0
Clinical Investigations: ASTHMA |

Relation of β2-Adrenoceptor Polymorphisms at Codons 16 and 27 to Persistence of Asthma Symptoms After the Onset of Puberty* FREE TO VIEW

Stefano Guerra, MD, PhD, MPH; Penelope E. Graves, ScD; Wayne J. Morgan, MD; Duane L. Sherrill, PhD; Catharine J. Holberg, PhD; Anne L. Wright, PhD; Fernando D. Martinez, MD
Author and Funding Information

*From the Arizona Respiratory Center (Drs. Graves, Guerra, Morgan, Holberg, Wright, and Martinez), College of Medicine, and Mel and Enid Zuckerman Arizona College of Public Health (Dr. Sherrill), University of Arizona, Tucson, AZ.

Correspondence to: Stefano Guerra, MD, PhD, Arizona Respiratory Center, University of Arizona, 1501 N Campbell Ave, PO Box 245030, Tucson, AZ 85724-5030; e-mail: sguerra@arc.arizona.edu



Chest. 2005;128(2):609-617. doi:10.1378/chest.128.2.609
Text Size: A A A
Published online

Background: It has long been recognized that many children with asthma outgrow the disease after the onset of puberty, but little is known about genetic factors influencing this outcome.

Objectives: The aim of the present study was to determine whether the polymorphisms at codons 16 and 27 of the β2-adrenoceptor are significant predictors of the persistence of asthma during adolescence.

Design and participants: We used data from the prospective Tucson Children’s Respiratory Study. Children were genotyped for the polymorphisms at codons 16 and 27. The presence of wheezing/asthma was assessed by questionnaire from age 6 years up to the reported onset of puberty (prepubertal period) and after the onset of puberty up to age 16 years (adolescence).

Results: Among children who wheezed in the prepubertal period (n = 168), subjects homozygous for Gly at codon 16 were at significantly increased risk for persistent wheezing after puberty, as compared with carriers of the other genotypes (relative risk [RR], 1.43; 95% confidence interval [CI], 1.06 to 1.92; p = 0.019). This relation was present among boys (RR, 2.17; 95% CI, 1.41 to 3.36) but not girls (RR, 0.85; 95% CI, 0.55 to 1.30), and increased linearly according to the frequency of wheezing episodes after the onset of puberty. These findings persisted after adjusting for ethnicity and other potential confounders and after selecting only white children. The polymorphism at codon 27 showed no relation with risk for persistent wheezing.

Conclusions: This study provides evidence for a strong gender-specific effect of the Gly16 polymorphism on the persistence of asthma after the onset of puberty.

Figures in this Article

Asthma is a common disease among school-age children in developed countries, and its prevalence has been increasing over the last decades.1In a large British cohort, the cumulative incidence of asthma or wheezy bronchitis was found to be 18.2% and 21.8% by the ages of 7 years and 11 years, respectively.2It has long been recognized that many children with asthma may outgrow the disease during adolescence.3 However, little is known about the genetic factors affecting the remission or persistence of asthma symptoms at puberty.

Population-based longitudinal cohort studies45 have consistently shown that severity and frequency of asthma symptoms are among the strongest predictors for the persistence of asthma from childhood to adulthood. Severity of asthma, in turn, has been shown to be affected by the genetic variation of the β2-adrenoceptor (β2AR). Although the polymorphisms at codons 16 (Arg16→Gly16) and 27 (Gln27→Glu27) of the β2AR have not been associated with the development of the disease per se, several studies have reported an association between the Gly16 polymorphism and severe asthma. In the original report describing these polymorphisms, Reihsaus et al6 found that patients with asthma who required oral steroids were significantly more likely to be homozygous for Gly16 than those with a milder form of the disease. Similarly, Holloway et al7found that patients with at least one admission to hospital with asthma were almost twice as likely to be homozygous for Gly16 than control subjects. No such association was present among patients with mild asthma. In another study, Weir et al8 reported the Gly16-Gln27 haplotype to be more prevalent in patients with moderate asthma (defined as receiving > 400 μg/d of inhaled beclomethasone or equivalent and/or having an FEV1 < 75% of predicted) than in those with mild asthma. Based on the link between β2AR polymorphisms at codons 16 and 27 and severity of asthma, we hypothesized that these polymorphisms may be associated with the persistence of the disease after the onset of puberty.

Study Population

The children included in this study are a subset from the large birth cohort of the Tucson Children’s Respiratory Study. Detailed information on the design and the enrollment process of this study has been provided elsewhere.9 Briefly, between May 1980 and October 1984, parents planning to use the pediatricians of a health maintenance organization in Tucson, AZ, were contacted shortly after their child was born, and a total of 1,246 healthy infants were enrolled in the study. Information on the ethnic backgrounds of both parents was available for 1,101 children. Among them, 997 children (91%) had both parents of either white or Hispanic ethnicity (the two major ethnic groups in the Tucson area) and were selected for this analysis. Parents completed questionnaires on their child’s health status at enrollment and at the year 2 survey (mean age ± SD, 1.62 ± 0.3 years), year 3 survey (mean age, 2.92 ± 0.5 years), year 6 survey (mean age, 6.27 ± 0.9 years), year 8 survey (mean age, 8.62 ± 0.7 years), year 11 survey (mean age, 10.90 ± 0.7 years), year 13 survey (mean age, 13.47 ± 0.6 years), and year 16 survey (mean age, 16.61 ± 0.6).

