with bronchial hyperresponsiveness (P = 0.03 and P = 0.009, respectively). The gene candidates fibroblast growth factor acidic and colony-stimulating factor receptor 1 also showed evidence of linkage with bronchial hyperresponsiveness (P = 0.015 and P = 0.05, respectively), despite being less informative markers than D5S658 or D5S436. When we used a more conservative histamine threshold of <16 mg per milliliter we identified linkage between bronchial hyperresponsiveness and D5S436 in 14 pairs of siblings (empirical P = 0.001; mean proportion of alleles that were identical by descent, 0.77; excess of parental alleles shared, 27 percent).

View this table: [in this window] [in a new window]   Table 2. Results of Linkage Analyses in Affected Pairs of Siblings with Bronchial Hyperresponsiveness to Histamine.

 

View larger version (5K): [in this window] [in a new window]   Figure 3. Map Showing the Relative Order of and Distance between the Polymorphic Genetic Markers Used and the Approximate location of the Gene Candidates for Asthma, Bronchial Hyperresponsiveness, and Atopy Relative to the MarkersStudied. The map includes the following genes: interleukin-4, 13, 5, and 3; immune regulatory factor 1 (IRF1); cell division cycle 25 (CDC25); granulocyte–macrophage colony-stimulating factor (CSF2); early growth response gene 1 (EGR1); CD14; 2-adrenergic receptor (ADRB2); lymphocyte-specific glucocorticoid receptor (GRL1); and platelet-derived growth factor receptor (PDGFR). Bands 5q31–q33 extend from approximately interleukin-4 to D5S410. The distances reported are sex-averaged recombination fractions.37 (The approximate location of and distances between gene candidates are derived from the Genome Data Base [recorded October 12, 1994] and the Cooperative Human Linkage Center Database.) Since the markers within colony-stimulating factor receptor 1 (CSF1R) and fibroblast growth factor acidic (FGFA) have not been incorporated into the published maps, we have placed them in their approximate location on the basis of our mapping data.

 
Table 3 shows the results of linkage analysis of bronchial responsiveness as a qualitative trait (histamine threshold value, <32 mg per milliliter) with D5S436. When both siblings were negative for bronchial hyperresponsiveness (173 pairs of siblings), there was an increased sharing of marker alleles, whereas if one member of a pair of siblings was positive for bronchial hyperresponsiveness and the other was negative (114 pairs of siblings), the pair tended not to share parental alleles (P<0.001). As discussed above, there was an excess sharing of alleles for D5S436 (P = 0.009) in the 35 pairs of siblings who were concordant for bronchial hyperresponsiveness. The linear regression showed that these data were significant (P = 0.000002) (Table 3). Statistical evidence of linkage was not found (P>0.01) for D5S470, D5S500, D5S393, or fibroblast growth factor acidic when we conducted a similar analysis using the data from all pairs of siblings. Finally, there was strong statistical evidence of linkage of D5S436 with bronchial hyperresponsiveness when bronchial hyperresponsiveness was analyzed as a quantitative trait (P<0.001) (see the Methods section). There was still significant evidence of linkage between bronchial hyperresponsiveness and D5S436 when log₁₀ serum total IgE levels were included as a covariate (P<0.002).

View this table: [in this window] [in a new window]   Table 3. Linkage Analysis of D5S436 with Bronchial Responsiveness as a Qualitative Trait in Pairs of Siblings.

 
Discussion

Dissecting the Complex Components of Asthma

The clinical characterization of asthma is difficult, and this complicates the mapping of genes for the disorder. However, critical components of asthma, such as bronchial-hyperresponsiveness and allergic status, can be defined more objectively. In our studies of families, we adopted a strategy that focused on identifying the genes predisposing subjects to these known abnormalities and the risk factors associated with asthma.^21,31,38 This strategy optimized the likelihood of success in dissecting the complex genetic factors determining susceptibility to asthma. Although this mapping approach has limitations,²⁹ the recent identification of major loci important in essential hypertension,³⁹ breast cancer,⁴⁰ and diabetes⁴¹ confirms that these methods are useful for investigating the pathogenesis of common complex genetic disorders. Moreover, the study of asthma was recently advanced by the identification of a major genetic locus regulating serum IgE levels on chromosome 5q31-q33.^20,21

Evidence Supporting the Colocalization of Bronchial Hyperresponsiveness and a Major Gene Regulating Serum Total IgE

In several different populations, serum IgE levels, bronchial hyperresponsiveness, and asthma are strongly associated in epidemiologic studies.^{17,18,19,42,43,44,45} We also observed a very strong association between IgE levels and bronchial hyperresponsiveness, since more than 50 percent of the offspring with elevated IgE levels in our study had physiologic evidence of bronchial hyperresponsiveness (data not shown). The striking feature of this study is the coinheritance and colocalization of a gene that determines both bronchial responsiveness and serum IgE levels. Moreover, the evidence of the coinheritance of these traits in this family study provides a potential genetic mechanism to explain the relation between these variables in prior epidemiologic studies.^{17,18,43,44,45} In particular, we interpret these results as suggesting that there are one or more closely associated susceptibility genes on the same chromosome that are important in the development of bronchial hyperresponsiveness and the regulation of serum IgE levels. For traits to be coinherited in siblings, they must cosegregate with each other at meiosis. This implies genetic linkage to the same chromosomal region. If bronchial hyperresponsiveness and serum IgE levels are not linked (i.e., these traits are determined by genes on separate chromosomes), they should be inherited independently of each other. In contrast, serum total IgE levels were highly correlated in pairs of siblings concordant for bronchial hyperresponsiveness (Figure 1A and Figure 1B). Since these traits appear to be coinherited, they should map to the same chromosomal region.

Mapping of Bronchial Hyperresponsiveness to Chromosome 5q31-q33

Linkage analysis was used to identify a genetic location for bronchial hyperresponsiveness. Because bronchial hyperresponsiveness mapped to a major gene for atopy, we examined chromosomal regions reported to be important in the regulation of serum IgE levels. Candidate regions for atopy have been described through linkage analyses.^{20,21,46,47,48} Previous studies have suggested that atopy and bronchial hyperresponsiveness in the current study population are not linked to a genetic locus on chromosome 11q.³¹ However, there is evidence of a major gene for atopy on chromosome 5q31-q33.^20,21 Therefore, to determine the chromosomal location of a gene or genes governing susceptibility to bronchial hyperresponsiveness, which would be coinherited with a major gene for atopy, we performed linkage analyses between bronchial hyperresponsiveness and genetic markers on chromosome 5q. Analyses of affected pairs of siblings demonstrated statistically significant evidence of linkage between bronchial hyperresponsiveness and D5S436, D5S658, and several other markers located nearby on chromosome 5q31-q33 (Table 2). These data strongly support the hypothesis that one or more closely spaced genes on chromosome 5q31-q33 determine susceptibility to bronchial hyperresponsiveness and atopy.

