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Published ahead of print on September 4, 2003, doi:10.1164/rccm.200306-877OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1312-1316, (2003)
© 2003 American Thoracic Society

ADAM33 Is Not Associated with Asthma in Puerto Rican or Mexican Populations

Denise L. Lind, Shweta Choudhry, Ngim Ung, Elad Ziv, Pedro C. Avila, Keyan Salari, Connie Ha, Elizabeth G. Lovins, Natasha E. Coyle, Sylvette Nazario, Jesus Casal, Alfonso Torres, Jose R. Rodriguez-Santana, Henry Matallana, Craig M. Lilly, Jorge Salas, Moises Selman, Homer A. Boushey, Scott T. Weiss, Rocio Chapela, Jean G. Ford, William Rodriguez-Cintron, Edwin K. Silverman, Dean Sheppard, Pui-Yan Kwok and Esteban González Burchard

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

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


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A recent study identified the ADAM33 gene as a promising candidate contributing to asthma. In Puerto Rican and Mexican populations, we have genotyped six single nucleotide polymorphisms (SNPs) that were used in the Genetics of Asthma in Latino Americans Study. We chose to study these two populations because in the United States, Puerto Ricans have the highest asthma prevalence, morbidity, and mortality and Mexicans the lowest. We used the transmission disequilibrium test to analyze associations between the ADAM33 gene variants and asthma, asthma severity, bronchodilator responsiveness, and total IgE levels using single SNPs, two to six SNP combinations, and specific haplotypes in 583 trios (proband with asthma and both biological parents). We also genotyped matched control samples to allow case–control analyses. None of the transmission disequilibrium test or case–control results showed significant association in either population. We found no evidence for association of single SNPs with asthma severity, bronchodilator response, or IgE levels in Mexicans or in the combined population. Two SNPs showed a modest association in Puerto Ricans, insignificant when the number of comparisons was taken into account. We conclude that the ADAM33 gene is not an important risk factor for asthma or for asthma-associated phenotypes in Mexicans or in Puerto Ricans.

Key Words: genetics • asthma • Latino populations • ADAM33

Asthma is a complex phenotype that likely results from interactions between multiple genetic (1) and environmental factors (2, 3). Because the etiology of asthma is likely to be multifactorial, it is not surprising that multiple genes have been reported to be associated with asthma (4) but none with so great a statistical significance as the ADAM33 gene. The functional effects of ADAM33 genetic variants are uncertain; several hypotheses surrounding ADAM33 and asthma involve airway remodeling (5). ADAM33, located on the short arm of chromosome 20, was recently identified through a genome-wide scan for asthma in affected sibling pairs who were Caucasian (6). Using case–control, family-based, and haplotype analyses, sequence variants in the ADAM33 gene were strongly associated with asthma (p = 0.04–0.000003).

Van Eerdewegh and coworkers, in the original description of ADAM33 as an asthma candidate gene, found 14 single nucleotide polymorphisms (SNPs) in the ADAM33 gene to be strongly associated with asthma in a case–control analysis; five of these SNPs were further investigated using a family-based test of association, the transmission disequilibrium test (TDT). From the TDT analysis, one individual SNP and several haplotypes were significantly overtransmitted to affected probands. Although these results represent a potential advancement in understanding asthma's genetic influences, this study was conducted exclusively in white subjects with asthma who were recruited from the United States and the UK. It remains to be seen whether the ADAM33 gene will also be associated with asthma in other populations.

The burden of asthma varies greatly between populations. The U.S. vital statistics of asthma suggest that asthma prevalence, morbidity, and mortality are highest amongst Puerto Ricans and lowest amongst Mexicans (7–9). These striking differences in asthma between Puerto Ricans and Mexicans led us to study these populations to gain some insight into the genetic factors that may explain these disparities. The Genetics of Asthma in Latino Americans (GALA) Study is an ongoing, multicenter, international, collaborative effort to identify novel clinical and genetic risk factors associated with asthma and asthma severity among Mexicans and Puerto Ricans, the two largest Latino populations in the United States.