Puberty Onset

The questionnaires at year 13 and year 16 included questions on whether and when puberty started. Specific examples of signs indicating the onset of puberty (pubic and/or underarm hair, breast development or menstruation in girls, voice changes in boys) were provided. We defined the prepubertal period as that between the year 6 survey and the reported onset of puberty. Remission and persistence of wheezing and asthma were studied between the onset of puberty and up to the year 16 survey (mean follow-up, 4.3 ± 1.6 years).

Wheezing and Asthma

Questions on the presence and frequency of wheezing episodes during the previous year were asked in each of the surveys. Wheezing in the prepubertal period was defined as the report of any wheezing episodes in any of the surveys completed between year 6 and the onset of puberty. Children who reported active wheezing in all the surveys completed during the prepubertal period were defined as having continuous wheezing in prepubertal period. Asthma in the prepubertal period was defined as either the report of more than three wheezing episodes during the previous year in at least one survey, or a physician-confirmed diagnosis of asthma during that period.

Outcomes in adolescence were then assessed among children who had wheezing and/or asthma in the prepubertal period. Wheezing and asthma groups were classified as persistent if any wheezing episodes were reported in at least one survey after the onset of puberty and remitting if they were not. The frequency of persistent wheezing after the onset of puberty was also assessed. Those who reported more than three wheezing episodes during the previous year in at least one survey after the onset of puberty were defined as having frequent persistent wheezing. Otherwise, persistent wheezing was coded as infrequent.

Risk Factors and Potential Confounders

Weight and height were measured by the study nurses at years 6, 11, and 16. Body mass index percentile was calculated for each child using current US sex- and age-standardized values for children.10 Children ≥ 85th percentile were defined as overweight.

At years 6, 11, and 16, skin-prick tests were performed for common allergens in the Tucson area. For reasons of consistency, only responses to the six allergens (ie, Alternaria alternata, Bermuda grass, olive, careless weed, mesquite, and mulberry) tested in each of the three surveys were considered. Positive skin-prick test results were defined as a wheal at least 3 mm larger than the control wheal for at least one tested allergen in at least one of the surveys. At the time of the year 11 survey, parents were surveyed by phone about specific medications (including β-agonists and corticosteroids) received by their child for asthma or wheezing problems in the last 12 months.

Exposure to environmental tobacco smoke was defined as a positive report of current smoking by either the mother or the father at the year 6, year 8, and/or year 11 surveys. Information on years of formal education for both mother and father was collected at the time of enrollment of the child in the study.

Genotyping

Genomic DNA was prepared from peripheral blood obtained at year 11 using standard techniques. β2AR genotypes were determined by a combination of primer-induced restriction site assay and restriction fragment assay as described previously.11 Informed consent was obtained from the parents of participating children, and the study was approved by the Human Subjects Committee of the University of Arizona.

Statistical Analysis

Because of the nature of our data (genotypic data with unknown gametic phase), maximum-likelihood haplotype frequencies were imputed using an expectation-maximization algorithm.12Through this method, it is possible to estimate the most likely distribution by haplotype in the total study population as well as in each ethnic group. Differences in the haplotype distributions among the ethnic groups were tested using the exact test of population differentiation.13For subjects heterozygous for both β2AR-16 and β2AR-27, haplotypes were inferred using the PHASE package14 with the threshold probability set at 95%.

Proportions of subjects with persistent wheezing/asthma were compared using χ2 tests across the β2AR-16 and β2AR-27 genotypes (analysis by subjects) and the corresponding haplotypes (analysis by chromosomes15). The 95% confidence intervals (CIs) of proportions were computed using the binomial distribution. Relative risks (RRs) for persistence of wheezing/asthma associated with the homozygous status for Gly16 were computed and adjusted for ethnic background using stratification according to the Mantel-Haenszel method. Interaction by gender was tested through the homogeneity test, testing the null hypothesis that the RRs for the association between the genotype Gly16/Gly16 and persistent wheezing/asthma were equal between male and female patients. Logistic regression models were used to adjust for potential confounding and adjusted odds ratios were converted to corrected RRs, as described by Zhang and Yu,16 in order to provide a better estimate of the risk for persistence of wheezing after puberty associated with prepubertal risk factors. An α = 0.05 level of significance was chosen for all the performed statistical tests.

Four hundred fourteen children were genotyped for polymorphisms at both codon 16 and codon 27. Genotyped children did not differ significantly from nongenotyped children (n = 583) in terms of average years of maternal and paternal education. However, the two groups differed by ethnic distribution. Almost 32% of genotyped children had at least one Hispanic parent, as compared to 22% of nongenotyped children (p = 0.004).

The two polymorphisms at codons 16 and 27 were found in strong linkage disequilibrium to the point that the haplotype Arg16-Glu27 was estimated to be absent in the study population (Table 1 ). We found the estimated haplotype frequencies to be significantly different by ethnic group (test for population differentiation, p = 0.001). No significant differences were found in the distribution of the allele Arg16 (and corresponding haplotype Arg16-Gln27) by ethnic group, but the allele Glu27 (and the corresponding haplotype Gly16-Glu27) was significantly more common among children with two white parents (0.418) compared with children having two Hispanic parents (0.261). Children with mixed ethnicity showed intermediate frequency (0.346). Because of these differences in β2AR-27 allele/haplotype frequencies, in this study all analyses were both controlled for and stratified by ethnicity. Findings stratified by ethnicity will be presented only for children with both white parents, since this was the only ethnic group with sufficient sample size.

