This Article Abstract Full Text (PDF) Online Supplement All Versions of this Article: 200409-1286OCv1 200409-1286OCv2 171/6/563    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choudhry, S. Search for Related Content PubMed PubMed Citation Articles by Choudhry, S.

Pharmacogenetic Differences in Response to Albuterol between Puerto Ricans and Mexicans with Asthma

University of California, San Francisco; Lung Biology Center, San Francisco General Hospital, San Francisco, California; San Juan Veterans Administration Medical Center, University of Puerto Rico School of Medicine; Pediatric Pulmonary Program of San Juan, San Juan, Puerto Rico; Brigham and Women's Hospital, Boston, Massachusetts; The Harlem Lung Center, Harlem Hospital and Columbia University, New York, New York; and Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

Correspondence and requests for reprints should be addressed to: Esteban González Burchard, M.D., University of California, San Francisco, San Francisco, CA 94143-0833. E-mail: eburch{at}itsa.ucsf.edu

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Background: In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the ß₂-adrenergic receptor (ß₂AR) may modify asthma severity and albuterol responsiveness. We tested the association of ß₂AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Ricans and Mexicans with asthma. Methods: We used both family-based and cross-sectional tests of association with 8 ß₂AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness. Results: Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001–0.01). We found a strong interaction of baseline FEV₁ with the Arg16Glycine (Gly) polymorphism in predicting bronchodilator response. Among Puerto Ricans with asthma with baseline FEV₁ < 80% of predicted, but not in those with FEV₁ > 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Gly genotypes and drug responsiveness among Mexicans with asthma. Conclusions: Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness.

Key Words: asthma genetics • ß₂-adrenergic receptor gene • Latinos • pharmacogenetic

Studies of racial/ethnic health disparities often define populations based on U.S. census definitions, which categorize Latinos as a single ethnic group. Latinos are the largest minority population in the United States, and Latino children represent the largest demographic group of all U.S. children (1). Although the terms "Hispanic" or "Latino" American describe a common language and cultural heritage, these terms do not refer to race, uniform ethnicity, or a common genetic background. The two largest Latino ethnic groups in the United States, Mexicans (63%) and Puerto Ricans (11%) (1), are genetically complex and comprised of various proportions of Native American, African, and European genetic origins (2). The relative proportions of these ancestral populations to the contemporary Latino gene pool make each Latino ethnic group genetically unique (2).

According to U.S. vital statistics, asthma prevalence, morbidity, and mortality are the highest among Puerto Ricans and the lowest among Mexicans for a total of a fourfold difference in asthma burden between these two ethnic groups (3, 4). Although there are many potential explanations for this observation, including environmental and socioeconomic factors, one potential explanation is that the genetic predisposition to asthma or to greater asthma severity differs among subgroups within the Latino population. These subgroups may have genetic variants, which may explain the variation in asthma severity and response to drug therapy between Latino ethnic groups.

Albuterol, a short-acting ß₂-adrenergic receptor (ß₂AR) agonist, is the most commonly prescribed treatment for asthma worldwide (5). ß₂AR mediates physiologic responses, including bronchial smooth muscle relaxation (bronchodilation), vasodilatation, and lipolysis (6). Genetic variations at the ß₂AR gene may play a role in the observed ethnic-specific differences in asthma severity and bronchodilator drug responsiveness.

Polymorphisms in the ß₂AR gene have been inconsistently associated with varying degrees of bronchodilatory response to ß-agonists (7–12) and with tachyphylaxis (13, 14). In one study, specific haplotypes, as opposed to individual single nucleotide polymorphisms (SNPs), were significantly associated with drug responsiveness (12). Consequently, there is no clear consensus regarding the extent to which genetic variants in the ß₂AR gene may influence asthma severity or bronchodilator drug responsiveness.