To test for association of ADAM33 with asthma and asthma-associated phenotypes in individuals of Mexican and Puerto Rican ancestry, we genotyped the same five SNPs that were genotyped in the original study for TDT analyses (S1, T1, V-1, V1, and V4) and an additional SNP (T2) in 610 family trios participating in the GALA Study and in 369 matched controls. We found no associations between ADAM33 SNP or haplotypes and asthma, asthma severity, bronchodilator responsiveness, or IgE levels using family-based and case–control studies in either Mexican or Puerto Rican populations.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Participants
A total of 684 subjects with asthma and their biological parents were enrolled in the San Francisco Bay Area, New York City, Puerto Rico, and Mexico City. Of these, 659 subjects were classified as mild or moderate-severe according to the study protocol, and clinical characteristics of all probands are shown in Table 1 . For this analysis, all but two probands with asthma had a physician diagnosis of asthma, and 98% were currently taking asthma medications or had had two or more asthma symptoms (wheezing, coughing, and shortness of breath) in the last 2 years. The median age of the Mexican and Puerto Rican probands was 13.2 and 11.9 years, respectively. Ethnically matched healthy control subjects (Mexican: n = 186, Puerto Rican: n = 183) were recruited through primary care clinics in the San Francisco Bay Area and Puerto Rico. Control subjects were recruited from the same clinics in the San Francisco Bay Area and Puerto Rico as were the probands with asthma. Control subjects were considered eligible if they did not report a clinical history of asthma, atopy, or any other allergic or pulmonary disease. Local institutional review boards approved the study, and all subjects signed forms indicating their consent to participate.


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  		TABLE 1. Characteristics of probands with asthma participating in the genetics of asthma in latino americans study

 
Questionnaire
Probands with asthma were assessed using a modified version of the 1978 American Thoracic Society-Division of Lung Diseases Epidemiology Questionnaire (10). Ethnicity was self-reported. Probands and healthy control subjects were enrolled if both biological parents and all biological grandparents were of Puerto Rican (for the New York City and Puerto Rico sites) or Mexican (for the San Francisco Bay Area and Mexico City sites) ethnicity. Individuals with mixed ethnic backgrounds were excluded.

Pulmonary Function Tests and IgE Measurements
Spirometry was performed according to the American Thoracic Society guidelines (11). Results from 633 subjects (Puerto Ricans: n = 343, Mexicans: n = 290) who performed lung function tests and who met the American Thoracic Society criteria were compared with predicted normal values using age-adjusted prediction equations from healthy Mexican-American nonsmokers (12) and are shown in Table 2 . Total plasma IgE was measured in duplicate using Uni-Cap technology (Pharmacia, Kalamazoo, MI).


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  		TABLE 2. Pulmonary function test results

 
Asthma Severity
Probands with asthma were classified as "mild" or "moderate-severe" based on four "yes/no" questions related to medication use, asthma symptoms, and FEV1% predicted.

Genotyping
Six SNPs used by Van Eerdewegh and coworkers (S1, T1, V-1, V1, V4, and T2) were genotyped using the AcycloPrime-FP (Perkin–Elmer, Boston, MA) method (13). Polymerase chain reaction conditions were: 5 µl volume with JumpStart Taq buffer, 2.5 mM MgCl2, 2.4 to 4.0 ng genomic DNA, 50 µM diethylnitrophyenyl thiophosphates, 0.1 to 0.2 µM primers, 0.1 to 0.2 U JumpStart Taq (Sigma, St. Louis, MO). Cycling conditions were: 95°C for 2 minutes, 35 cycles of 92°C for 10 seconds, 58°C for 20 seconds, 68°C for 30 seconds, and final extension at 68°C for 10 minutes. Enzymatic cleanup of all reactions was performed with AcycloPrime-FP kits. Plates were read on an EnVision fluorescence polarization plate reader (Perkin–Elmer). Primer sequences for polymerase chain reaction and fluorescence polarization of template-directed dye-terminator incorporation are presented in Table E1 in the online supplement. Marker typing incompatibilities in trios were detected using PedCheck (14).