Information on wheezing in the prepubertal period and after the onset of puberty was available for 358 genotyped children. There were no differences in the genotype distribution for both β2AR-16 and β2AR-27 between children with (n = 168) and without (n = 190) wheezing in the prepubertal period (data not shown). Haplotype frequencies were also similar for children with and without wheezing in the prepubertal period (Arg16-Gln27, 33.6% vs 38.2%; Gly16-Gln27, 25.6% vs 25.8%; and Gly16-Glu27, 40.8% vs 36.1%, respectively; p = 0.358).

Among the 168 children who wheezed in the prepubertal period, 85 children (50.6%) experienced wheezing episodes after the onset of puberty (persistent wheezing group), and the remaining 83 children (49.4%) did not (remitting wheezing). In Figure 1 , the proportions of children with persistent wheezing at puberty are compared across the β2AR-16 and β2AR-27 genotypes. More than 60% of the children homozygous for Gly16 experienced persistent wheezing vs only 42.6% of the children carrying a different genotype (RR, 1.43; 95% CI, 1.06 to 1.92; p = 0.019). In contrast, rates of persistence and remission of wheezing after the onset of puberty were similar across the genotypes for β2AR-27. The increased risk for persistent wheezing associated with the Gly16/Gly16 genotype remained after adjusting for ethnicity (adjusted RR, 1.43; 95% CI, 1.06 to 1.92; p = 0.029) and after selecting only children with white parents (RR, 1.55; 95% CI, 1.08 to 2.21; p = 0.015).

We found an interaction by gender in the association between Gly16/Gly16 genotype and persistent wheezing (Table 2 ). Boys homozygous for Gly16 were twice as likely to experience persistent wheezing after the onset of puberty than those carrying a different β2AR-16 genotype (RR, 2.17; 95% CI, 1.41 to 3.36; p = 0.0003). In contrast, no association between β2AR-16 genotypes and persistent wheezing at puberty was found among girls (RR, 0.85; 95% CI, 0.55 to 1.30). The test for homogeneity (which assessed whether the RRs for the association between Gly16/Gly16 and persistent wheezing were identical between the groups of males and females) was significant (p = 0.003), indicating effect modification by gender. These findings were virtually identical among the 118 children who met the criteria for presence of asthma during the prepubertal period (Table 2). Furthermore, we confirmed the increased risk for persistent wheezing associated with the Gly16/Gly16 genotype among male children after adjusting for ethnicity (adjusted RR, 2.26; 95% CI, 1.44 to 3.55; p = 0.0005) and when analyses were restricted to children with white parents (RR, 2.48; 95% CI, 1.39 to 4.40; p = 0.0007).

Figure 2 shows that the risk associated with the Gly16/Gly16 genotype increased linearly among males according to the frequency of wheezing episodes after the onset of puberty. Males homozygous for Gly16 were, in fact, 2.4 times more likely to experience infrequent wheezing (p = 0.003), but up to 3.5 times more likely to experience frequent wheezing (p = 0.002) at puberty, as compared with carriers of the other genotypes. The corresponding RRs among white male children were 2.47 (p = 0.018) for infrequent wheezing and 5.06 (p = 0.001) for frequent wheezing. No trend was evident among female children, either in the whole population or in the white group.

Results of the haplotype analysis are presented in Figure 3 . Because of the significantly different haplotype distributions across the ethnic groups, only children with both white parents were included in this analysis. Persistent wheezing appeared somewhat more common among female than male children, but this association reached only borderline significance. Among male children, the haplotypes carrying the Gly16 allele (Gly16-Gln27 and Gly16-Glu27) showed percentages of persistent wheezing very similar to each other, but significantly higher than those associated with the Arg16 allele (and the corresponding Arg16-Gln27 haplotype) [p = 0.006]. In contrast, the percentages of female children with persistent wheezing did not differ by haplotype.

We have previously shown that being overweight is a significant risk factor for persistence of asthma after puberty.17 In this study, among the cohort of children with prepubertal wheezing we found no relation between body mass index at any age and the β2AR-16 or the β2AR-27 polymorphisms (data not shown). Consistently, the β2AR-16 genotype remained significantly associated with persistence of wheezing among boys after adjusting for being overweight or obese at year 11. Table 3 shows results of the logistic regression model, in which being overweight at year 11 was considered only if the subject had completed the year 11 survey before the onset of puberty.

Consistent with our previous report,17 we found the presence of continuous wheezing in the prepubertal period to be an independent risk factor for persistent asthma after puberty among male and female patients. However, continuous prepubertal wheezing was not associated with the β2AR polymorphisms and did not confound the association between β2AR-16 genotype and persistence of asthma after puberty among male children (Table 3). After adjusting for ethnicity, continuous wheezing, and being overweight, male children homozygous for Gly16 were still 2.3 times more likely to have persistent wheezing compared with carriers of other genotypes.

When further adjustment for exposure to environmental tobacco smoke, use of β-agonists and corticosteroids at year 11, positive skin-prick test results, and parental education was performed, the association between homozygous status for Gly16 and persistent wheezing became even stronger, with males homozygous for Gly16 showing a 2.6-fold increased risk for persistent wheezing after the onset of puberty (p = 0.0002).