Candidate Genes for Asthma on Chromosome 5q31-q33

Chromosome 5q31-q33 was originally examined because it is especially rich in genes that are implicated in bronchial inflammation associated with asthma (Figure 3).^{24,25,26,27,28,49,50,51} Granulocyte–macrophage colony-stimulating factor, fibroblast growth factor acidic, other colony-stimulating factors and receptors, the lymphocyte-specific glucocorticoid receptor 1, and the ₂-adrenergic receptor map to this area.²⁴ A cluster of cytokines, interleukin-3, 4, 5, 9, and 13, are also tightly linked and map to this region.^{24,25,26,27,28} These cytokines have overlapping effects on the growth and proliferation of B cells and other cells associated with allergic inflammation.^49,50,51 Interleukin-9 enhances interleukin-4–dependent synthesis of immunoglobulin, and interleukin-13 regulates the expression of CD23, an IgE surface-antigen–binding factor.^26,28 One of the limitations of our study is that we cannot exclude any of these candidates. However, further mapping with genetic markers through this region may provide evidence in the future of linkage disequilibrium and should facilitate the positional cloning of a specific candidate gene.^29,52 Moreover, although our data strongly support the localization to chromosome 5q31-q33 of genetic factors important to susceptibility to asthma, we cannot yet establish whether these linkages are due to a single gene, nor can we offer a precise location for the gene or genes on chromosome 5q31-q33. Further studies aimed at identifying a specific genetic model for bronchial hyperresponsiveness and asthma will be useful in this regard.

Implications for the Clinical Assessment of Asthma

Our findings have potential implications for the role of bronchial hyperresponsiveness in the clinical assessment of asthma. We found evidence that elevated levels of IgE are coinherited with bronchial hyperresponsiveness, yet bronchial responsiveness was not correlated in siblings concordant for elevated serum total IgE levels (log₁₀ value, >2) (Figure 2). These data imply that serum total IgE levels can be influenced by multiple genetic and environmental factors that may not be common to the development of bronchial hyperresponsiveness. Because allergy is prevalent, it is likely that certain factors affecting serum total IgE levels are not common to the development of asthma. Moreover, because bronchial hyperresponsiveness is a known risk factor in asthma,^2,3 one interpretation of these data is that bronchial hyperresponsiveness may be a more specific measure of susceptibility to asthma than serum total IgE levels. Since these measurements were made simultaneously, discordance between pairs of siblings for bronchial hyperresponsiveness would represent an inability to detect this risk factor despite concomitant environmental exposure in these subjects resulting in elevated serum total IgE levels. This latter explanation seems less likely in our view, since numerous studies suggest that these traits are generally expressed together in asthma.^{17,18,19,42,43,44,45}

Conclusions

This study mapped bronchial hyperresponsiveness to a region of chromosome 5q31-q33 previously reported as one site for a major locus regulating serum total IgE.^20,21 These data provide strong evidence of one or more susceptibility loci on chromosome 5q31-q33 that contribute to bronchial hyperresponsiveness and atopy and that are closely associated with bronchial inflammation critical in the pathogenesis of asthma. The coinheritance and genetic colocalization of essential components of asthma generate many important new questions about the molecular basis of susceptibility to this disorder. However, replication of our findings in other populations, including those identified randomly, will be useful to allow their generalization and to guide future studies on the molecular relations between these risk factors and the development of asthma.

Supported by a grant (90.39) from the Dutch Asthma Funds, a grant (HL-48341) from the National Institutes of Health, and a grant from the American Lung Association.

We are indebted to Mr. Carl Dragwa, Ms. Anne Jedlicka, Ms. Jennifer Chon, Mr. E. Gankema, and Mr. E.W. Taylor for technical assistance, to Dr. Jonathon Samet for his suggestions, to the families who participated in this study, and to the Public Health Service for developing the computer program Sage.

Source Information

From University Hospital, Groningen, the Netherlands (D.S.P.); the University of Maryland School of Medicine, Baltimore (E.R.B., P.J.A.); the Asthma Center, Beatrixoord, Haren, the Netherlands (C.I.M.P.); and Johns Hopkins University School of Medicine, Baltimore (K.J.H., J.X., D.A.M., R.C.L.).

Address reprint requests to Dr. Levitt at Meyer 8-134, 600 N. Wolfe St., Johns Hopkins Hospital, Baltimore, MD 21287-7834.