Statistical Analysis
Excess transmission was tested in individual SNP and SNP haplotypes from parents to affected probands using TRANSMIT (15). Associations were analyzed by global tests for distortion of transmission for all SNP genotyped and their SNP combinations (global analysis). Overtransmission of specific haplotypes reported previously to be associated with asthma was also examined. Allele and genotype frequencies in cases and control subjects were compared using Fisher's Exact Test. Odds ratios and 95% confidence intervals were calculated for each genotype using logistic regression models. Ethnic background was included as a covariate in the models.

Quantitative traits relating to asthma severity (mild vs. moderate-severe), IgE level (< 100 vs. > 100), bronchodilator responsiveness (FEV1, FVC, FEV1/FVC, and peak expiratory flow), and log10 IgE levels were analyzed using the FBAT test statistic (16, 17).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We genotyped 610 of the 684 families recruited in the GALA Study. We obtained complete genotyping information for 583 family trios (265 Mexican and 318 Puerto Rican) for the TDT analysis as well as 190 Mexican probands with asthma, 160 matched Mexican controls, 183 Puerto Rican probands with asthma, and 165 matched Puerto Rican controls for the case–control analysis. Our TDT analysis of Mexican and Puerto Rican family trios showed that none of the six individual SNPs was significantly overtransmitted to affected offspring (p > 0.05). Because multiple SNPs may act together and confer an increased disease risk, we also performed the TDT analysis using two to six SNPs in combinations, looking at the global p value for each SNP combination. Table E2 in the online supplement shows the results of these TDT analyses in Mexican, Puerto Rican, and combined Mexican and Puerto Rican populations. None of the SNP combinations was significantly overtransmitted to probands in either population.

The original study of ADAM33 demonstrated significant associations between individual haplotypes (rather than a global haplotype analysis) and asthma and bronchial hyperresponsiveness by TDT analysis. In an attempt to compare our results with those previously reported, we performed the same analysis looking at the specific haplotypes reported and their association to asthma using TDT. We found no association between any of the reported haplotypes and asthma in either the Mexican or Puerto Rican population (Table 3) .


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  		TABLE 3. Comparison of transmission disequilibrium test results for overtransmitted haplotypes from the study of van eerdewegh and coworkers (2002) with that of the genetics of asthma in latino americans study

 
We also performed case–control association studies. We compared genotype results from Mexican probands with asthma with matched Mexican controls (recruited from the San Francisco Bay Area) and from Puerto Rican probands with asthma with matched Puerto Rican controls (recruited from Puerto Rico) for association between single SNPs and asthma (Table 4) . In Table 4, we included the allele frequencies in the combined U.S. and UK populations from Van Eerdewegh and coworkers. Although there were several allele frequency differences between Puerto Ricans, Mexicans, and Caucasians (as well as between U.S. and UK whites), there were no significant allele frequency differences between cases and control subjects for any of the single SNPs in our study. In addition, we combined the Puerto Rican and Mexican populations and calculated the adjusted odds ratios for association with each genotype. We found no significant associations in this analysis. Figure E1 in the online supplement presents the odds ratios and 95% confidence intervals. For some rare genotypes, the confidence intervals are relatively wide. However, for the common genotypes (heterozygous genotypes of S1, T1, T2, V-1, V1, and V4), our 95% confidence intervals exclude odds ratios less than 0.55 or more than 2.1. These results strongly suggest that the variants in the ADAM33 gene reported by Van Eerdewegh and colleagues are not strongly associated with the risk for asthma in Mexicans or in Puerto Ricans participating in the GALA Study.


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  		TABLE 4. Case–control analysis of ADAM33

 
To ensure that the lack of association of ADAM33 with asthma in our population was not due to phenotypic differences, we stratified our samples on the basis of asthma severity, bronchodilator responsiveness, and IgE levels and tested for association with single SNPs in the ADAM33 gene (Table 5) . There were three nominally significant p values (p < 0.05), however, on the basis of the number of different SNPs and phenotypes tested, these associations are not significant after correcting for multiple testing.