Our findings provide evidence for a strong effect of the β2AR-16 polymorphism on persistence of asthma after the onset of puberty among male children, but not female children. Male adolescents homozygous for Gly16 were more than twice as likely to experience persistent wheezing and persistent asthma than carriers of the other genotypes. In addition, the risk associated with having the Gly16/Gly16 genotype increased linearly according to the frequency of wheezing episodes after the onset of puberty. Both the genotype and the haplotype analyses showed no effect of the β2AR-27 polymorphism on persistence of asthma.

From in vitro studies,1819 it has been long known that, although neither the β2AR-16 nor the β2AR-27 polymorphism alters the affinity of the receptor for the agonists, the Gly16 receptor undergoes enhanced down-regulation as compared with the Arg16 receptor. Down-regulation is the gradual decrease in the total number of cellular receptors with agonist exposure. Interestingly, this effect of the Gly16 polymorphism has been shown directly in primary cell lines of airway smooth muscle,,19 in which the β2AR acts to relax and dilate the airway. This is the major mechanism by which β-agonists exert their therapeutic effects in asthma treatment.

The Gly16 polymorphism has been already shown to influence airway response to sporadic11 and regular2023 use of inhaled β-agonists, with apparently contrasting results. A possible explanation can be found in the frame of the so-called “dynamic model,”2425 according to which alleles (such as Gly16) associated with increased downregulation by endogenous catecholamines might be less responsive to acute exposure to exogenous β-agonists but, at the same time, relatively resistant to the tachyphylactic effects of regular β-agonist use. Consistent with this model, at the population level subjects homozygous for Arg16 appear to respond to the sporadic administration of albuterol to a greater extent than carriers of Gly16,11 but in asthmatic cohorts carriers of the Arg16/Arg16 genotype have been shown to be more susceptible to the adverse effects of regular albuterol use.2021,23 In the current study, about 50% of the children with wheezing in the prepubertal period reported use of β-agonists at year 11. However, data on regular vs as-needed albuterol use were not available. Although the main effect of Gly16 on persistent wheezing remained significant after adjustment for use of β-agonists, we cannot exclude that this effect might be modified by regular use of albuterol in childhood. Further studies are needed to elucidate the possible combined effect of β2AR polymorphisms and pharmacologic treatment on the long-term outcomes of childhood asthma.

We found the Gly16 polymorphism to be associated with persistent asthma among male, but not female children. A similar interaction by gender in relation to asthma diagnosis was found among 907 unrelated Mexican adults.26If the patterns of persistence of asthma we found in our adolescents persist into adult life, we will observe a similar association between β2-AR polymorphisms and asthma prevalence only among men, as reported by Santillan and colleagues.27

There are several possible explanations for our finding of a strong interaction by gender in the association between Gly16 polymorphism and persistent asthma. First, this finding may be related to the possible functional regulation of adrenergic receptors by steroid and sex hormones. Lymphocyte β2-AR density has been shown to increase in women during the luteal phase of the menstrual cycle, responding to hormonal flux,28and after administration of exogenous progesterone in the follicular phase.29Administration of exogenous progesterone during the follicular phase induces paradoxical down-regulation of β2-AR in women with asthma,30 suggesting that regulation of β2-AR by sex hormones may be altered in asthmatics. A possible differential regulation of β2-AR by male and female sex hormones might explain why the Gly16 polymorphism influences asthma persistence only among boys, but not girls.

Alternatively, the effect of Gly16 on asthma persistence may be evident only among boys because this is the gender more likely to experience symptom remission during adolescence. It is postulated that in multifactorial diseases genetic risk factors can be harder to identify in the most affected gender,31since the effect of genetic liability can be masked by the stronger effect of other risk factors. In addition to hormonal factors, the physical and behavioral changes that characterize puberty are likely to be very different between boys and girls and to affect differentially the natural history of asthma in the two genders. For instance, the height and weight spurts show gender-specific patterns. By increasing the airway caliber, these spurts may have a more positive impact on the course of asthma among boys than girls, since boys are known to have narrower airways than girls before puberty.32

Another possible interpretation of our findings is that, despite the commonly held view, the natural tendency of asthma might be to persist during adolescence and boys carrying the Arg16 allele are the only “protected” group. Indeed, the rates of persistent wheezing were lower among boys carrying the Arg16 allele (31%) than among any of the other three groups (67% for boys homozygous for Gly16, 61% for girls carrying the Arg16 allele, and 52% for girls homozygous for Gly16). Most likely, the complex interrelationships between puberty-specific hormonal, developmental, and behavioral factors are involved in explaining the interaction between gender and β2-AR polymorphisms on the natural history of asthma during adolescence.

Consistent with previous reports,8,3334 we found the frequencies of the β2AR haplotypes to differ significantly by ethnic group. Therefore, all the analyses were controlled for and stratified by ethnicity. We could confirm the increased risk for persistent wheezing/asthma associated with the polymorphism Gly16 after adjusting for ethnicity as well as after selecting only subjects with both white parents. Such an association could not be tested in the other ethnic groups because of the small sample size.