We used a family-based genetic association study to determine whether polymorphisms (SNPs and haplotypes) in the ß₂AR gene are associated with ethnic-specific differences in asthma severity and bronchodilator response in Puerto Rican and Mexican subjects with asthma participating in the Genetics of Asthma in Latino Americans (GALA) Study. We selected a family-based approach because it removes the effect of population stratification, a potentially important source of confounding (15). Spurious associations between genetic variants and phenotypes may arise as a result of population stratification when non–family-based approaches are used (16). Moreover, racial and ethnic background can influence genetic variation and genotypic relative risk (17). Some of the results of this study have been previously reported in the form of an abstract (18).

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Study Participants
Recruitment and pulmonary function testing are described elsewhere and in detail in the online supplement (19). Briefly, 684 subjects with asthma (probands) and their biological parents were enrolled in the San Francisco Bay Area (SF), New York City (NY), Puerto Rico (PR), and Mexico City (MX). Clinical characteristics of all probands are shown in Table 1. Ethnicity was self-reported. Probands were enrolled only if both biological parents and all four biological grandparents were of Puerto Rican (for the NY and PR sites) or Mexican (for the SF and MX sites) ethnicity.

Probands with asthma were classified as having "mild" or "moderate-severe" asthma based on their baseline FEV₁ expressed as percent of predicted or Pre-FEV₁ levels. Subjects with a Pre-FEV₁ greater or less than 80% of predicted were categorized as having "mild" and "moderate-severe" asthma, respectively. A quantitative measure of bronchodilator responsiveness was calculated as FEV₁, which is the relative percent change in Pre-FEV₁ after albuterol administration. Total plasma IgE was measured in duplicate using Uni-Cap technology (Pharmacia, Kalamazoo, MI).

Genotyping
Genotyping details are described further in the online supplement. Eight ß₂AR SNPs (–709, –654, –47, +46, +79, +252, +491, and +523) were genotyped and used to assign haplotypes.

Statistical Analysis
Statistical analyses are further described in the online supplement. Mendelian inconsistencies were identified using PEDCHECK (http://watson.hgen.pitt.edu/register/docs/pedcheck.html) (22). Hardy-Weinberg equilibrium was calculated by means of ² goodness-of-fit tests. The degree of linkage disequilibrium (LD) was estimated by using the r² statistic (23).

Family-based tests (24) and family-based tests for associating haplotypes (25) were used to assess the association between individual SNPs and haplotypes, respectively, with quantitative measures of asthma-related traits. Quantitative phenotypes included: asthma severity (defined by Pre-FEV₁), bronchodilator responsiveness (defined by FEV₁, relative % of predicted), and IgE levels. Qualitative phenotypes included: Pre-FEV₁ greater or less than 80%, FEV₁ greater or less than 12%, and IgE levels greater or less than 100 IU/ml.

To determine the magnitude of the interaction between genotype/haplotype, Pre-FEV₁, ethnicity, and drug responsiveness, we used linear regression models (among subjects with asthma only) to test for an association between genotypes or haplotypes and bronchodilator responsiveness. In each model, the most common homozygous genotype served as the reference group with heterozygotes and the less common homozygote treated as two separate predictors. Other independent variables included in the model were Pre-FEV₁, age, birthplace, sex, regular or as-needed use of ß₂-receptor agonist, use of long acting ß₂-receptor agonist, use of steroids, albuterol dose used for spirometry, environmental tobacco smoke exposure, and, for selected analysis, an interaction term between genotype and Pre-FEV₁ (genotype*Pre-FEV₁). This interaction term was considered because the response to albuterol and effect of genotype on the response may be more substantial in subjects with severe airway obstruction (low initial FEV₁) as opposed to subjects with less airway obstruction at the time of pulmonary function testing. To correct for the effect of population stratification, cross-sectional analyses were also adjusted for individual admixture using 44 unlinked ancestry informative genetic markers (see online supplement). All cross-sectional analyses were performed using STATA 8.0 S/E statistical software (College Station, TX).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Allele Frequencies, Hardy-Weinberg Equilibrium, and LD
Of the 684 GALA Study trios, we obtained genotyping information for 667 trios, which were used for these analyses. The allele frequencies of eight ß₂AR SNPs in the combined (Puerto Rican and Mexican together), Puerto Rican, and Mexican probands are listed in Table 2. All SNPs were found to be in conformance with Hardy-Weinberg equilibrium with the exception of SNP –47 in combined (p value = 0.03) and SNPs +252 and +523 in Mexican parents (p values 0.05 and 0.03, respectively). However, with eight SNPs tested in combined and separate populations, these deviations could result from multiple testing. We did not find the rare allele of SNP –709 in any of our samples and therefore this SNP was excluded from further analyses. For purposes of consistency, the haplotypes discussed below continue to list –709 position, although it was invariant in our populations.