References

1. Orie NGM, Sluiter HJ, de Vries K, Tammeling GJ, Witkop J. The host factor in bronchitis. In: Orie NGM, Sluiter HJ, eds. Bronchitis. Assen, the Netherlands: Royal VanGorcum, 1961:43-59. 
2. Hopp RJ, Bewtra AK, Biven R, Nair NM, Townley RG. Bronchial reactivity pattern in nonasthmatic parents of asthmatics. Ann Allergy 1988;61:184-186. [Medline]
3. Hopp RJ, Townley RG, Biven RE, Bewtra AK, Nair NM. The presence of airway reactivity before the development of asthma. Am Rev Respir Dis 1990;141:2-8. [Medline]
4. Longo G, Strinati R, Poli F, Fumi F. Genetic factors in nonspecific bronchial hyperreactivity: an epidemiologic study. Am J Dis Child 1987;141:331-334. [Abstract]
5. Townley RG, Bewtra A, Wilson AF, et al. Segregation analysis of bronchial response to methacholine inhalation challenge in families with and without asthma. J Allergy Clin Immunol 1986;77:101-107. [CrossRef][Medline]
6. Levitt RC, Mitzner W. Autosomal recessive inheritance of airway hyperreactivity of 5-hydroxytryptamine. J Appl Physiol 1989;67:1125-1132. [Free Full Text]
7. Levitt RC, Mitzner W. Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice. FASEB J 1988;2:2605-2608. [Abstract]
8. Pauwels R, Van Der Straeten M, Weyne J, Bazin H. Genetic factors in non-specific bronchial reactivity in rats. Eur J Respir Dis 1985;66:98-104. [Medline]
9. König P, Godfrey S. Exercise-induced bronchial lability in monozygotic (identical) and dizygotic (nonidentical) twins. J Allergy Clin Immunol 1974;54:280-287. 
10. Townley RG, Guirgis H, Bewtra A, Watt G, Burke K, Carney K. IgE levels and methacholine inhalation responses in monozygous and dizygous twins. J Allergy Clin Immunol 1976;57:277-277.abstract 
11. Ackerman V, Marini M, Vittori E, Bellini A, Vassali G, Mattoli S. Detection of cytokines and their cell sources in bronchial biopsy specimens from asthmatic patients: relationship to atopic status, symptoms, and level of airway hyperresponsiveness. Chest 1994;105:687-696. [Free Full Text]
12. Hamid Q, Azzawi M, Ying S, et al. Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J Clin Invest 1991;87:1541-1546.
13. Djukanovic R, Roche WR, Wilson JW, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:434-457. [Medline]
14. Robinson DS, Hamid Q, Ying S, et al. Predominant T_H2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298-304. [Abstract]
15. Robinson DS, Hamid Q, Ying S, et al. Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon- cytokine gene expression. Am Rev Respir Dis 1993;148:401-406. [Medline]
16. Robinson DS, Ying S, Bentley A, et al. Relationships among numbers of bronchoalveolar lavage cells expressing messenger ribonucleic acid for cytokines, asthma symptoms, and airway methacholine responsiveness in atopic asthma. J Allergy Clin Immunol 1993;92:397-403. [CrossRef][Medline]
17. Sears MR, Burrows B, Flannery EM, Herbison GP, Hewitt CJ, Holdaway MD. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med 1991;325:1067-1071. [Abstract]
18. Burrows B, Sears MR, Flannery EM, Herbison GP, Holdaway MD. Relationships of bronchial responsiveness assessed by methacholine to serum IgE, lung function, symptoms, and diagnoses in 11-year-old New Zealand children. J Allergy Clin Immunol 1992;90:376-385. [CrossRef][Medline]
19. Clifford RD, Pugsley A, Radford M, Holgate ST. Symptoms, atopy, and bronchial response to methacholine in parents with asthma and their children. Arch Dis Child 1987;62:66-73. [Abstract]
20. Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 1994;264:1152-1156. [Free Full Text]
21. Meyers DA, Postma DS, Panhuysen CIM, et al. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics 1994;23:464-470. [CrossRef][Medline]
22. Bradley BL, Azzawi M, Jacobson M, et al. Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial responsiveness. J Allergy Clin Immunol 1991;88:661-674. [CrossRef][Medline]
23. Azzawi M, Bradley B, Jeffery PK, et al. Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis 1990;142:1407-1413. [Medline]
24. Chandrasekharappa SC, Rebelsky MS, Firak TA, Le Beau MM, Westbrook CA. A long-range restriction map of the interleukin-4 and interleukin-5 linkage group on chromosome 5. Genomics 1990;6:94-99. [CrossRef][Medline]
25. van Leeuwen BH, Martinson ME, Webb GC, Young IG. Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5 and GM-CSF genes, on chromosome 5. Blood 1989;73:1142-1148. [Free Full Text]
26. Boulay JL, Paul WE. The interleukin-4 related lymphokines and their binding to hemapoietin receptors. J Biol Chem 1992;267:20525-20528. [Free Full Text]
27. Kelleher K, Bean K, Clark SC, et al. Human interleukin-9: genomic sequence, chromosomal location, and sequences essential for its expression in human T-cell leukemia virus (HTLV)-I-transformed human T cells. Blood 1991;77:1436-1441. [Free Full Text]
28. McKenzie AN, Li X, Largaespada DA, et al. Structural comparison and chromosomal localization of the human and mouse IL-13 genes. J Immunol 1993;150:5436-5444. [Abstract]
29. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994;265:2037-2048. [Erratum, Science 1994;266:1584.] [Free Full Text]
30. Postma DS, Sluiter HJ. Prognosis of chronic obstructive pulmonary disease: the Dutch experience. Am Rev Respir Dis 1989;140:S100-S105. [Medline]
31. Amelung PJ, Panhuysen CI, Postma DS, et al. Atopy and bronchial hyperresponsiveness: exclusion of linkage to markers on chromosome 11q and 6p. Clin Exp Allergy 1992;22:1077-1084. [CrossRef][Medline]
32. de Vries K, Goei JT, Booy-Noord H, Orie NGM. Changes during 24 hours in the lung function and histamine hyperreactivity of the bronchial tree in asthmatic and bronchitic patients. Int Arch Allergy Appl Immunol 1962;20:93-101. [Medline]
33. Weber JL, May PE. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 1989;44:388-396. [Medline]
34. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487-491. [Free Full Text]
35. SAGE: statistical analysis for genetic epidemiology (1992), release 2.1. New Orleans: Department of Biometry and Genetics, LSU Medical Center, 1992.
36. Ott J. Analysis of human genetic linkage. Rev. ed. Baltimore: Johns Hopkins University Press, 1991.
37. Gyapay G, Morissette J, Vignal A, et al. The 1993-94 Généthon human genetic linkage map. Nat Genet 1994;7:246-339. [CrossRef][Medline]
38. Levitt RC, Mitzner W, Kleeberger SR. A genetic approach to the study of lung physiology: understanding biological variability in airway responsiveness. Am J Physiol 1990;258:L157-L164. [Free Full Text]
39. Caulfield M, Lavender P, Martin F, et al. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 1994;330:1629-1633. [Free Full Text]
40. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71. [Free Full Text]
41. Davies JL, Kawaguchi Y, Bennett ST, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nat Genet 1994;371:130-136. 
42. Rijcken B, Schouten JP, Weiss ST, Speizer FE, van der Lende R. The relationship between airway responsiveness to histamine and pulmonary function level in a random population sample. Am Rev Respir Dis 1988;137:826-832. [Medline]
43. Cockcroft DW, Murdock KY, Berscheid BA. Relationship between atopy and bronchial responsiveness to histamine in a random population. Ann Allergy 1984;53:26-29. [Medline]
44. Cline MG, Burrows B. Distribution of allergy in a population sample residing in Tucson, Arizona. Thorax 1989;44:425-431. [Free Full Text]
45. Sears MR, Burrows B, Herbison GP, Flannery EM, Holdaway MD. Atopy in childhood. III. Relationship with pulmonary function and airway responsiveness. Clin Exp Allergy 1993;23:957-963. [CrossRef][Medline]
46. Cookson WOCM, Sharp PA, Faux JA, Hopkin JM. Linkage between immunoglobin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1989;1:1292-1295. [CrossRef][Medline]
47. Moffatt MF, Sharp PA, Faux JA, Young RP, Cookson WOCM, Hopkins JM. Factors confounding genetic linkage between atopy and chromosome 11q. Clin Exp Allergy 1992;22:1046-1051. [CrossRef][Medline]
48. Moffatt MF, Hill MR, Cornelis F, et al. Genetic linkage of T-cell receptor / complex to specific IgE responses. Lancet 1994;343:1597-1600. [CrossRef][Medline]
49. Kay AB. Asthma and inflammation. J Allergy Clin Immunol 1991;87:893-910. [CrossRef][Medline]
50. Kelley J. Cytokines of the lung. Am Rev Respir Dis 1990;141:765-788. [Medline]
51. Katz MF, Beer DJ. T lymphocytes and cytokine networks in asthma: clinical and therapeutic implications. Adv Intern Med 1993;38:189-221. [Medline]
52. Collins FS. Positional cloning: let's not call it reverse anymore. Nat Genet 1992;1:3-6. [CrossRef][Medline]