In multivariate analyses, we could rule out that the effect of β2AR polymorphisms on asthma persistence among boys was due to confounding by other known risk factors. Some of these risk factors hold particular interest from a clinical standpoint. First, the association between Gly16 and persistent asthma after the onset of puberty was independent of the frequency of wheezing during the prepubertal period. This finding reinforces the hypothesis that the β2AR polymorphisms interact with puberty-specific factors in affecting the natural history of asthma. Second, the association between Gly16 and persistent asthma remained significant also after adjusting for obesity. β2AR polymorphisms have been suggested to be associated with obesity35 which in turn has been shown to be a strong risk factor for incidence and persistence of asthma.17,36 However, our data suggest that Gly16 is associated with asthma persistence through pathways that are independent of obesity. Finally, adjustment for use of β-agonists did not affect our findings, although in our study we could not distinguish between regular vs as-needed albuterol use. There is growing evidence that the β2AR-16 polymorphism modifies the effect of regular treatment with albuterol on several asthma outcomes,,2021,23 raising the question whether the β2AR polymorphisms might also interact with pharmacological treatment in affecting the natural history of the disease. In the current study, we could not address this question because of the lack of sufficiently detailed information on medication use.

The Gly16 polymorphism appeared to affect persistence of asthma at puberty according to a recessive model. Subjects with the β2AR-16 genotypes Arg/Arg and Arg/Gly, in fact, showed proportions of persistent wheezing very similar to each other (42% and 43%, respectively) and significantly lower than that of carriers of the Gly/Gly genotype (61%). This finding is consistent with the observation by Holloway and coworkers7 that homozygous but not heterozygous subjects for Gly16 are at increased risk for severe asthma. Similarly, Reihsaus et al6 found subjects homozygous for Gly16 to be overrepresented among cases of severe asthma that required oral steroids. In our study, boys homozygous for Gly16 were 2.2 times more likely to have persistent asthma than boys carrying other genotypes. This RR increased to 2.6 after adjustment for potential confounders. Based on these findings and under the assumption of causality, up to one third of cases of asthma persistence after puberty might be attributable to the Gly16/Gly16 genotype among males (population-attributable risk percentage). However, this cause-effect recessive model should be interpreted cautiously in our study because of the relatively small sample size and because we cannot rule out the possibility that the association between Gly16 and persistent asthma is due to some other single-nucleotide polymorphism (SNP) in very strong linkage disequilibrium with β2AR-16.

This study has several limitations. We used only two of the numerous SNPs present in the β2-AR gene. This precluded us from testing whether persistence of asthma was associated with other β2-AR SNPs, such as the synonymous SNP at codon 175, which has been recently linked to bronchodilator responsiveness.24 We acknowledge that haplotype analyses should include multiple SNPs in order to increase the power of association studies on highly polymorphic genes, such as that of the β2AR.,37 However, findings from others24,33 show that, when up to 13 SNPs in the promoter and coding regions of the β2AR gene were genotyped, only three major haplotypes out of the theoretically possible several thousand combinations encompassed 95% of the chromosomes among white subjects. We thus acknowledge that with the sample size available for this study we are unable to determine the specific influence of minor haplotypes that are known to be present in the population with a frequency < 2%.,33 Wheezing as reported by questionnaire was used as the major phenotypic outcome in most analyses in order to minimize potential bias in reporting asthma. This could lead to some concern about sensitivity and specificity of wheezing as an indicator for detecting active asthma. However, findings were replicated when we used a more stringent definition of prepuberty asthma (Table 2). In addition, in our study wheezing showed a satisfactory concordance with physician-confirmed active asthma in all the surveys, with specificity between 42% and 76% and sensitivity between 85% and 100%.

In conclusion, our findings from a population-based longitudinal birth cohort suggest that males with asthma homozygous for Gly16 are more likely to experience persistence of asthma after puberty than carriers of the other genotypes. These findings hold true after adjusting for potential confounders and after restricting the analyses only to white children.

Abbreviations: β2AR = β2-adrenoceptor; CI = confidence interval; RR = relative risk; SNP = single-nucleotide polymorphism

This study was funded in part by National Heart, Lung, and Blood Institute grant HL 56177.

Table Graphic Jump Location
Table 1. Estimated Haplotype Frequencies (± SD) Across the Groups by Parental Ethnic Background*
* 

Test for population differentiation, p = 0.001. p = 0.01, white/white vs white/Hispanic; p = 0.002, white/white vs Hispanic/Hispanic; p = 0.01, white/Hispanic vs Hispanic/Hispanic.

Figure Jump LinkFigure 1. Proportions (and corresponding binomial 95% CIs) of children with persistent wheezing after the onset of puberty across the genotypes of β2AR-16 and β2AR-27.Grahic Jump Location
Table Graphic Jump Location
Table 2. Proportion With Persistent Wheezing and Persistent Asthma Among Subjects Homozygous for Gly16 and Among Carriers of Other β2AR-16 Genotypes, With Results Stratified by Gender
* 

p = 0.0003.

 

p = 0.0005.

 

The test for homogeneity tests the null hypothesis that the RRs for persistent wheezing/asthma associated with the Gly16/Gly16 genotype are equal among male and female subjects.

Figure Jump LinkFigure 2. RRs and corresponding SEs for infrequent and frequent wheezing at puberty associated with the Gly16/Gly16 genotype. Results are presented stratified by gender within the total population and within the group of children with both white parents.Grahic Jump Location
Figure Jump LinkFigure 3. Proportions and corresponding binomial 95% CIs with persistent wheezing after the onset of puberty associated with the β2AR haplotypes among children with both white parents. Results are presented stratified by gender. Numbers refer to chromosomes.Grahic Jump Location
Table Graphic Jump Location
Table 3. Logistic Regression Models for Predicting Persistence of Wheezing After Onset of Puberty Among Males and Females
* 

Forty-seven cases with persistent wheezing.