View larger version (34K): [in this window] [in a new window]   Figure 1. Linkage disequilibrium (LD) between ß2-adrenergic receptor (ß2AR) single nucleotide polymorphisms (SNPs) in Puerto Rican and Mexican subjects with asthma. The degree of LD was estimated by using the r2 statistic. The results are color coded as shown by the color bar.

View this table: [in this window] [in a new window]   TABLE 4. Family-based association analysis of qualitative and quantitative asthma traits with ß2-adrenergic receptor single nucleotide polymorphisms in puerto ricans* and mexicans

View larger version (15K): [in this window] [in a new window]   Figure 2. Responsiveness to ß2AR agonist expressed as FEV1 (relative % predicted) in different codon 16 genotypes among all Puerto Rican subjects with asthma (solid bars) and Puerto Rican subjects with asthma with baseline Pre-FEV1 values less than (open bars) and greater than (hatched bars) 80% of predicted.

View larger version (21K): [in this window] [in a new window]   Figure 3. Responsiveness to ß2AR agonist expressed as FEV1 (relative % predicted) in different codon 16/codon 27 haplotype pairs among all Puerto Rican subjects with asthma (solid bars) and Puerto Rican subjects with asthma with baseline Pre-FEV1 values less than (open bars) and greater than (hatched bars) 80% of predicted.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Although most studies of racial/ethnic health disparities often categorize Latinos as a single ethnic group, this classification masks important ethnic-specific differences in health outcomes and therapeutic effectiveness. Despite this classification, it is well accepted that in all regions of the United States, Puerto Ricans have higher asthma morbidity and mortality rates than other Latino ethnic groups. This observation has not so far been satisfactorily explained by environmental or socioeconomic factors. Our results demonstrate that Puerto Ricans with asthma have an ethnic-specific genetic predisposition to more severe asthma. Specifically, our study of ß₂AR polymorphisms shows that the Arg16 allele is significantly associated with asthma severity (Pre-FEV₁) and bronchodilator responsiveness ( FEV₁) in Puerto Rican but not in Mexican subjects with asthma. The large size and clinical diversity of these two study populations have allowed us to address many outstanding questions relating to the clinical relevance of ß₂AR polymorphisms in terms of asthma severity and bronchodilator drug responsiveness. Most importantly, however, this comprehensive family-based study of ß₂AR polymorphisms demonstrates striking ethnic-specific pharmacogenetic differences between Puerto Rican and Mexican subjects with asthma. Despite the fact that Puerto Ricans and Mexicans are classified as the same population, "Hispanic or Latino," our results demonstrate that there are different patterns of LD, haplotypes, and genetic associations between these two ethnic groups. To our knowledge, this is the first report of an ethnic-specific pharmacogenetic association for subjects with asthma.

Martinez and colleagues previously demonstrated that when compared with Gly16 homozygotes, Arg16 homozygotes and Arg16Gly heterozygotes were, respectively, 5.3 and 2.3 times more likely to respond to albuterol, respectively. (8). Our results demonstrate that Arg16Gly is an important modifier of asthma severity and drug responsiveness among Puerto Ricans. These results corroborate and extend previous reports of associations between ß₂AR polymorphisms and asthma (8, 9, 27, 28). Among Puerto Ricans with asthma with low baseline FEV₁ values, for whom the ß₂-agonist response is probably most crucial, there was approximately a 20% difference in FEV₁ values between the Arg16 and Gly16 homozygotes, a highly significant and clinically important difference. The intermediate value of heterozygotes is consistent with an additive model, which corroborates a dose-response effect of this allele in Puerto Ricans.