Abstract PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

This article has been cited by other articles:

• Li, Y., Chang, M., Schrodi, S. J., Callis-Duffin, K. P., Matsunami, N., Civello, D., Bui, N., Catanese, J. J., Leppert, M. F., Krueger, G. G., Begovich, A. B. (2008). The 5q31 variants associated with psoriasis and Crohn's disease are distinct. Hum Mol Genet 17: 2978-2985 [Abstract] [Full Text]  
• Forbes, E. E., Groschwitz, K., Abonia, J. P., Brandt, E. B., Cohen, E., Blanchard, C., Ahrens, R., Seidu, L., McKenzie, A., Strait, R., Finkelman, F. D., Foster, P. S., Matthaei, K. I., Rothenberg, M. E., Hogan, S. P. (2008). IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. JEM 205: 897-913 [Abstract] [Full Text]  
• Lloyd, C. M., Robinson, D. S. (2007). Allergen-induced airway remodelling. Eur Respir J 29: 1020-1032 [Abstract] [Full Text]  
• Steenwinckel, V., Louahed, J., Orabona, C., Huaux, F., Warnier, G., McKenzie, A., Lison, D., Levitt, R., Renauld, J.-C. (2007). IL-13 Mediates In Vivo IL-9 Activities on Lung Epithelial Cells but Not on Hematopoietic Cells. J. Immunol. 178: 3244-3251 [Abstract] [Full Text]  
• Fukui, Y., Hizawa, N., Takahashi, D., Maeda, Y., Jinushi, E., Konno, S., Nishimura, M. (2006). Association Between Nonspecific Airway Hyperresponsiveness and Arg16Gly {beta}2-Adrenergic Receptor Gene Polymorphism in Asymptomatic Healthy Japanese Subjects.. Chest 130: 449-454 [Abstract] [Full Text]  
• Chiba, Y., Kurotani, R., Kusakabe, T., Miura, T., Link, B. W., Misawa, M., Kimura, S. (2006). Uteroglobin-related Protein 1 Expression Suppresses Allergic Airway Inflammation in Mice. Am. J. Respir. Crit. Care Med. 173: 958-964 [Abstract] [Full Text]  
• (2005). Immunotherapy. CMAJ 173: S46-S50 [Full Text]  
• Postma, D. S., Meyers, D. A., Jongepier, H., Howard, T. D., Koppelman, G. H., Bleecker, E. R. (2005). Genomewide Screen for Pulmonary Function in 200 Families Ascertained for Asthma. Am. J. Respir. Crit. Care Med. 172: 446-452 [Abstract] [Full Text]  
• Oostendorp, J., Postma, D. S., Volders, H., Jongepier, H., Kauffman, H. F., Boezen, H. M., Meyers, D. A., Bleecker, E. R., Nelemans, S. A., Zaagsma, J., Meurs, H. (2005). Differential Desensitization of Homozygous Haplotypes of the {beta}2-Adrenergic Receptor in Lymphocytes. Am. J. Respir. Crit. Care Med. 172: 322-328 [Abstract] [Full Text]  
• Pekkanen, J., Sunyer, J., Anto, J. M., Burney, P., on behalf of the European Community Respiratory He, (2005). Operational definitions of asthma in studies on its aetiology. Eur Respir J 26: 28-35 [Abstract] [Full Text]  
• LeVan, T. D., Von Essen, S., Romberger, D. J., Lambert, G. P., Martinez, F. D., Vasquez, M. M., Merchant, J. A. (2005). Polymorphisms in the CD14 Gene Associated with Pulmonary Function in Farmers. Am. J. Respir. Crit. Care Med. 171: 773-779 [Abstract] [Full Text]  
• Arshad, S. H., Kurukulaaratchy, R. J., Fenn, M., Matthews, S. (2005). Early Life Risk Factors for Current Wheeze, Asthma, and Bronchial Hyperresponsiveness at 10 Years of Age. Chest 127: 502-508 [Abstract] [Full Text]  
• Hiromatsu, Y., Fukutani, T., Ichimura, M., Mukai, T., Kaku, H., Nakayama, H., Miyake, I., Shoji, S., Koda, Y., Bednarczuk, T. (2005). Interleukin-13 Gene Polymorphisms Confer the Susceptibility of Japanese Populations to Graves' Disease. J. Clin. Endocrinol. Metab. 90: 296-301 [Abstract] [Full Text]  
• Hegab, A. E., Sakamoto, T., Saitoh, W., Massoud, H. H., Massoud, H. M., Hassanein, K. M., Sekizawa, K. (2004). Polymorphisms of IL4, IL13, and ADRB2 Genes in COPD. Chest 126: 1832-1839 [Abstract] [Full Text]  
• Chiba, Y., Kusakabe, T., Kimura, S. (2004). Decreased expression of uteroglobin-related protein 1 in inflamed mouse airways is mediated by IL-9. Am. J. Physiol. Lung Cell. Mol. Physiol. 287: L1193-L1198 [Abstract] [Full Text]  
• Schwartz, D. A., Freedman, J. H., Linney, E. A. (2004). Environmental genomics: a key to understanding biology, pathophysiology and disease. Hum Mol Genet 13: R217-R224 [Abstract] [Full Text]  
• Gounni, A. S., Hamid, Q., Rahman, S. M., Hoeck, J., Yang, J., Shan, L. (2004). IL-9-Mediated Induction of Eotaxin1/CCL11 in Human Airway Smooth Muscle Cells. J. Immunol. 173: 2771-2779 [Abstract] [Full Text]  
• Hjoberg, J., Le, L., Imrich, A., Subramaniam, V., Mathew, S. I., Vallone, J., Haley, K. J., Green, F. H. Y., Shore, S. A., Silverman, E. S. (2004). Induction of early growth-response factor 1 by platelet-derived growth factor in human airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 286: L817-L825 [Abstract] [Full Text]  
• Paraskakis, E., Sourvinos, G., Passam, F., Tzanakis, N., Tzortzaki, E.G., Zervou, M., Spandidos, D., Siafakas, N.M. (2003). Microsatellite DNA instability and loss of heterozygosity in bronchial asthma. Eur Respir J 22: 951-955 [Abstract] [Full Text]  