 

Thirty-eight cases with persistent wheezing.

 

Only if the subject completed year 11 survey before the onset of puberty.

§ 

White/white is the reference group.

 

As measure of goodness of fit.

Anderson, HR, Butland, BK, Strachan, DP (1994) Trends in prevalence and severity of childhood asthma.BMJ308,1600-1604. [CrossRef] [PubMed]
 
Anderson, HR, Pottier, AC, Strachan, DP Asthma from birth to age 23: incidence and relation to prior and concurrent atopic disease.Thorax1992;47,537-542. [CrossRef] [PubMed]
 
von Mutius, E Paediatric origins of adult lung disease.Thorax2001;56,153-157. [CrossRef] [PubMed]
 
Jenkins, MA, Hopper, JL, Bowes, G, et al Factors in childhood as predictors of asthma in adult life.BMJ1994;309,90-93. [CrossRef] [PubMed]
 
Oswald, H, Phelan, PD, Lanigan, A, et al Outcome of childhood asthma in mid-adult life.BMJ1994;309,95-96. [CrossRef] [PubMed]
 
Reihsaus, E, Innis, M, MacIntyre, N, et al Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects.Am J Respir Cell Mol Biol1993;8,334-339. [PubMed]
 
Holloway, JW, Dunbar, PR, Riley, GA, et al Association of β2-adrenergic receptor polymorphisms with severe asthma.Clin Exp Allergy2000;30,1097-1103. [CrossRef] [PubMed]
 
Weir, TD, Mallek, N, Sandford, AJ, et al β2-Adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma.Am J Respir Crit Care Med1998;158,787-791. [PubMed]
 
Taussig, LM, Wright, AL, Morgan, WJ, et al The Tucson Children’s Respiratory Study: I. Design and implementation of a prospective study of acute and chronic respiratory illness in children.Am J Epidemiol1989;129,1219-1231. [PubMed]
 
Rosner, B, Prineas, R, Loggie, J, et al Percentiles for body mass index in U.S. children 5 to 17 years of age.J Pediatr1998;132,211-222. [CrossRef] [PubMed]
 
Martinez, FD, Graves, PE, Baldini, M, et al Association between genetic polymorphisms of the β2-adrenoceptor and response to albuterol in children with and without a history of wheezing.J Clin Invest1997;100,3184-3188. [CrossRef] [PubMed]
 
Excoffier, L, Slatkin, M Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population.Mol Biol Evol1995;12,921-927. [PubMed]
 
Goudet, J, Raymond, M, de Meeus, T, et al Testing differentiation in diploid populations.Genetics1996;144,1933-1940. [PubMed]
 
Stephens, M, Smith, NJ, Donnelly, P A new statistical method for haplotype reconstruction from population data.Am J Hum Genet2001;68,978-989. [CrossRef] [PubMed]
 
Clayton, D Population association. Cannings, C eds. Handbook of statistical genetics. 2001; John Wiley & Sons. Chichester, UK:.
 
Zhang, J, Yu, KF What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes.JAMA1998;280,1690-1691. [CrossRef] [PubMed]
 
Guerra, S, Wright, AL, Morgan, WJ, et al Persistence of asthma symptoms during adolescence: role of obesity and age at onset of puberty.Am J Respir Crit Care Med2004;170,78-85. [CrossRef] [PubMed]
 
Green, SA, Turki, J, Innis, M, et al Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties.Biochemistry1994;33,9414-9419. [CrossRef] [PubMed]
 
Green, SA, Turki, J, Bejarano, P, et al Influence of β2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells.Am J Respir Cell Mol Biol1995;13,25-33. [PubMed]
 
Israel, E, Chinchilli, VM, Ford, JG, et al Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.Lancet2004;364,1505-1512. [CrossRef] [PubMed]
 
Israel, E, Drazen, JM, Liggett, SB, et al The effect of polymorphisms of the β(2)-adrenergic receptor on the response to regular use of albuterol in asthma.Am J Respir Crit Care Med2000;162,75-80. [PubMed]
 
Tan, S, Hall, IP, Dewar, J, et al Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics.Lancet1997;350,995-999. [CrossRef] [PubMed]
 
Taylor, DR, Drazen, JM, Herbison, GP, et al Asthma exacerbations during long-term β-agonist use: influence of β(2)-adrenoceptor polymorphism.Thorax2000;55,762-767. [CrossRef] [PubMed]
 
Silverman, EK, Kwiatkowski, DJ, Sylvia, JS, et al Family-based association analysis of β2-adrenergic receptor polymorphisms in the childhood asthma management program.J Allergy Clin Immunol2003;112,870-876. [CrossRef] [PubMed]
 
Liggett, SB Polymorphisms of the β2-adrenergic receptor and asthma.Am J Respir Crit Care Med1997;156,S156-162. [PubMed]
 
Santillan, AA, Camargo, CA, Jr, Ramirez-Rivera, A, et al Association between β2-adrenoceptor polymorphisms and asthma diagnosis among Mexican adults.J Allergy Clin Immunol2003;112,1095-1100. [CrossRef] [PubMed]
 
Roth, M, Johnson, PR, Rudiger, JJ, et al Interaction between glucocorticoids and β2-agonists on bronchial airway smooth muscle cells through synchronised cellular signalling.Lancet2002;360,1293-1299. [CrossRef] [PubMed]
 