We did not see a convincing association between ß₂AR genotype and drug responsiveness among Mexicans with asthma. The lack of a clear association may be due to several factors, including differences in LD patterns between Puerto Ricans and Mexicans. For example, the Arg16Gly allele may be in LD with another important risk allele in Puerto Ricans, but not in LD with this risk allele in Mexicans. There may also be ethnic-specific genetic and/or environmental modifiers that attenuate the effect of the Arg16Gly allele in Mexicans. By design, neither environmental nor cultural differences were a primary focus of the GALA study, and therefore, could be confounders.

Drysdale and coworkers demonstrated that haplotypes but not individual SNPs were associated with bronchodilator responsiveness (12). Our results differ in that both individual SNPs and haplotypes modulate asthma severity and bronchodilator drug responsiveness. Specifically, Drysdale and coworkers demonstrated that Drysdale haplotype 6 (corresponding to GALA haplotype 2) was associated with increased measures of bronchodilator drug responsiveness, whereas Drysdale haplotype 4 (corresponding to GALA haplotype 1) was associated with lower measures of bronchodilator drug responsiveness. In contrast, our results demonstrate that GALA haplotype 1 (Drysdale haplotype 4) was associated with increased measures of bronchodilator responsiveness, whereas GALA haplotype 2 (Drysdale haplotype 6) was associated with lower levels of bronchodilator responsiveness. There are several important differences between our study and the study of Drysdale and coworkers, however, which might help to explain differences in our respective results. Drysdale and coworkers studied 121 unrelated Caucasian subjects with asthma who all had FEV₁ values greater than 12% from baseline. Our study was a family-based study and included probands with asthma from two populations, Puerto Ricans (n = 393) and Mexicans (n = 274). Unlike case-control and case-only genetic association studies, family-based studies are robust to the effects of population stratification (16). It is unlikely that inadequate sample size precluded the replication of the previously reported association. We analyzed data from 667 family trios for a total of 2,001 individuals, which exceeds the sample size (n = 121) that Drysdale and coworkers used for their study. Although it is possible that the limited sample size precluded Drysdale and coworkers from finding associations between individual SNPs and asthma related phenotypes, there might be other potential reasons why our results differed from those reported previously. One important difference is that we studied different populations, and racial/ethnic-specific differences in environmental or genetic risk factors may account for the observed differences (17). Drysdale and coworkers performed their study exclusively in Caucasians from the United States, whereas we studied Latinos recruited from Mexico City, Puerto Rico, and the continental United States.

In contrast to the results of Drysdale and coworkers, our results corroborate recently published results from the Childhood Asthma Management Program (CAMP), a large family-based study primarily consisting of subjects with mild asthma (10). Similar to the GALA Study, the CAMP Study was a family-based study and included genotype data of 8 ß₂AR SNPs in 700 complete trios (mother, father and child with asthma); 516 white, 70 African American, 56 Hispanic, and 56 listed as "other." An important difference between the CAMP and GALA Studies is that we directly compared two Latino ethnic groups consisting of subjects with mild and moderate-severe asthma. Results from GALA and CAMP differ in that CAMP demonstrated association of Pre-FEV₁ values of less than 80% with SNPs –654, –47, +46, and +79 and association of bronchodilator responsiveness only with SNP +523. The most significant individual haplotype results were for GALA haplotype 2 (corresponding to CAMP haplotype 3), which had lower bronchodilator response measures in both CAMP and GALA Mexicans.

We have previously demonstrated that Puerto Ricans with asthma have significantly more airway obstruction, more health care utilization, and lower bronchodilator response to albuterol than Mexicans with asthma (19). Although our results do not entirely explain the significant disparities in asthma prevalence, morbidity, and mortality among Latino ethnic groups, our study raises several provocative issues regarding ethnic-specific pharmacogenetic differences between these two populations. This large family-based study consists of two well characterized, ethnically diverse populations of Puerto Ricans and Mexicans with asthma from four geographically diverse locations. Studies performed in these populations may have important public health implications because Latino children represent the largest demographic group of all U.S. children (1) and because asthma morbidity and mortality are highest amongst Puerto Ricans and the lowest amongst Mexicans for a fourfold difference in asthma burden between these two ethnic groups (3, 4). The fact that Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively, underscores the clinical significance and public health implications of these findings.