• Kang, H.-S., Blink, S. E., Chin, R. K., Lee, Y., Kim, O., Weinstock, J., Waldschmidt, T., Conrad, D., Chen, B., Solway, J., Sperling, A. I., Fu, Y.-X. (2003). Lymphotoxin Is Required for Maintaining Physiological Levels of Serum IgE That Minimizes Th1-mediated Airway Inflammation. JEM 198: 1643-1652 [Abstract] [Full Text]  
• Lind, D. L., Choudhry, S., Ung, N., Ziv, E., Avila, P. C., Salari, K., Ha, C., Lovins, E. G., Coyle, N. E., Nazario, S., Casal, J., Torres, A., Rodriguez-Santana, J. R., Matallana, H., Lilly, C. M., Salas, J., Selman, M., Boushey, H. A., Weiss, S. T., Chapela, R., Ford, J. G., Rodriguez-Cintron, W., Silverman, E. K., Sheppard, D., Kwok, P.-Y., Burchard, E. G. (2003). ADAM33 Is Not Associated with Asthma in Puerto Rican or Mexican Populations. Am. J. Respir. Crit. Care Med. 168: 1312-1316 [Abstract] [Full Text]  
• Koh, Y. Y., Kang, E. K., Kang, H., Yoo, Y., Park, Y., Kim, C. K. (2003). Bronchial Hyperresponsiveness in Adolescents With Long-term Asthma Remission: Importance of a Family History of Bronchial Hyperresponsiveness. Chest 124: 819-825 [Abstract] [Full Text]  
• Baraldo, S., Faffe, D. S., Moore, P. E., Whitehead, T., McKenna, M., Silverman, E. S., Panettieri, R. A. Jr., Shore, S. A. (2003). Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. Am. J. Physiol. Lung Cell. Mol. Physiol. 284: L1093-L1102 [Abstract] [Full Text]  
• He, J.-Q., Connett, J. E., Anthonisen, N. R., Sandford, A. J. (2003). Polymorphisms in the IL13, IL13RA1, and IL4RA Genes and Rate of Decline in Lung Function in Smokers. Am. J. Respir. Cell Mol. Bio. 28: 379-385 [Abstract] [Full Text]  
• Eden, E., Hammel, J., Rouhani, F. N., Brantly, M. L., Barker, A. F., Buist, A. S., Fallat, R. J., Stoller, J. K., Crystal, R. G., Turino, G. M. (2003). Asthma Features in Severe {alpha}1-Antitrypsin Deficiency: Experience of the National Heart, Lung, and Blood Institute Registry. Chest 123: 765-771 [Abstract] [Full Text]  
• O'Byrne, P. M., Inman, M. D. (2003). Airway Hyperresponsiveness. Chest 123: 411S-416S [Abstract] [Full Text]  
• Howard, T. D., Meyers, D. A., Bleecker, E. R. (2003). Mapping Susceptibility Genes for Allergic Diseases. Chest 123: 363S-368S [Abstract] [Full Text]  
• Bracken, M. B., Belanger, K., Cookson, W. O., Triche, E., Christiani, D. C., Leaderer, B. P. (2002). Genetic and Perinatal Risk Factors for Asthma Onset and Severity: A Review and Theoretical Analysis. Epidemiol Rev 24: 176-189 [Full Text]  
• Wong, G. W., Foster, P. S., Yasuda, S., Qi, J. C., Mahalingam, S., Mellor, E. A., Katsoulotos, G., Li, L., Boyce, J. A., Krilis, S. A., Stevens, R. L. (2002). Biochemical and Functional Characterization of Human Transmembrane Tryptase (TMT)/Tryptase gamma . TMT IS AN EXOCYTOSED MAST CELL PROTEASE THAT INDUCES AIRWAY HYPERRESPONSIVENESS IN VIVO VIA AN INTERLEUKIN-13/INTERLEUKIN-4 RECEPTOR alpha /SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 6-DEPENDENT PATHWAY. J. Biol. Chem. 277: 41906-41915 [Abstract] [Full Text]  
• de Haan, G., Bystrykh, L. V., Weersing, E., Dontje, B., Geiger, H., Ivanova, N., Lemischka, I. R., Vellenga, E., Van Zant, G. (2002). A genetic and genomic analysis identifies a cluster of genes associated with hematopoietic cell turnover. Blood 100: 2056-2062 [Abstract] [Full Text]  
• Koh, Y. Y., Lee, M. H., Sun, Y. H., Park, Y., Kim, C. K. (2002). Improvement in Bronchial Hyperresponsiveness with Inhaled Corticosteroids in Children with Asthma: Importance of Family History of Bronchial Hyperresponsiveness. Am. J. Respir. Crit. Care Med. 166: 340-345 [Abstract] [Full Text]  
• Woszczek, G., Kowalski, M.L., Borowiec, M. (2002). Association of asthma and total IgE levels with human leucocyte antigen-DR in patients with grass allergy. Eur Respir J 20: 79-85 [Abstract] [Full Text]  
• Emala, C. W., McQuitty, C. K., Eleff, S. M., Hopkins-Price, P., Lawyer, C., Hoh, J., Ott, J., Levine, M. A., Hirshman, C. A. (2002). Asthma, Allergy, and Airway Hyperresponsiveness Are Not Linked to the {beta}2-Adrenoceptor Gene. Chest 121: 722-731 [Abstract] [Full Text]  
• Rahaman, S. O., Sharma, P., Harbor, P. C., Aman, M. J., Vogelbaum, M. A., Haque, S. J. (2002). IL-13R{alpha}2, a Decoy Receptor for IL-13 Acts As an Inhibitor of IL-4-dependent Signal Transduction in Glioblastoma Cells. Cancer Res. 62: 1103-1109 [Abstract] [Full Text]  
• McMillan, S. J., Bishop, B., Townsend, M. J., McKenzie, A. N., Lloyd, C. M. (2002). The Absence of Interleukin 9 Does Not Affect the Development of Allergen-induced Pulmonary Inflammation nor Airway Hyperreactivity. JEM 195: 51-57 [Abstract] [Full Text]  
• Niimi, T., Keck-Waggoner, C. L., Popescu, N. C., Zhou, Y., Levitt, R. C., Kimura, S. (2001). UGRP1, a Uteroglobin/Clara Cell Secretory Protein-Related Protein, Is a Novel Lung-Enriched Downstream Target Gene for the T/EBP/NKX2.1 Homeodomain Transcription Factor. Mol. Endocrinol. 15: 2021-2036 [Abstract] [Full Text]  