Wheeldon, NM, Newnham, DM, Coutie, WJ, et al Influence of sex-steroid hormones on the regulation of lymphocyte β2-adrenoceptors during the menstrual cycle.Br J Clin Pharmacol1994;37,583-588. [CrossRef] [PubMed]
 
Tan, KS, McFarlane, LC, Coutie, WJ, et al Effects of exogenous female sex-steroid hormones on lymphocyte β2-adrenoceptors in normal females.Br J Clin Pharmacol1996;41,414-416. [CrossRef] [PubMed]
 
Tan, KS, McFarlane, LC, Lipworth, BJ Paradoxical down-regulation and desensitization of β2-adrenoceptors by exogenous progesterone in female asthmatics.Chest1997;111,847-851. [CrossRef] [PubMed]
 
Carter, CO Genetics of common disorders.Br Med Bull1969;25,52-57. [PubMed]
 
Hibbert, ME, Couriel, JM, Landau, LI Changes in lung, airway, and chest wall function in boys and girls between 8 and 12 yr.J Appl Physiol1984;57,304-308. [PubMed]
 
Drysdale, CM, McGraw, DW, Stack, CB, et al Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.Proc Natl Acad Sci U S A2000;97,10483-10488. [CrossRef] [PubMed]
 
Xie, HG, Stein, CM, Kim, RB, et al Frequency of functionally important β2-adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals.Pharmacogenetics1999;9,511-516. [PubMed]
 
Arner, P, Hoffstedt, J Adrenoceptor genes in human obesity.J Intern Med1999;245,667-672. [CrossRef] [PubMed]
 
Camargo, CA, Jr, Weiss, ST, Zhang, S, et al Prospective study of body mass index, weight change, and risk of adult-onset asthma in women.Arch Intern Med1999;159,2582-2588. [CrossRef] [PubMed]
 
Liggett, SB Pharmacogenetic applications of the Human Genome Project.Nat Med2001;7,281-283. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Proportions (and corresponding binomial 95% CIs) of children with persistent wheezing after the onset of puberty across the genotypes of β2AR-16 and β2AR-27.Grahic Jump Location
Figure Jump LinkFigure 2. RRs and corresponding SEs for infrequent and frequent wheezing at puberty associated with the Gly16/Gly16 genotype. Results are presented stratified by gender within the total population and within the group of children with both white parents.Grahic Jump Location
Figure Jump LinkFigure 3. Proportions and corresponding binomial 95% CIs with persistent wheezing after the onset of puberty associated with the β2AR haplotypes among children with both white parents. Results are presented stratified by gender. Numbers refer to chromosomes.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Estimated Haplotype Frequencies (± SD) Across the Groups by Parental Ethnic Background*
* 

Test for population differentiation, p = 0.001. p = 0.01, white/white vs white/Hispanic; p = 0.002, white/white vs Hispanic/Hispanic; p = 0.01, white/Hispanic vs Hispanic/Hispanic.

Table Graphic Jump Location
Table 2. Proportion With Persistent Wheezing and Persistent Asthma Among Subjects Homozygous for Gly16 and Among Carriers of Other β2AR-16 Genotypes, With Results Stratified by Gender
* 

p = 0.0003.

 

p = 0.0005.

 

The test for homogeneity tests the null hypothesis that the RRs for persistent wheezing/asthma associated with the Gly16/Gly16 genotype are equal among male and female subjects.

Table Graphic Jump Location
Table 3. Logistic Regression Models for Predicting Persistence of Wheezing After Onset of Puberty Among Males and Females
* 

Forty-seven cases with persistent wheezing.

 

Thirty-eight cases with persistent wheezing.

 

Only if the subject completed year 11 survey before the onset of puberty.

§ 

White/white is the reference group.

 

As measure of goodness of fit.

References

Anderson, HR, Butland, BK, Strachan, DP (1994) Trends in prevalence and severity of childhood asthma.BMJ308,1600-1604. [CrossRef] [PubMed]
 
Anderson, HR, Pottier, AC, Strachan, DP Asthma from birth to age 23: incidence and relation to prior and concurrent atopic disease.Thorax1992;47,537-542. [CrossRef] [PubMed]
 
von Mutius, E Paediatric origins of adult lung disease.Thorax2001;56,153-157. [CrossRef] [PubMed]
 
Jenkins, MA, Hopper, JL, Bowes, G, et al Factors in childhood as predictors of asthma in adult life.BMJ1994;309,90-93. [CrossRef] [PubMed]
 
Oswald, H, Phelan, PD, Lanigan, A, et al Outcome of childhood asthma in mid-adult life.BMJ1994;309,95-96. [CrossRef] [PubMed]
 
Reihsaus, E, Innis, M, MacIntyre, N, et al Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects.Am J Respir Cell Mol Biol1993;8,334-339. [PubMed]
 
Holloway, JW, Dunbar, PR, Riley, GA, et al Association of β2-adrenergic receptor polymorphisms with severe asthma.Clin Exp Allergy2000;30,1097-1103. [CrossRef] [PubMed]
 
Weir, TD, Mallek, N, Sandford, AJ, et al β2-Adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma.Am J Respir Crit Care Med1998;158,787-791. [PubMed]
 
Taussig, LM, Wright, AL, Morgan, WJ, et al The Tucson Children’s Respiratory Study: I. Design and implementation of a prospective study of acute and chronic respiratory illness in children.Am J Epidemiol1989;129,1219-1231. [PubMed]
 