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  		TABLE 5. Test for association of ADAM33 single nucleotide polymorphisms with asthma severity, bronchodilator responsiveness, and total iGe levels

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using both case–control and family-based tests of association, we failed to find robust associations of individual SNPs or SNP haplotypes in the ADAM33 gene with asthma in our populations of Mexicans and Puerto Ricans. This is in contrast to the results reported by Van Eerdewegh and colleagues, where both ADAM33 SNPs and several haplotypes were found to be strongly associated with asthma in a Caucasian population. To reproduce the earlier analysis, we analyzed our data in various ways. Not only did we carry out a global analysis to test for association using various SNP combinations, we also tested individual haplotypes for overtransmission on the basis of the original report. We found no association with asthma for any of these analyses. Van Eerdewegh and coworkers stratified their patients based on the presence of bronchial hyperresponsiveness, which increased the significance of their association. We did not assess bronchial hyperresponsiveness in our subjects but instead stratified our patients based on asthma severity, bronchodilator responsiveness, and IgE levels. Although we did everything possible to make our results directly comparable with those from the previous study, it is possible the difference in our association results is due to phenotypic heterogeneity.

It is unlikely that inadequate sample size precluded the replication of the previously reported association. We had complete genotype data from 583 family trios for a total of 1,749 individuals, which is comparable with the sample size that Van Eerdewegh and coworkers used for their study (460 Caucasian trios). However, there might be several other potential reasons why our results differed from those reported previously. First, we studied a different population. Van Eerdewegh and coworkers performed their study exclusively in Caucasians from the United States and UK, whereas we studied Latinos recruited from Mexico City, Puerto Rico, and the continental United States. Ethnic-specific differences in environmental or genetic risk factors may account for the observed differences (18). Our results suggest that ADAM33 is not a major gene for asthma, asthma severity, bronchodilator responsiveness, or IgE levels in Puerto Ricans or Mexicans participating in the GALA Study.

It is known that the frequency of SNPs can differ between ethnic groups, and we in fact observed as high as 10% allele frequency differences for these SNPs between Latino and Caucasian populations. Therefore, it is possible that additional ethnic-specific SNPs or multilocus genotypes, which contribute to asthma in Mexicans or Puerto Ricans were not identified in the initial Caucasian group screened. Furthermore, the genetic basis of asthma may differ between ethnic groups, and whereas a particular subset of SNPs identified by Van Eerdewegh and coworkers may be risk factors for asthma in Caucasians, a different subset may increase risk in Latino ethnic groups. By restricting our analysis to replicate the earlier study, we may have limited the possibility of identifying other significant genetic variants in the ADAM33 gene. Nonetheless, our results exclude the strong effect of the previously reported ADAM33 SNPs or multilocus genotypes on asthma susceptibility or asthma-associated phenotypes in the Mexican or Puerto Rican populations.

It would not have been surprising if different association results were found between Mexicans and Puerto Ricans due to their striking differences in asthma prevalence, morbidity, and mortality. However, neither population showed an association with the ADAM33 gene. This suggests that ADAM33 does not appear to play a major role in asthma among Mexicans or Puerto Ricans. These results are of particular importance for the Puerto Rican population because of the greater burden of asthma and the high asthma morbidity and mortality in this population. Identification of environmental and ethnic-specific genetic risk factors for asthma will help us understand the mechanisms and develop more effective therapies for all populations.


   Acknowledgments
 
The authors acknowledge the patients and their families for their participation. The authors thank the numerous health care providers and community clinics for their support and participation in the GALA Study. The authors also thank Lisa Barcellos and Neil Risch for their thoughtful suggestions for improvements in the manuscript and helpful discussions on the topic.


   FOOTNOTES
 
Jean G. Ford is currently affiliated to the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Supported by National Institutes of Health; the Sandler Family Foundation; and the Sandler Center for Basic Research in Asthma; and in part by the National Heart, Lung, and Blood Institute (NHLBI) grants K23 HL04464 and HL07185 (E.G.B.); the National Human Genome Research Institute grant R01-HG01720 (P.-Y.K.); the San Francisco General Hospital Medical Center General Clinical Research Center grant RR00083–40; the NHLBI Asthma Clinical Research Network (ACRN) Centers of the Brigham and Women's Hospital; the Harlem Lung Center and the University of California, San Francisco grants HL51823, HL56443, and HL51831; Pharmacogenetics of Asthma Treatment grant U01-HL 65899 (S.T.W.).