• Walter, D. M., McIntire, J. J., Berry, G., McKenzie, A. N. J., Donaldson, D. D., DeKruyff, R. H., Umetsu, D. T. (2001). Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity. J. Immunol. 167: 4668-4675 [Abstract] [Full Text]  
• Lee, J. H., Kaminski, N., Dolganov, G., Grunig, G., Koth, L., Solomon, C., Erle, D. J., Sheppard, D. (2001). Interleukin-13 Induces Dramatically Different Transcriptional Programs in Three Human Airway Cell Types. Am. J. Respir. Cell Mol. Bio. 25: 474-485 [Abstract] [Full Text]  
• Zhou, Y., Dong, Q., Louahed, J., Dragwa, C., Savio, D., Huang, M., Weiss, C., Tomer, Y., McLane, M. P., Nicolaides, N. C., Levitt, R. C. (2001). Characterization of a Calcium-Activated Chloride Channel as a Shared Target of Th2 Cytokine Pathways and Its Potential Involvement in Asthma. Am. J. Respir. Cell Mol. Bio. 25: 486-491 [Abstract] [Full Text]  
• Little, F. F., Cruikshank, W. W., Center, D. M. (2001). IL-9 Stimulates Release of Chemotactic Factors from Human Bronchial Epithelial Cells. Am. J. Respir. Cell Mol. Bio. 25: 347-352 [Abstract] [Full Text]  
• Howard, T. D., Whittaker, P. A., Zaiman, A. L., Koppelman, G. H., Xu, J., Hanley, M. T., Meyers, D. A., Postma, D. S., Bleecker, E. R. (2001). Identification and Association of Polymorphisms in the Interleukin-13 Gene with Asthma and Atopy in a Dutch Population. Am. J. Respir. Cell Mol. Bio. 25: 377-384 [Abstract] [Full Text]  
• Renauld, J-C (2001). New insights into the role of cytokines in asthma. J. Clin. Pathol. 54: 577-589 [Abstract] [Full Text]  
• LAPORTE, J. C., MOORE, P. E., BARALDO, S., JOUVIN, M.-H., CHURCH, T. L., SCHWARTZMAN, I. N., PANETTIERI, R. A. Jr, KINET, J.-P., SHORE, S. A., SHORE, S. A. (2001). Direct Effects of Interleukin-13 on Signaling Pathways for Physiological Responses in Cultured Human Airway Smooth Muscle Cells. Am. J. Respir. Crit. Care Med. 164: 141-148 [Abstract] [Full Text]  
• Palmer, L. J., Barnes, K. C., Burton, P. R., Chen, H., Cookson, W. O.C.M., Collaborative Study on the Genetics of Asthma, , Deichmann, K. A., Elston, R. C., Holloway, J. W., Jacobs, K. B., Laitinen, T., Wjst, M. (2001). Meta-analysis for linkage to asthma and atopy in the chromosome 5q31-33 candidate region. Hum Mol Genet 10: 891-899 [Abstract] [Full Text]  
• Hoyle, G. W., Brody, A. R. (2001). IL-9 and Lung Fibrosis . A Th2 Good Guy?. Am. J. Respir. Cell Mol. Bio. 24: 365-367 [Full Text]  
• KOPPELMAN, G. H., REIJMERINK, N. E., COLIN STINE, O., HOWARD, T. D., WHITTAKER, P. A., MEYERS, D. A., POSTMA, D. S., BLEECKER, E. R. (2001). Association of a Promoter Polymorphism of the CD14 Gene and Atopy. Am. J. Respir. Crit. Care Med. 163: 965-969 [Abstract] [Full Text]  
• SILVERMAN, E. S., DE SANCTIS, G. T., BOYCE, J., MACLEAN, J. A., JIAO, A., GREEN, F. H. Y., GRASEMANN, H., FAUNCE, D., FITZMAURICE, G., SHI, G.-P., STEIN-STREILEIN, J., MILBRANDT, J., COLLINS, T., DRAZEN, J. M. (2001). The Transcription Factor Early Growth-response Factor 1 Modulates Tumor Necrosis Factor-{alpha}, Immunoglobulin E, and Airway Responsiveness in Mice. Am. J. Respir. Crit. Care Med. 163: 778-785 [Abstract] [Full Text]  
• Abdelilah, S. G., Latifa, K., Esra, N., Cameron, L., Bouchaib, L., Nicolaides, N. C., Levitt, R. C., Hamid, Q. (2001). Functional Expression of IL-9 Receptor by Human Neutrophils from Asthmatic Donors: Role in IL-8 Release. J. Immunol. 166: 2768-2774 [Abstract] [Full Text]  
• Louahed, J., Zhou, Y., Maloy, W. L., Rani, P. U., Weiss, C., Tomer, Y., Vink, A., Renauld, J.-C., Van Snick, J., Nicolaides, N. C., Levitt, R. C., Haczku, A. (2001). Interleukin 9 promotes influx and local maturation of eosinophils. Blood 97: 1035-1042 [Abstract] [Full Text]  
• SCICHILONE, N., PERMUTT, S., TOGIAS, A. (2001). The Lack of the Bronchoprotective and Not the Bronchodilatory Ability of Deep Inspiration Is Associated with Airway Hyperresponsiveness. Am. J. Respir. Crit. Care Med. 163: 413-419 [Abstract] [Full Text]  
• Wenzel, S. (2000). Proceedings of the ATS Workshop on Refractory Asthma . Current Understanding, Recommendations, and Unanswered Questions. Am. J. Respir. Crit. Care Med. 162: 2341-2351 [Full Text]  
• Mehlhop, P. D., van de Rijn, M., Brewer, J. P., Kisselgof, A. B., Geha, R. S., Oettgen, H. C., Martin, T. R. (2000). CD40L, but Not CD40, Is Required for Allergen-Induced Bronchial Hyperresponsiveness in Mice. Am. J. Respir. Cell Mol. Bio. 23: 646-651 [Abstract] [Full Text]  
• Ewart, S. L., Kuperman, D., Schadt, E., Tankersley, C., Grupe, A., Shubitowski, D. M., Peltz, G., Wills-Karp, M. (2000). Quantitative Trait Loci Controlling Allergen-Induced Airway Hyperresponsiveness in Inbred Mice. Am. J. Respir. Cell Mol. Bio. 23: 537-545 [Abstract] [Full Text]  