Rosner, B, Prineas, R, Loggie, J, et al Percentiles for body mass index in U.S. children 5 to 17 years of age.J Pediatr1998;132,211-222. [CrossRef] [PubMed]
 
Martinez, FD, Graves, PE, Baldini, M, et al Association between genetic polymorphisms of the β2-adrenoceptor and response to albuterol in children with and without a history of wheezing.J Clin Invest1997;100,3184-3188. [CrossRef] [PubMed]
 
Excoffier, L, Slatkin, M Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population.Mol Biol Evol1995;12,921-927. [PubMed]
 
Goudet, J, Raymond, M, de Meeus, T, et al Testing differentiation in diploid populations.Genetics1996;144,1933-1940. [PubMed]
 
Stephens, M, Smith, NJ, Donnelly, P A new statistical method for haplotype reconstruction from population data.Am J Hum Genet2001;68,978-989. [CrossRef] [PubMed]
 
Clayton, D Population association. Cannings, C eds. Handbook of statistical genetics. 2001; John Wiley & Sons. Chichester, UK:.
 
Zhang, J, Yu, KF What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes.JAMA1998;280,1690-1691. [CrossRef] [PubMed]
 
Guerra, S, Wright, AL, Morgan, WJ, et al Persistence of asthma symptoms during adolescence: role of obesity and age at onset of puberty.Am J Respir Crit Care Med2004;170,78-85. [CrossRef] [PubMed]
 
Green, SA, Turki, J, Innis, M, et al Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties.Biochemistry1994;33,9414-9419. [CrossRef] [PubMed]
 
Green, SA, Turki, J, Bejarano, P, et al Influence of β2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells.Am J Respir Cell Mol Biol1995;13,25-33. [PubMed]
 
Israel, E, Chinchilli, VM, Ford, JG, et al Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.Lancet2004;364,1505-1512. [CrossRef] [PubMed]
 
Israel, E, Drazen, JM, Liggett, SB, et al The effect of polymorphisms of the β(2)-adrenergic receptor on the response to regular use of albuterol in asthma.Am J Respir Crit Care Med2000;162,75-80. [PubMed]
 
Tan, S, Hall, IP, Dewar, J, et al Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics.Lancet1997;350,995-999. [CrossRef] [PubMed]
 
Taylor, DR, Drazen, JM, Herbison, GP, et al Asthma exacerbations during long-term β-agonist use: influence of β(2)-adrenoceptor polymorphism.Thorax2000;55,762-767. [CrossRef] [PubMed]
 
Silverman, EK, Kwiatkowski, DJ, Sylvia, JS, et al Family-based association analysis of β2-adrenergic receptor polymorphisms in the childhood asthma management program.J Allergy Clin Immunol2003;112,870-876. [CrossRef] [PubMed]
 
Liggett, SB Polymorphisms of the β2-adrenergic receptor and asthma.Am J Respir Crit Care Med1997;156,S156-162. [PubMed]
 
Santillan, AA, Camargo, CA, Jr, Ramirez-Rivera, A, et al Association between β2-adrenoceptor polymorphisms and asthma diagnosis among Mexican adults.J Allergy Clin Immunol2003;112,1095-1100. [CrossRef] [PubMed]
 
Roth, M, Johnson, PR, Rudiger, JJ, et al Interaction between glucocorticoids and β2-agonists on bronchial airway smooth muscle cells through synchronised cellular signalling.Lancet2002;360,1293-1299. [CrossRef] [PubMed]
 
Wheeldon, NM, Newnham, DM, Coutie, WJ, et al Influence of sex-steroid hormones on the regulation of lymphocyte β2-adrenoceptors during the menstrual cycle.Br J Clin Pharmacol1994;37,583-588. [CrossRef] [PubMed]
 
Tan, KS, McFarlane, LC, Coutie, WJ, et al Effects of exogenous female sex-steroid hormones on lymphocyte β2-adrenoceptors in normal females.Br J Clin Pharmacol1996;41,414-416. [CrossRef] [PubMed]
 
Tan, KS, McFarlane, LC, Lipworth, BJ Paradoxical down-regulation and desensitization of β2-adrenoceptors by exogenous progesterone in female asthmatics.Chest1997;111,847-851. [CrossRef] [PubMed]
 
Carter, CO Genetics of common disorders.Br Med Bull1969;25,52-57. [PubMed]
 
Hibbert, ME, Couriel, JM, Landau, LI Changes in lung, airway, and chest wall function in boys and girls between 8 and 12 yr.J Appl Physiol1984;57,304-308. [PubMed]
 
Drysdale, CM, McGraw, DW, Stack, CB, et al Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.Proc Natl Acad Sci U S A2000;97,10483-10488. [CrossRef] [PubMed]
 
Xie, HG, Stein, CM, Kim, RB, et al Frequency of functionally important β2-adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals.Pharmacogenetics1999;9,511-516. [PubMed]
 
Arner, P, Hoffstedt, J Adrenoceptor genes in human obesity.J Intern Med1999;245,667-672. [CrossRef] [PubMed]
 
Camargo, CA, Jr, Weiss, ST, Zhang, S, et al Prospective study of body mass index, weight change, and risk of adult-onset asthma in women.Arch Intern Med1999;159,2582-2588. [CrossRef] [PubMed]
 
Liggett, SB Pharmacogenetic applications of the Human Genome Project.Nat Med2001;7,281-283. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543