Our study demonstrates that the two largest Latino ethnic groups in the United States have different patterns of LD, haplotypes, and pharmacogenetic associations, and, therefore, should be considered as separate groups in future drug trials and pharmacogenetic studies of asthma. Ethnic-specific pharmacogenetic differences among populations with asthma have not been previously reported and thus merit further investigation.

	Acknowledgments

 
The authors thank the families and the subjects for their participation and the numerous health care providers and community clinics for their support and participation in the GALA Study. In addition, they thank the primary clinical centers of the investigators, participating community clinics, and hospitals: La Clinica de La Raza, Oakland, CA; UCSF-Children's Hospital of Oakland Pediatric Clinical Research Center, Oakland, CA; General Clinical Research Center, SFGH, San Francisco, CA; Alliance Medical Center, Healdsburg, CA; Santa Clara Valley Medical Center, San José, CA; Fair Oaks Family Health Center, Redwood City, CA; Clinica de Salud del Valle de Salinas, Salinas, CA; Natividad Medical Center, Salinas, CA; Asthma Education and Management Program, Community Medical Centers, Fresno, CA; Diagnostic Health Centers of: Corozal, Naranjito, Catano, Orocovis, Barranquitas and San Antonio Hospital of Mayaguez; Morris Heights Health Center, Bronx, NY; Paterson School Board, Paterson, NJ; Eva's Clinic, Paterson, NJ; Lincoln Medical Center, Bronx; Harlem Hospital Center, NY; and the Metropolitan Hospital Center, New York, NY. They also thank Carmen Jimenez, Yannett Marcano, Pedro Yapor, M.D., Alma Ortiz, M.D., Lisandra Perez, M.D., Daniel Navarro, M.D., and Sheila Gonzalez, M.D., for their assistance with recruitment and Pui Yan Kwok, M.D., Ph.D., for his assistance with genotyping.

	FOOTNOTES

 
Supported by National Institutes of Health grants: K23 HL04464, HL07185, and GM61390; National Center on Minority Health and Health Disparities, Extramural Clinical Research Loan Repayment Program for Individuals from Disadvantaged Backgrounds, 2001–2003, to EGB; HL51823, HL074204, 3M01RR000083–38S30488, HL56443 and HL51831 to the Asthma Clinical Research Network; SFGH General Clinical Research Center M01RR00083–41, U01-HL 65899, UCSF-Children's Hospital of Oakland Pediatric Clinical Research Center (M01 RR01271), Oakland, CA, Sandler Center for Basic Research in Asthma; and the Sandler Family Foundation.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: S.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.U. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.C.A. received $1,500 in lecture fees from GlaxoSmithKline (GSK) in 2003, $1,500 in consulting fees from Aventis in 2004, and will receive $215,000 in research grants from GSK in 2004–2005; E.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.D.G. will be receiving $195,000 from 2004–2007 as a recipient of the Pfizer Scholars Grants in Clinical Epidemiology; K.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.R.R.-S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.K.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.L. received support from Merck for lectures in 2003–2004; H.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.T.W. received a grant for $900,065 (Asthma Policy Modeling Study) from AstraZeneca from 1997 to 2003, has been a coinvestigator on a grant from Boehringer Ingelheim to investigate a chronic obstructive pulmonary disease (COPD) natural history model, which began in 2003 but he received no funds for his involvement in this project, has been an advisor to the TENOR Study for Genentech for which he received $5,000 for 2003–2004, received a grant from Glaxo-Wellcome for $500,000 for genomic equipment from 2000 to 2003, and was a consultant for Roche Pharmaceuticals in 2000 but received no financial remuneration for this consultancy; J.G.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.A.B. received payment from GSK for service on the Scientific Committee for a clinical trial (the GOAL Study), received payments as honoraria for lectures in 2003, and was responsible for the Regents of the University of California receiving from GSK $485,000 for research conducted under his direction between 1999 and 2001, unrestricted gifts for research and training of $8,323 in 2002, $4,500 in 2003, $2,371 in 2004, and $7,390 for his service to the Scientific Advisory Board for this study; J.M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.R.-C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.K.S. received grant support and honoraria from GSK for a study of COPD genetics and received a $500 Speaker Fee from Wyeth for a talk on COPD genetics; E.G.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form September 28, 2004; accepted in final form November 8, 2004