• Lonjou, C., Barnes, K., Chen, H., Cookson, W. O. C. M., Deichmann, K. A., Hall, I. P., Holloway, J. W., Laitinen, T., Palmer, L. J., Wjst, M., Morton, N. E. (2000). A first trial of retrospective collaboration for positional cloning in complex inheritance: Assay of the cytokine region on chromosome 5 by the Consortium on Asthma Genetics (COAG). Proc. Natl. Acad. Sci. USA 97: 10942-10947 [Abstract] [Full Text]  
• Gounni, A. S., Gregory, B., Nutku, E., Aris, F., Latifa, K., Minshall, E., North, J., Tavernier, J., Levit, R., Nicolaides, N., Robinson, D., Hamid, Q. (2000). Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 96: 2163-2171 [Abstract] [Full Text]  
• Palmer, L. J., Cookson, W. O.C.M. (2000). Genomic Approaches to Understanding Asthma. Genome Res 10: 1280-1287 [Abstract] [Full Text]  
• MARTINEZ, F. D. (2000). Viruses and Atopic Sensitization in the First Years of Life. Am. J. Respir. Crit. Care Med. 162: S95-99 [Full Text]  
• POSTMA, D. S., KOPPELMAN, G. H., MEYERS, D. A. (2000). The Genetics of Atopy and Airway Hyperresponsiveness. Am. J. Respir. Crit. Care Med. 162: S118-123 [Full Text]  
• SUMMERHILL, E., LEAVITT, S. A., GIDLEY, H., PARRY, R., SOLWAY, J., OBER, C. (2000). beta 2-Adrenergic Receptor Arg16/Arg16 Genotype Is Associated with Reduced Lung Function, but Not with Asthma, in the Hutterites. Am. J. Respir. Crit. Care Med. 162: 599-602 [Abstract] [Full Text]  
• Louahed, J., Toda, M., Jen, J., Hamid, Q., Renauld, J.-C., Levitt, R. C., Nicolaides, N. C. (2000). Interleukin-9 Upregulates Mucus Expression in the Airways. Am. J. Respir. Cell Mol. Bio. 22: 649-656 [Abstract] [Full Text]  
• PALMER, L. J., BURTON, P. R., FAUX, J. A., JAMES, A. L., WILLIAM MUSK, A., COOKSON, W. O. C. M. (2000). Independent Inheritance of Serum Immunoglobulin E Concentrations and Airway Responsiveness. Am. J. Respir. Crit. Care Med. 161: 1836-1843 [Abstract] [Full Text]  
• BOUSQUET, J., JEFFERY, P. K., BUSSE, W. W., JOHNSON, M., VIGNOLA, A. M. (2000). Asthma . From Bronchoconstriction to Airways Inflammation and Remodeling. Am. J. Respir. Crit. Care Med. 161: 1720-1745 [Full Text]  
• Lacy, D. A., Wang, Z.-E., Symula, D. J., McArthur, C. J., Rubin, E. M., Frazer, K. A., Locksley, R. M. (2000). Faithful Expression of the Human 5q31 Cytokine Cluster in Transgenic Mice. J. Immunol. 164: 4569-4574 [Abstract] [Full Text]  
• Hadeiba, H., Corry, D. B., Locksley, R. M. (2000). Baseline Airway Hyperreactivity in A/J Mice Is not Mediated by Cells of the Adaptive Immune System. J. Immunol. 164: 4933-4940 [Abstract] [Full Text]  
• Heinzmann, A., Mao, X.-Q., Akaiwa, M., Kreomer, R.T., Gao, P.-S., Ohshima, K., Umeshita, R., Abe, Y., Braun, S., Yamashita, T., Roberts, M.H., Sugimoto, R., Arima, K., Arinobu, Y., Yu, B., Kruse, S., Enomoto, T., Dake, Y., Kawai, M., Shimazu, S., Sasaki, S., Adra, C.N., Kitaichi, M., Inoue, H., Yamauchi, K., Tomichi, N., Kurimoto, F., Hamasaki, N., Hopkin, J.M., Izuhara, K., Shirakawa, T., Deichmann, K.A. (2000). Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet 9: 549-559 [Abstract] [Full Text]  
• ULBRECHT, M., HERGETH, M. T., WJST, M., HEINRICH, J., BICKEBÖLLER, H., WICHMANN, H.-E., WEISS, E. H. (2000). Association of beta 2-Adrenoreceptor Variants with Bronchial Hyperresponsiveness. Am. J. Respir. Crit. Care Med. 161: 469-474 [Abstract] [Full Text]  
• De Sanctis, G. T., Singer, J. B., Jiao, A., Yandava, C. N., Lee, Y. H., Haynes, T. C., Lander, E. S., Beier, D. R., Drazen, J. M. (1999). Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7 in inbred mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 277: L1118-L1123 [Abstract] [Full Text]  
• Kraan, T. C. d. P., Aarden, L. A., Verweij;, C. L., Gillespie, K. M., Anderson, K. L., Mathieson;, P. W. (1999). Polymorphism in the IL-13 Promoter. Science 286: 1647b-1647 [Full Text]  
• Aronica, M. A., Mora, A. L., Mitchell, D. B., Finn, P. W., Johnson, J. E., Sheller, J. R., Boothby, M. R. (1999). Preferential Role for NF-{kappa}B/Rel Signaling in the Type 1 But Not Type 2 T Cell-Dependent Immune Response In Vivo. J. Immunol. 163: 5116-5124 [Abstract] [Full Text]  
• BREWER, J. P., KISSELGOF, A. B., MARTIN, T. R. (1999). Genetic Variability in Pulmonary Physiological, Cellular, and Antibody Responses to Antigen in Mice. Am. J. Respir. Crit. Care Med. 160: 1150-1156 [Abstract] [Full Text]  
• BURCHARD, E. G., SILVERMAN, E. K., ROSENWASSER, L. J., BORISH, L., YANDAVA, C., PILLARI, A., WEISS, S. T., HASDAY, J., LILLY, C. M., FORD, J. G., DRAZEN, J. M. (1999). Association Between a Sequence Variant in the IL-4 Gene Promoter and FEV1 in Asthma. Am. J. Respir. Crit. Care Med. 160: 919-922 [Abstract] [Full Text]  
• TAO, F. C., TOLLOCZKO, B., EIDELMAN, D. H., MARTIN, J. G. (1999). Enhanced Ca2+ Mobilization in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness in an Inbred Strain of Rat. Am. J. Respir. Crit. Care Med. 160: 446-453 [Abstract] [Full Text]  