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

Conflict of Interest Statement: D.L.L. has no declared conflict of interest; S.C. has no declared conflict of interest; N.U. has no declared conflict of interest; E.Z. has no declared conflict of interest; P.C.A. has no declared conflict of interest; K.S. has no declared conflict of interest; C.H. has no declared conflict of interest; E.G.L. has no declared conflict of interest; N.E.C. has no declared conflict of interest; S.N. has no declared conflict of interest; J.C. has no declared conflict of interest; A.T. has no declared conflict of interest; J.R.R-S. has no declared conflict of interest; H.M. has no declared conflict of interest; C.M.L. has no declared conflict of interest; J.S. has no declared conflict of interest; M.S. has no declared conflict of interest; H.A.B. has no declared conflict of interest; S.T.W. received a grant for $900,065, Asthma Policy Modeling Study, from AstraZeneca from 1997–2003, was Coinvestigator on a grant from Millennium Pharmaceuticals to pursue asthma genetics in China from 1996–2001, received a grant from Pfizer to examine diabetes mellitus and its relationship to lung function from 2000–2003, was a consultant for Schering-Plough and received $5,000 from 1999–2000, has been a Coinvestigator on a grant from Boehringer Ingelheim to investigate a COPD natural history model which began in 2003 (has received no funds for his involvement in this project), has been a consultant for Variagenics on human subjects issues and received $5,000 in 2003, has been a consultant to Genome Therapeutics in 2003 and received $1,500, was a consultant for Merck Frost on asthma genetics in 2002 and received $2,000, has been an advisor to the TENOR Study for Genentech and has received $5,000 for 2002–2003, received a grant from Glaxo-Wellcome for $500,000 for genomic equipment from 2000–2003, was a consultant for Roche Pharmaceuticals in 2000 and received no financial remuneration for this consultancy; R.C. has no declared conflict of interest; J.G.F. has no declared conflict of interest; W.R-C. has no declared conflict of interest; E.K.S. received a research grant from GlaxoSmithKline to study COPD genetics (approximately $250,000 per year from 2000–2003); D.S. has no declared conflict of interest; P-Y.K. has no declared conflict of interest; E.G.B. has no declared conflict of interest.

Received in original form June 30, 2003; accepted in final form September 1, 2003


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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J Blakey, E Halapi, U S Bjornsdottir, A Wheatley, S Kristinsson, R Upmanyu, K Stefansson, H Hakonarson, and I P Hall
Contribution of ADAM33 polymorphisms to the population risk of asthma
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K. G. Ackerman, H. Huang, H. Grasemann, C. Puma, J. B. Singer, A. E. Hill, E. Lander, J. H. Nadeau, G. A. Churchill, J. M. Drazen, et al.
Interacting genetic loci cause airway hyperresponsiveness
Physiol Genomics, March 21, 2005; 21(1): 105 - 111.
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R. Lazarus, B. A. Raby, C. Lange, E. K. Silverman, D. J. Kwiatkowski, D. Vercelli, W. J. Klimecki, F. D. Martinez, and S. T. Weiss
TOLL-like Receptor 10 Genetic Variation Is Associated with Asthma in Two Independent Samples
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N. E. King, N. Zimmermann, S. M. Pope, P. C. Fulkerson, N. M. Nikolaidis, A. Mishra, D. P. Witte, and M. E. Rothenberg
Expression and Regulation of a Disintegrin and Metalloproteinase (ADAM) 8 in Experimental Asthma
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B. A. Raby and S. T. Weiss
ADAM33: Where Are We Now?
Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 1 - 2.
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S. T. Weiss and B. A. Raby
Asthma genetics 2003
Hum. Mol. Genet., April 1, 2004; 13(90001): R83 - 89.
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M. J. Tobin
Asthma, Airway Biology, and Nasal Disorders in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 265 - 276.
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