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 

1. US Census Bureau U.S.DoC. United States Census 2000: United States Department of Commerce, 2000.
2. Hanis CL, Hewett-Emmett D, Bertin TK, Schull WJ. Origins of U.S. Hispanics: implications for diabetes. Diabetes Care 1991;14:618–627.[Abstract]
3. Carter-Pokras OD, Gergen PJ. Reported asthma among Puerto Rican, Mexican-American, and Cuban children: 1982 through 1984. Am J Public Health 1993;83:580–582.[Abstract/Free Full Text]
4. Homa DM, Mannino DM, Lara M. Asthma mortality in U.S. Hispanics of Mexican, Puerto Rican, and Cuban heritage, 1990–1995. Am J Respir Crit Care Med 2000;161:504–509.[Abstract/Free Full Text]
5. Nelson HS. Beta-adrenergic bronchodilators. N Engl J Med 1995;333:499–506.[Free Full Text]
6. Insel PA. Seminars in medicine of the Beth Israel Hospital, Boston: adrenergic receptors–evolving concepts and clinical implications. N Engl J Med 1996;334:580–585.[Free Full Text]
7. Ohe M, Munakata M, Hizawa N, Itoh A, Doi I, Yamaguchi E, Homma Y, Kawakami Y. Beta 2 adrenergic receptor gene restriction fragment length polymorphism and bronchial asthma. Thorax 1995;50:353–359.[Abstract/Free Full Text]
8. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997;100:3184–3188.[Medline]
9. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, Johnson JA. Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999;65:519–525.[CrossRef][Medline]
10. Silverman EK, Kwiatkowski DJ, Sylvia JS, Lazarus R, Drazen JM, Lange C, Laird NM, Weiss ST. Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program. J Allergy Clin Immunol 2003;112:870–876.[CrossRef][Medline]
11. Lipworth BJ, Hall IP, Tan S, Aziz I, Coutie W. Effects of genetic polymorphism on ex vivo and in vivo function of beta2-adrenoceptors in asthmatic patients. Chest 1999;115:324–328.[Abstract/Free Full Text]
12. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000;97:10483–10488.[Abstract/Free Full Text]
13. Tan KS, McFarlane LC, Lipworth BJ. Effects of oral and inhaled corticosteroid on lymphocyte beta2- adrenoceptor function in asthmatic patients. Br J Clin Pharmacol 1997;44:565–568.[CrossRef][Medline]
14. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, Cooper DM, Fahy JV, Fish JE, Ford JG, et al. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162:75–80.[Abstract/Free Full Text]
15. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52:506–516.[Medline]
16. Ziv E, Burchard EG. Human population structure and genetic association studies. Pharmacogenomics 2003;4:431–441.[CrossRef][Medline]
17. Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ, Mountain JL, Perez-Stable EJ, Sheppard D, Risch N. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 2003;348:1170–1175.[Free Full Text]
18. Burchard E, Choudhry S, Ung N, Avila PC, Ziv E, Nazario S, Casal J, Torres A, Salari K, Rodriguez Santana J, et al. Pharmacogenetic differences in response to bronchodilators between Puerto Rican and Mexican asthmatics [abstract]. American Society of Human Genetics, Toronto, Canada, 2004. Vol. 54th Annual.
19. Burchard EG, Avila PC, Nazario S, Casal J, Torres A, Rodriguez-Santana JR, Toscano M, Sylvia JS, Alioto M, Salazar M, et al. Lower bronchodilator responsiveness in Puerto Rican than in Mexican asthmatic subjects. Am J Respir Crit Care Med 2003.
20. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995; 152:1107–1136.[Medline]
21. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999;159:179–187.[Abstract/Free Full Text]
22. O'Connell JR, Weeks DE. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998;63:259–266.[CrossRef][Medline]
23. Ott J. Analysis of human genetic linkage. In: The Johns Hopkins University Press, 3rd ed. Baltimore, 1999.
24. Laird NM, Horvath S, Xu X. Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000;19:S36–S42.
25. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM. Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genetic Epidemiol 2004;26(1):61–69.[CrossRef][Medline]
26. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotypes reconstruction from population data. Am J Hum Genet 2001;68:978–989.[CrossRef][Medline]
27. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the ß2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993;8:334–339.
28. Summerhill E, Leavitt SA, Gidley H, Parry R, Solway J, Ober C. 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 2000;162:599–602.[Abstract/Free Full Text]

This article has been cited by other articles:

				C. L. Carroll, P. Stoltz, C. M. Schramm, and A. R. Zucker {beta}2-Adrenergic Receptor Polymorphisms Affect Response to Treatment in Children With Severe Asthma Exacerbations Chest, May 1, 2009; 135(5): 1186 - 1192. [Abstract] [Full Text] [PDF]

				G. Vacca, K. Schwabe, R. Duck, H.-P. Hlawa, A. Westphal, S. Pabst, C. Grohe, and A. Gillissen Polymorphisms of the ss2 adrenoreceptor gene in chronic obstructive pulmonary disease Therapeutic Advances in Respiratory Disease, February 1, 2009; 3(1): 3 - 10. [Abstract] [PDF]

				K. Blake, R. Madabushi, H. Derendorf, and J. Lima Population Pharmacodynamic Model of Bronchodilator Response to Inhaled Albuterol in Children and Adults With Asthma Chest, November 1, 2008; 134(5): 981 - 989. [Abstract] [Full Text] [PDF]

				M. C. Aldrich, S. Selvin, H. M. Hansen, L. F. Barcellos, M. R. Wrensch, J. D. Sison, C. P. Quesenberry, R. A. Kittles, G. Silva, P. A. Buffler, et al. Comparison of Statistical Methods for Estimating Genetic Admixture in a Lung Cancer Study of African Americans and Latinos Am. J. Epidemiol., November 1, 2008; 168(9): 1035 - 1046. [Abstract] [Full Text] [PDF]

				D. Fullwiley The biologistical construction of race: 'admixture' technology and the new genetic medicine. Social Studies of Science, October 1, 2008; 38(5): 695 - 735. [Abstract] [PDF]

				J. Galanter, S. Choudhry, C. Eng, S. Nazario, J. R. Rodriguez-Santana, J. Casal, A. Torres-Palacios, J. Salas, R. Chapela, H. G. Watson, et al. ORMDL3 Gene Is Associated with Asthma in Three Ethnically Diverse Populations Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1194 - 1200. [Abstract] [Full Text] [PDF]

				N. Hizawa, H. Makita, Y. Nasuhara, T. Betsuyaku, Y. Itoh, K. Nagai, M. Hasegawa, and M. Nishimura {beta}2-Adrenergic Receptor Genetic Polymorphisms and Short-term Bronchodilator Responses in Patients With COPD Chest, November 1, 2007; 132(5): 1485 - 1492. [Abstract] [Full Text] [PDF]

				K. B. Weiss Eliminating Asthma Disparities: A National Workshop To Set a Working Agenda Chest, November 1, 2007; 132(5_suppl): 753S - 756S. [Abstract] [Full Text] [PDF]

				C. V. Scirica and J. C. Celedon Genetics of Asthma: Potential Implications for Reducing Asthma Disparities Chest, November 1, 2007; 132(5_suppl): 770S - 781S. [Abstract] [Full Text] [PDF]

				S. Choudhry, M. A. Seibold, L. N. Borrell, H. Tang, D. Serebrisky, R. Chapela, J. R. Rodriguez-Santana, P. C. Avila, E. Ziv, W. Rodriguez-Cintron, et al. Dissecting Complex Diseases in Complex Populations: Asthma in Latino Americans Proceedings of the ATS, July 1, 2007; 4(3): 226 - 233. [Abstract] [Full Text] [PDF]

				R. B. Penn, V. E. Ortega, and E. R. Bleecker A Roadmap to functional genomics Physiol Genomics, June 19, 2007; 30(1): 82 - 88. [Abstract] [Full Text] [PDF]

				A. Panebra, M. R. Schwarb, C. B. Glinka, and S. B. Liggett Allele-Specific Binding of Airway Nuclear Extracts to Polymorphic beta2-Adrenergic Receptor 5' Sequence Am. J. Respir. Cell Mol. Biol., June 1, 2007; 36(6): 654 - 660. [Abstract] [Full Text] [PDF]

				R. T. Cohen, G. J. Canino, H. R. Bird, S. Shen, B. A. Rosner, and J. C. Celedon Area of Residence, Birthplace, and Asthma in Puerto Rican Children Chest, May 1, 2007; 131(5): 1331 - 1338. [Abstract] [Full Text] [PDF]

				S. Choudhry, E. G. Burchard, L. N. Borrell, H. Tang, I. Gomez, M. Naqvi, S. Nazario, A. Torres, J. Casal, J. C. Martinez-Cruzado, et al. Ancestry-Environment Interactions and Asthma Risk among Puerto Ricans Am. J. Respir. Crit. Care Med., November 15, 2006; 174(10): 1088 - 1093. [Abstract] [Full Text] [PDF]

				D. Rose, D. M. Mannino, and B. P. Leaderer Asthma Prevalence Among US Adults, 1998-2000: Role of Puerto Rican Ethnicity and Behavioral and Geographic Factors Am J Public Health, May 1, 2006; 96(5): 880 - 888. [Abstract] [Full Text] [PDF]

				S. E. Wenzel and R. Covar Update in asthma 2005. Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 698 - 706. [Full Text] [PDF]

				M. E. Wechsler, E. Lehman, S. C. Lazarus, R. F. Lemanske Jr., H. A. Boushey, A. Deykin, J. V. Fahy, C. A. Sorkness, V. M. Chinchilli, T. J. Craig, et al. beta-Adrenergic Receptor Polymorphisms and Response to Salmeterol Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 519 - 526. [Abstract] [Full Text] [PDF]

				G. M. Hunninghake, S. T. Weiss, and J. C. Celedon Asthma in Hispanics Am. J. Respir. Crit. Care Med., January 15, 2006; 173(2): 143 - 163. [Abstract] [Full Text] [PDF]

				E. Gonzalez Burchard, L. N. Borrell, S. Choudhry, M. Naqvi, H.-J. Tsai, J. R. Rodriguez-Santana, R. Chapela, S. D. Rogers, R. Mei, W. Rodriguez-Cintron, et al. Latino Populations: A Unique Opportunity for the Study of Race, Genetics, and Social Environment in Epidemiological Research Am J Public Health, December 1, 2005; 95(12): 2161 - 2168. [Abstract] [Full Text] [PDF]

				K. C. Barnes Genetic Determinants and Ethnic Disparities in Sepsis-associated Acute Lung Injury Proceedings of the ATS, October 1, 2005; 2(3): 195 - 201. [Abstract] [Full Text] [PDF]

				D. R. Taylor, M. J. Epton, M. A. Kennedy, A. D. Smith, S. Iles, A. L. Miller, M. D. Littlejohn, J. O. Cowan, T. Hewitt, M. P. Swanney, et al. Bronchodilator Response in Relation to {beta}2-Adrenoceptor Haplotype in Patients with Asthma Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 700 - 703. [Abstract] [Full Text] [PDF]

				M. E. Wechsler and E. Israel How Pharmacogenomics Will Play a Role in the Management of Asthma Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 12 - 18. [Full Text] [PDF]

				I. P. Hall Pharmacogenetics and Ethnicity: More Complexities of Personalized Prescribing Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 535 - 536. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Online Supplement All Versions of this Article: 200409-1286OCv1 200409-1286OCv2 171/6/563    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choudhry, S. Search for Related Content PubMed PubMed Citation Articles by Choudhry, S.