• Sporik, R., Squillace, S. P, Ingram, J. M., Rakes, G., Honsinger, R. W, Platts-Mills, T. A E (1999). Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in children: a case-control study of three schools. Thorax 54: 675-680 [Abstract] [Full Text]  
• Sheikh, S., Goldsmith, L. J., Howell, L., Parry, L., Eid, N. (1999). Comparison of Lung Function in Infants Exposed to Maternal Smoking and in Infants With a Family History of Asthma. Chest 116: 52-58 [Abstract] [Full Text]  
• Bogardus, S. T. Jr, Concato, J., Feinstein, A. R. (1999). Clinical Epidemiological Quality in Molecular Genetic Research: The Need for Methodological Standards. JAMA 281: 1919-1926 [Abstract] [Full Text]  
• Vink, A., Warnier, G., Brombacher, F., Renauld, J.-C. (1999). Interleukin 9-induced In Vivo Expansion of the B-1 Lymphocyte Population. JEM 189: 1413-1423 [Abstract] [Full Text]  
• Baldini, M., Carla Lohman, I., Halonen, M., Erickson, R. P., Holt, P. G., Martinez, F. D. (1999). A Polymorphism* in the 5' Flanking Region of the CD14 Gene Is Associated with Circulating Soluble CD14 Levels and with Total Serum Immunoglobulin E. Am. J. Respir. Cell Mol. Bio. 20: 976-983 [Abstract] [Full Text]  
• Wierenga, E. A., Walchner, M., Kick, G., Kapsenberg, M. L., Weiss, E. H., Messer, G. (1999). Evidence for suppressed activity of the transcription factor NFAT1 at its proximal binding element P0 in the IL-4 promoter associated with enhanced IL-4 gene transcription in T cells of atopic patients. Int Immunol 11: 297-306 [Abstract] [Full Text]  
• Guler, M. L., Gorham, J. D., Dietrich, W. F., Murphy, T. L., Steen, R. G., Parvin, C. A., Fenoglio, D., Grupe, A., Peltz, G., Murphy, K. M. (1999). Tpm1, a Locus Controlling IL-12 Responsiveness, Acts by a Cell-Autonomous Mechanism. J. Immunol. 162: 1339-1347 [Abstract] [Full Text]  
• Hall, I P (1999). Genetics and pulmonary medicine bullet  8: Genetics and pulmonary medicine: asthma. Thorax 54: 65-69 [Full Text]  
• Grünig, G., Warnock, M., Wakil, A. E., Venkayya, R., Brombacher, F., Rennick, D. M., Sheppard, D., Mohrs, M., Donaldson, D. D., Locksley, R. M., Corry, D. B. (1998). Requirement for IL-13 Independently of IL-4 in Experimental Asthma. Science 282: 2261-2263 [Abstract] [Full Text]  
• MARTINEZ, F. D., SOLOMON, S., HOLBERG, C. J., GRAVES, P. E., BALDINI, M., ERICKSON, R. P. (1998). Linkage of Circulating Eosinophils to Markers on Chromosome 5q. Am. J. Respir. Crit. Care Med. 158: 1739-1744 [Abstract] [Full Text]  
• PALMER, L. J., DANIELS, S. E., RYE, P. J., GIBSON, N. A., TAY, G. K., COOKSON, W. O. C. M., GOLDBLATT, J., BURTON, P. R., LESOUEF, P. N. (1998). Linkage of Chromosome 5q and 11q Gene Markers to Asthma-associated Quantitative Traits in Australian Children. Am. J. Respir. Crit. Care Med. 158: 1825-1830 [Abstract] [Full Text]  
• Spinozzi, F., Agea, E., Fizzotti, M., Bassotti, G., Russano, A., Droetto, S., Bistoni, O., Grignani, F., Bertotto, A. (1998). Role of T-helper type 2 cytokines in down-modulation of Fas mRNA and receptor on the surface of activated CD4+ T cells: molecular basis for the persistence of the allergic immune response. FASEB J. 12: 1747-1753 [Abstract] [Full Text]  
• Youn, J., Chen, J., Goenka, S., Aronica, M. A., Mora, A. L., Correa, V., Sheller, J. R., Boothby, M. (1998). In Vivo Function of an Interleukin 2 Receptor beta  Chain (IL-2Rbeta )/IL-4Ralpha Cytokine Receptor Chimera Potentiates Allergic Airway Disease. JEM 188: 1803-1816 [Abstract] [Full Text]  
• Grasso, L., Huang, M., Sullivan, C. D., Messler, C. J., Kiser, M. B., Dragwa, C. R., Holroyd, K. J., Renauld, J.-C., Levitt, R. C., Nicolaides, N. C. (1998). Molecular Analysis of Human Interleukin-9 Receptor Transcripts in Peripheral Blood Mononuclear Cells. IDENTIFICATION OF A SPLICE VARIANT ENCODING FOR A NONFUNCTIONAL CELL SURFACE RECEPTOR. J. Biol. Chem. 273: 24016-24024 [Abstract] [Full Text]  
• Graham, C. M., Smith, C. A., Thomas, D. B. (1998). Novel Diversity in Th1, Th2 Type Differentiation of Hemagglutinin-Specific T Cell Clones Elicited by Natural Influenza Virus Infection in Three Major Haplotypes (H-2b,d,k). J. Immunol. 161: 1094-1103 [Abstract] [Full Text]  
• PANHUYSEN, C. I. M., BLEECKER, E. R., KOETER, G. H., MEYERS, D. A., POSTMA, D. S. (1998). Characterization of Obstructive Airway Disease in Family Members of Probands with Asthma . An Algorithm for the Diagnosis of Asthma. Am. J. Respir. Crit. Care Med. 157: 1734-1742 [Abstract] [Full Text]  
• Anderson, G G, Morrison, J F J (1998). Molecular biology and genetics of allergy and asthma. Arch. Dis. Child. 78: 488-496 [Full Text]  
• LAITINEN, T., RASANEN, M., KAPRIO, J., KOSKENVUO, M., LAITINEN, L. A. (1998). Importance of Genetic Factors in Adolescent Asthma . A Population-based Twin-family Study. Am. J. Respir. Crit. Care Med. 157: