Chest ACCP Career Connection
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
doi:10.1378/chest.07-1905
(Chest. 2007; 132:770S-781)
© 2007 American College of Chest Physicians
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scirica, C. V.
Right arrow Articles by Celedón, J. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scirica, C. V.
Right arrow Articles by Celedón, J. C.

Genetics of Asthma*

Potential Implications for Reducing Asthma Disparities

Christina V. Scirica, MD and Juan C. Celedón, MD, DrPH, FCCP

* From the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, MA.

Correspondence to: Juan C. Celedón, MD, DrPH, FCCP, Channing Laboratory, Room 451, 181 Longwood Ave, Boston, MA 02115; e-mail: juan.celedon{at}channing.harvard.edu


   Abstract
TOP
 Abstract
Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
 References
 
Although genetic factors may partly explain the differences in asthma prevalence, morbidity, and mortality among ethnic groups in the United States, few studies of the genetics of asthma have included members of ethnic minority groups. Only one genome-wide linkage analysis of asthma and/or asthma-related phenotypes (conducted by the Collaborative Study on the Genetics of Asthma) has included any members of ethnic minority populations. The interpretation of the findings of genetic association studies of asthma in ethnic minority groups is complicated by reduced statistical power due to small sample sizes; the failure to correct for multiple comparisons; a lack of homogeneity of the populations studied with regard to area of residence, ancestral background, and/or country of origin; a lack of measurement of relevant environmental exposures; and (for case-control studies of genetic association) a lack of detection and control of potential population stratification. Genetic studies may improve our understanding of asthma and lead to new methods to prevent, diagnose, and treat this disease. Limited study of asthma genetics in ethnic minority populations is unacceptable, as it may prevent these groups from benefiting from future developments in asthma management and thus widen existing disparities in asthma care. Future genetic association studies of asthma among ethnic minorities in the United States should include large samples of populations that have been adequately defined with regard to area of residence, self-designated ancestry, and country of origin. These studies should also include an adequate assessment of potentially relevant environmental exposures and (for case-control association studies) population stratification.

Key Words: asthma genetics • ethnic minority groups


   Introduction
TOP
 Abstract
 Introduction
Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
 References
 
Asthma affects > 14 million people in the United States.1 The prevalence of asthma in the United States increased by 74.9% from 1980 to 1996.1 For reasons that are not entirely clear, certain ethnic groups are disproportionately represented in this trend of increasing asthma morbidity.234

Poverty, which is a common condition among ethnic minority groups with a high prevalence of asthma,56 is associated with environmental risk factors for asthma morbidity (eg, cockroach allergen exposure)7 and inadequate access to health care.4 However, poverty is unlikely to be the sole explanation for the association between Puerto Rican and/or African-American ethnicity and asthma and asthma morbidity.8910 Studies11 of ethnic subgroups sharing similar socioeconomic conditions and environmental exposures have shown significant differences in asthma prevalence, suggesting that yet-unidentified factors (eg, genetic or environmental) influence asthma prevalence in these groups. We review what is known about the genetics of asthma in ethnic minorities and discuss how an increased understanding of asthma genetics may contribute to reduce asthma disparities. Please see Table 1 for a glossary of terms commonly used in genetic studies.


View this table:
[in this window]
[in a new window]

  		Table 1. Glossary of Terms Commonly Used in Genetic Studies

 

   Race, Ethnicity, and Research in Human Genetics
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
 References
 
Race has been defined as a group of persons who are relatively homogeneous with respect to ancestry,12 and racial groups have been defined on the basis of their primary continent of origin (eg, Africans, Caucasians, Pacific Islanders, East Asians, and Native Americans).13 Ethnicity is a more broadly defined construct that is characterized by a shared social, linguistic, and cultural heritage (eg, African Americans, Hispanics, and whites).1314 The use of race and/or ethnicity in biomedical research has been the subject of much debate over the past few years.13141516171819

For studies of complex diseases resulting from the interaction between genetic and environmental factors, self-reported ethnicity is an attractive unit of study because it categorizes ancestral20 and cultural backgrounds. To the extent that an ethnic group defines an endogamous group that can be differentiated from other such groups, ethnicity can be useful in genetic studies.13 However, it is important to recognize that the broad ethnic categories that have been traditionally used by the US census do not adequately reflect the vast heterogeneity within these groups. Individuals who belong to an ethnic group may have a mixed racial heritage. For example, Hispanics are part of an ethnic group with variable proportions of white, Native American, and African admixture212223; African Americans can have average proportions of white admixture ranging from 12 to 23%, depending on the geographic region studied.24

Multiple studies13252627 have demonstrated significant genetic variation within racial/ethnic groups, and there may be important differences in socioeconomic, cultural, and environmental factors among subgroups within an ethnic group. The interaction between unique genetic and environmental factors may explain marked differences in disease prevalence among subgroups of an ethnic group. For example, asthma prevalence, morbidity, and mortality are higher in Puerto Ricans than in Mexican Americans and other Hispanic subgroups.231128 Of note, factors associated with place of birth might modify the effect of genetic and environmental exposures on asthma within an ethnic subgroup. Among participants in the Third National Health and Nutrition Examination Survey,29 Mexican Americans born in the United States had approximately twice the odds of having asthma than Mexican Americans born in Mexico.

How may understanding the genetics of complex diseases (eg, asthma) in ethnic minorities help to reduce health disparities? First, rare disease- susceptibility alleles (frequency, ≤ 2%) may be found only in certain ethnic subgroups. For example, a rare mutation associated with inherited deafness was identified in an isolated Hispanic population in Costa Rica.30 The identification of rare variants of common disorders in ethnic subgroups may lead to important insights into disease pathogenesis in general, and to better means of disease prevention and treatment among high-risk subgroups in particular. Second, disease-susceptibility alleles that are common in certain ethnic groups may be less common in other groups. For example, a mutation associated with an increased risk of venous thromboembolism (factor V Leiden) is relatively common in whites (frequency, approximately 5%) but is rare in African Americans.31 Knowledge of the allelic frequencies of functional variants in disease-susceptibility genes may be important in designing strategies for disease screening and diagnosis in ethnic minority groups. Third, disease-susceptibility alleles that are common in most ethnic groups may have differential effects on disease risk because of interactions with environmental and/or genetic variants that are unique to or more common in certain ethnic groups. Knowledge of the risk of disease that is attributable to a particular allele in an ethnic group or subgroup may be important in disease prevention and treatment. Fourth, genetic variants and their interaction with other genetic and environmental factors within an ethnic group may impact the response to and side effects from therapy. For example, polymorphisms in the gene for the ß2-adrenergic receptor (ADRB2) may explain reduced bronchodilator responsiveness among Puerto Ricans.32 Table 2 shows some current and potential applications of genetic variation among ethnic groups to the screening, diagnosis, and treatment of monogenic and complex diseases, including asthma.2132154155


View this table:
[in this window]
[in a new window]

  		Table 2. Current and Potential Applications of Known Genetic Variation Among Ethnic Groups to Screening, Diagnosis, and Treatment of Monogenic and Complex Diseases

 
Although there are potential benefits as a result of conducting research studies on the genetics of complex diseases in ethnic minority groups, there are also potential risks. For example, information from genetic studies of asthma could be used to restrict adequate access to health care and/or public health measures to reduce exposure to detrimental environmental factors (eg, cockroach allergen). In addition, data from genetic studies could be used as an excuse to avoid the implementation of social reforms that could benefit the members of a particular ethnic group.


   Genetics of Asthma
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
 References
 
Twin studies333435363738 and studies of familial aggregation3940414243 have demonstrated a significant genetic contribution to asthma. Estimates of the heritability of asthma in twin studies have ranged from 36 to 79%.333435363738

To date, 15 groups have reported results of genome-wide linkage analysis for asthma and/or its intermediate phenotypes in 17 distinct populations.444546474849505152535455565758 Several of these groups have published second-generation surveys5459606162636465 with larger numbers of subjects and markers. One of these genome-wide linkage studies55 for asthma reported only partial results. Fourteen chromosomal regions have shown significant evidence of linkage66 to asthma or its intermediate phenotypes in at least one genome scan, as follows: chromosomes 2p1658 and 2p2551 (to increased airway responsiveness); 2q32 (to FEV1/FVC ratio)67; 2q33 (to eosinophil count)57; 5q31-q33 (to mite-sensitive asthma)48; 7p14-p1550 and 7q21 (to total serum IgE level)54; 11q12-q13 (to atopy)5968; 6p21,69 12q24,6514q24,53 and 20p1355 (to asthma); and 19p13 and 20q13 (to dust mite allergy).5670

Many studies of the genetic association for asthma phenotypes have been conducted, often yielding inconsistent results. The potential reasons for the conflicting findings of studies of genetic association in asthma include small sample sizes, a failure to correct for multiple comparisons, genetic and environmental heterogeneity, publication bias, the inadequate assessment of asthma and/or its intermediate phenotypes, and (for case-control studies) population stratification.7172 To date, there have been reports73 of association between variants in > 100 genes and asthma phenotypes. Of these, 25 genes (eg, ADRB2 and IL10) had variants that were associated with asthma phenotypes in at least six populations,73 suggesting that alleles in or near these genes influence the pathogenesis of asthma. Data from studies in experimental models and/or functional studies in humans are needed to firmly identify the functional variants responsible for the observed genetic associations.

Five potential asthma susceptibility genes (PDH finger protein 11 [PHF11], dipeptidylpeptidase 10 [DPP10], disintegrin and metalloprotease 33 [ADAM 33], G protein-coupled receptor for asthma susceptibility [GPR154], and human leukocyte antigen G [HLA-G]) have been identified by positional cloning.5569747576 In all cases, suggestive or significant linkage between a chromosomal region and asthma phenotypes was found in a genome-wide linkage analysis, and fine-mapping studies of linkage and association were then performed in the linked genomic region ("positional cloning").

The biochemical mechanisms linking four of the positionally cloned asthma-susceptibility genes (PHF11, DPP10, HLA-G, and ADAM33)55697576 to asthma phenotypes are insufficiently understood. Although some replication studies777879 of the association between asthma phenotypes and two potential asthma-susceptibility genes (ADAM33 and GPR154) yielded negative results, variants in these two genes have been associated with asthma and/or its intermediate phenotypes in at least six distinct populations.73 Functional data in rodents and humans provide strong support for a significant role of GPR154 in asthma pathogenesis.74

In summary, the current evidence suggests that asthma is a disease influenced by multiple genetic and environmental factors. Despite promising developments, there has been no incontrovertible evidence for the identification of an asthma-susceptibility gene.


   Genetics of Asthma in African Americans
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
 References
 
Genome-Wide Linkage Analyses
The Collaborative Study on the Genetics of Asthma (CSGA)45 included African-American families recruited at several centers in the United States. These families were ascertained through two siblings with asthma and then extended to include other affected relatives. The initial genome-wide linkage analysis of asthma in the CSGA included 117 African-American individuals with asthma in 43 families.45 This analysis identified modest evidence of linkage (p ≤ 0.01) between two genomic regions (chromosomes 5p and 17p) and asthma among African Americans. After the inclusion of 64 additional families, a repeat genome-wide analysis showed suggestive evidence of linkage66 (maximum log10 of the odds of linkage [LOD], 2.0) between chromosome 11q21 and asthma in African Americans.60 Following the inclusion of additional markers in the analysis, there was significant evidence of linkage66 (maximum LOD, 4.4) between chromosome 11q and asthma among African Americans.59

Among African-American families in the CSGA, there was modest evidence of linkage (maximum LOD, 1.1) between two genomic regions (chromosomes 2q and 4q) and total serum IgE level, after adjustment for relevant covariates,61 and modest evidence of linkage (p ≤ 0.01) between two genomic regions (chromosomes 12p and 17p) and atopy.62 Of note, the genomic regions linked to asthma, total serum IgE level, and atopy among African Americans differed from those linked to these asthma phenotypes in whites and Hispanics in the CSGA.


   Selected Candidate Gene Association Studies
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
Genetics of Asthma in...
 Summary
 Future Directions
 References
 
ADAM33:
Howard et al80 conducted a study of the association between eight polymorphisms in the 3' end of the ADAM33 gene and asthma phenotypes in ethnically diverse populations (US whites, Dutch, African Americans, and Hispanics). Among African Americans with asthma (n = 160) and without asthma (n = 253), there was a weak association (p = 0.03) between an exonic single-nucleotide polymorphism (SNP) [S2] in the ADAM33 gene and asthma. Two noncoding SNPs (ST + 4 and V4) were weakly associated with allergen sensitization (p = 0.02 for both SNPs). Of note, there were no consistent associations across the four ethnic populations studied and those observed in the reports by van Eerdenwegh et al55 and Slutsky and Zamel.81 Raby and colleagues78 conducted a family-based study of association between 17 SNPs in the ADAM33 gene and asthma phenotypes in three ethnic groups. Among white families (n = 474) and African-American families (n = 66) of children with asthma, there was no single-SNP association with asthma, airway responsiveness, or FEV1.

Interleukin-4 and Interleukin-4 Receptor:
Through the activation of its receptor, interleukin (IL)-4 stimulates the production of total serum IgE level. The IL4 and IL4 receptor (IL4R) chain loci are on genomic regions linked to asthma phenotypes (5q31 for IL4 and 16p12 for IL4R). A functional SNP in the promoter of IL4 has been associated with total serum IgE level,828384 asthma,8283858687 and other asthma-related phenotypes.86888990 SNPs in exons of IL4R have been associated with asthma,9192939495 total serum IgE level,9196979899100 and other asthma-related phenotypes.101102 Burchard and colleagues89 tested for association between a polymorphism (C-589T) in the promoter of IL4 and two asthma-related phenotypes (FEV1 and total serum IgE level) among 772 patients with asthma. There was a significant difference in the frequency of the T allele between 682 white asthmatic persons and 90 African-American asthmatic persons (0.183 vs 0.544, respectively; p < 0.001). Among white asthmatic individuals, the T allele was associated with an FEV1 of < 50% predicted (p = 0.01) but not with total serum IgE level. Among African-American asthmatic individuals, there was no association between the T allele and either a reduced FEV1 or the total serum IgE level. Ober et al95 showed that polymorphisms in IL4R differed across three ethnic groups (Hutterites, African Americans, and whites). Although several SNPs in IL4R were associated with asthma and/or atopy in the Hutterites, there was no significant association between any of the five SNPs examined and either asthma or atopy in 56 African-American families. Basehore et al103 conducted a population-based case-control study of the association between 11 SNPs in IL4R and asthma and total serum IgE level in three ethnic groups (whites, African Americans, and Hispanics). There were significant differences in the frequencies of the SNPs and haplotypes included in the study across the three ethnic groups. Multiple SNPs were associated with asthma and/or total serum IgE level in whites. Among African Americans with asthma (n = 168) and without asthma (n = 269), only one SNP (3017 G/T) was weakly associated with total serum IgE level (p = 0.04), and no SNP was associated with asthma.

Human Leukocyte Antigen:
The human leukocyte antigen (HLA) loci are on chromosome 6p21, a genomic region that is linked to asthma phenotypes. Functional SNPs and/or haplotypes in HLA loci have been associated with atopy,104105106107108109110111112113114115116117118119120121122 asthma,119121122123 and total serum IgE level.110112117119123 Donfack et al108 conducted a population-based case-control study of the association between 14 alleles in HLA loci and cockroach allergy in sensitized African Americans (n = 54) and nonsensitized African Americans (n = 65). In these subjects, only the DRB1*0102 allele was associated with cockroach allergy. In the same report, a family-based study showed that a different HLA allele (DRB*0101) was associated with cockroach allergy in the Hutterites.

Prostanoid DP Receptor:
Experimental evidence in rodents124 and data from genome scans in humans support a potential role of the prostanoid D receptor in asthma pathogenesis. Oguma et al conducted a study of association between functional variants in the promoter of the prostanoid DP receptor (PTGDR) gene and asthma and total serum IgE level.125 Among whites with asthma (n = 518) and without asthma (n = 175), genotypes containing the C allele of the T-549C SNP and the T allele of the C-441T allele were associated with asthma. Among African Americans with asthma (n = 80) and without asthma (n = 45), genotypes containing the C allele of the T-549C SNP were weakly associated with asthma (p = 0.04). Haplotypes of the PTGDR gene with low transcriptional efficiency were inversely associated with asthma in whites and African Americans.

Toll-Like Receptors:
In humans, Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns as part of innate immunity. In a family-based study, Raby et al126 tested for an association between five common polymorphisms in the TLR4 gene and asthma and asthma-related phenotypes. Among 589 nuclear families of children with asthma, there was no significant association between any of the TLR4 SNPs and asthma or asthma-related phenotypes in white families (n = 480), African-American families (n = 63), or Hispanic families (n = 46). Among African Americans with asthma (n = 102) and without asthma (n = 80), Lazarus et al127 found no association between SNPs in the TLR9 gene and asthma.


   Genetics of Asthma in Hispanics
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
Summary
 Future Directions
 References
 
Genome-Wide Linkage Analyses
The CSGA128 included Hispanic families, most of whom came from an area of Albuquerque (New Mexico) where 38% of Hispanics are of Mexican descent and 60% of Hispanics identify themselves as other Hispanic or Latino. The initial genome-wide linkage analysis of asthma in the CSGA included 48 Hispanics with asthma in 18 families.45 This analysis identified a modest evidence of linkage (p ≤ 0.01) between two genomic regions (chromosomes 2q and 21q) and asthma among Hispanics. After the inclusion of 12 additional families, a repeat genome-wide analysis showed suggestive evidence of linkage66 (maximum LOD, 2.9) between chromosome 1p and asthma in Hispanics.60

Among Hispanics in the CSGA, Mathias et al61 showed modest evidence of linkage (maximum LOD = 1.5) between two chromosomal regions (9q and 12p) and total serum IgE level. In addition, Blumenthal et al62 showed suggestive evidence of linkage between chromosome 21q and atopy (maximum LOD, 2.2) in Hispanics.

Selected Candidate-Gene Association Studies
ADAM33:
Among 112 Hispanics with asthma who participated in the CSGA and 126 control subjects, Howard et al80 found an association between SNPs in ADAM33 and asthma and allergen sensitization. In contrast, there was no association between six SNPs in ADAM33 and asthma or asthma-related phenotypes in a study of 583 nuclear families (265 Mexican families and 318 Puerto Rican families) of Hispanics with asthma in the Genetics of Asthma in Latino Americans study.77 Of note, this study recruited families living in different environments (Puerto Rican families from New York and Puerto Rico, and Mexican families from San Francisco and Mexico City). Among 47 nuclear families of Hispanic children with asthma, Raby et al78 found no significant association between any of 17 SNPs in the ADAM33 gene and asthma or asthma-related phenotypes after adjustment for multiple comparisons.

ADRB2:
The ADRB2 gene is on chromosome 5q31–33, which is a region linked to asthma phenotypes. SNPs and/or haplotypes in the ADRB2 gene have been associated with the response to inhaled ß2-agonists,129130131132133 asthma severity,132134135136137138 and other asthma-related phenotypes.139140141142143144145146 Among Mexican adults with asthma (n = 303) and without asthma (n = 604) in Monterrey (Mexico), Santillan and colleagues147 found an inverse association between alleles (Glu27) and haplotypes (Gly16-Glu27) in the ADRB2 gene and asthma. Choudry et al32 tested for an association between seven SNPs in the ADRB2 gene and asthma-related phenotypes (ie, asthma severity, bronchodilator responsiveness, and total serum IgE level) in Puerto Rican (n = 393) and Mexican (n = 274) families of asthmatics in the Genetics of Asthma in Latino Americans Study. Among Puerto Rican families, two SNPs (A-654G and A + 46G [Arg16Gly]) were associated with baseline FEV1 and bronchodilator responsiveness. Among Mexican families, only one SNP (G + 79C [Glu27Gln]) was marginally associated with bronchodilator responsiveness. Confirmatory analyses in the Puerto Rican probands (index cases) showed an association between the number of Arg16 alleles in the ADRB2 gene and bronchodilator responsiveness only among subjects with reduced lung function.

IL4 and IL4R Genes:
Among 116 Hispanics with asthma in the CSGA and 130 control subjects, 2 of 11 SNPs in the IL4 gene were associated with total serum IgE level (p = 0.01 to 0.02),103 but no significant association was found between any of the 11 SNPs in the IL4 gene and asthma. Among 30 Hispanic families in the CSGA, there was no association between any of five SNPs in the IL4R gene and atopy,95 and only one SNP in the IL4R gene was weakly associated with asthma (p = 0.03).

IL13 Gene:
IL-13 has been implicated in the regulation of IgE synthesis and the pathogenesis of asthma,148149 and a coding SNP (+2044 or Arg130Gln) in exon 4 of the IL13 gene was associated with total serum IgE level among nonatopic whites.150 Celedón et al151 found no association between the Arg130Gln allele of IL13 and asthma or asthma-related phenotypes (total serum IgE level and allergen sensitization) in 83 nuclear families of children with asthma in Costa Rica.


   Summary
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
Future Directions
 References
 
Genome-Wide Linkage Analyses
Interpretation of the findings of the CSGA in ethnic minority groups is limited by the lack of homogeneity of the study populations with regard to area of residence and/or country of origin, as well as reduced statistical power due to a relatively small sample size.45 Genome-wide linkage analyses of asthma have not included most Hispanic subgroups (eg, Puerto Ricans), Native Americans, Hawaiians, or Pacific Islanders. With the possible exception of chromosome 11q in African Americans, the genomic regions influencing asthma and/or asthma-related phenotypes in ethnic minority populations have not been confidently identified.

Studies of Genetic Association
Most studies of genetic association for asthma in ethnic minority groups have been limited by a small sample size, a lack of correction for multiple comparisons, a lack of homogeneity of the populations studied with regard to ancestral background and area of residence, a lack of adequate information on environmental exposures, and (for case-control studies) a lack of control for potential population stratification (Table 3Go ).327778808995103108125126127147151 The absence of data from large-genome scans for asthma has not allowed the adequate selection of positional candidate genes and/or fine-mapping association studies of asthma in ethnic minority groups in the United States. Finally, the lack of adequate data on the patterns of linkage disequilibrium in candidate genes and/or candidate genomic regions among ethnic minority groups in the United States is another obstacle to association studies of asthma in these groups.


View this table:
[in this window]
[in a new window]

  		Table 3. Results of Selected Candidate-Gene Association Studies for Asthma and/or Asthma-Related Phenotypes in Ethnic Minority Groups

 

View this table:
[in this window]
[in a new window]

  		Table 3A. Continued

 
Overall Summary
Relatively few genetic studies of asthma have included members of ethnic minority groups. This is far from ideal, given the potential impact of genetic studies on reducing disparities in the prevention and treatment of asthma (see above). While the mandatory inclusion of minorities in studies sponsored by the National Institutes of Health is laudable, this approach has unfortunately resulted in the recruitment of inadequate (ie, "token") numbers of members of poorly characterized ethnic minority groups for most studies of asthma genetics.


   Future Directions
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
References
 
Genome-wide analyses of linkage and association for asthma should be conducted in large family-based studies of well-defined ethnic minority groups in the United States in general, and among Puerto Ricans and African Americans in particular. Because self-reported ethnicity is a surrogate for genetic and environmental exposures, future genetic association studies of asthma among ethnic minorities should include large samples of populations that have been adequately assessed with regard to area of residence, self-designated ancestry, country of origin, and potentially relevant environmental exposures. The adequate measurement of asthma-related phenotypes is also essential. Because of the potential for population stratification in case-control studies of genetic association for asthma among ethnic minorities, particular attention should be given to the detection and control of this source of bias by available statistical methods (eg, genomic control).152153

Genetic studies may improve our understanding of complex diseases such as asthma. Recognition of the biochemical pathways that contribute to the pathogenesis of asthma should ultimately lead to new methods to prevent, diagnose, and treat this disease. The limited study of asthma genetics in ethnic minority populations is unacceptable, as it may prevent these groups from benefiting from future developments in the prevention, diagnosis, and management of asthma, and thus widen existing disparities in care. Although cultural, socioeconomic, and/or language barriers are often invoked to justify the suboptimal recruitment of members of well-defined ethnic minority groups, such barriers can and should be overcome by appropriately trained and highly motivated investigators. In particular, engaging and partnering with the communities of interest is an essential but often neglected aspect of designing genetic studies of asthma in minorities.


   Acknowledgements
 
The authors thank Ms. Jaylyn Olivo for editorial assistance, Mr. Chris Garcia for help in preparing the manuscript, and Drs. Ed Silverman and Scott T. Weiss for helpful comments on the manuscript.


   Footnotes
 
Abbreviations: CSGA = Collaborative Study on the Genetics of Asthma; HLA = human leukocyte antigen; IL = interleukin; IL4R = interleukin-4 receptor; LOD = log10 of the odds of linkage; PTGDR = prostanoid DP receptor; TLR = Toll-like receptor

Dr. Scirica is supported by training grant T32 HL07427; Dr. Celedón is supported by grants HL004370, HL66289 and HL073373 from the National Institutes of Health.

The authors have reported to the ACCP that no significant conflicts of interest exist wtih any companies/organizations whose products or services may be discussed in this article.

Received for publication December 20, 2006. Accepted for publication August 2, 2007.


   References
TOP
 Abstract
 Introduction
 Race, Ethnicity, and Research...
 Genetics of Asthma
 Genetics of Asthma in...
 Selected Candidate Gene...
 Genetics of Asthma in...
 Summary
 Future Directions
 References
 

  1. Mannino, DM, Homa, DM, Akinbami, LJ, et al (2002) Surveillance for asthma: United States, 1980–1999. MMWR Surveill Summ 51,1-13[Medline]
  2. Centers for Disease Control and Prevention.. Asthma prevalence and control characteristics by race/ethnicity: United States, 2002. MMWR Morb Mortal Wkly Rep 2004;53,145-148[Medline]
  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. Strunk, RC, Ford, JG, Taggart, V Reducing disparities in asthma care: priorities for research: National Heart, Lung, and Blood Institute workshop report. J Allergy Clin Immunol 2002;109,229-237[CrossRef][Medline]
  5. Therrien, M, Ramirez, RR The Hispanic population in the United States: March 2000: current population reports P20–535. 2000 US Census Bureau. Washington, DC:
  6. Proctor, BD, Dalaker, J Poverty in the United States: 2001; current population reports, P60–219. 2001 US Census Bureau. Washington, DC:
  7. Rosenstreich, DL, Eggleston, P, Kattan, M, et al The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336,1356-1363[Abstract/Free Full Text]
  8. Ray, NF, Thamer, M, Fadillioglu, B, et al Race, income, urbanicity, and asthma hospitalization in California: a small area analysis. Chest 1998;113,1277-1284[ISI][Medline]
  9. Beckett, WS, Belanger, K, Gent, JF, et al Asthma among Puerto Rican Hispanics: a multi-ethnic comparison study of risk factors. Am J Respir Crit Care Med 1996;154,894-899[Abstract]
  10. Boudreaux, ED, Emond, SD, Clark, S, et al Acute asthma among adults presenting to the emergency department: the role of race/ethnicity and socioeconomic status. Chest 2003;124,803-812[CrossRef][ISI][Medline]
  11. Ledogar, RJ, Penchaszadeh, A, Garden, CC, et al Asthma and Latino cultures: different prevalence reported among groups sharing the same environment. Am J Public Health 2000;90,929-935[Abstract/Free Full Text]
  12. Last, J A dictionary of epidemiology. 1995 Oxford University Press. New York, NY:
  13. Risch, N, Burchard, E, Ziv, E, et al Categorization of humans in biomedical research: genes, race and disease. Genome Biol 2002;3,comment2007[Medline]
  14. Bamshad, M, Wooding, S, Salisbury, BA, et al Deconstructing the relationship between genetics and race. Nat Rev Genet 2004;5,598-609[ISI][Medline]
  15. Cooper, RS, Kaufman, JS, Ward, R Race and genomics. N Engl J Med 2003;348,1166-1170[Free Full Text]
  16. Burchard, EG, Ziv, E, Coyle, N, et al The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 2003;348,1170-1175[Free Full Text]
  17. Ioannidis, JP, Ntzani, EE, Trikalinos, TA "Racial" differences in genetic effects for complex diseases. Nat Genet 2004;36,1312-1318[CrossRef][ISI][Medline]
  18. Goldstein, DB, Hirschhorn, JN In genetic control of disease, does ‘race’ matter? Nat Genet 2004;36,1243-1244[CrossRef][ISI][Medline]
  19. Foster, MW, Sharp, RR Beyond race: towards a whole-genome perspective on human populations and genetic variation. Nat Rev Genet 2004;5,790-796[CrossRef][ISI][Medline]
  20. Tang, H, Quertermous, T, Rodriguez, B, et al Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 2005;76,268-275[CrossRef][ISI][Medline]
  21. Bertoni, B, Budowle, B, Sans, M, et al Admixture in Hispanics: distribution of ancestral population contributions in the continental United States. Hum Biol 2003;75,1-11[ISI][Medline]
  22. Fernandez-Cobo, M, Jobes, DV, Yanagihara, R, et al Reconstructing population history using JC virus: Amerinds, Spanish, and Africans in the ancestry of modern Puerto Ricans. Hum Biol 2001;73,385-402[ISI][Medline]
  23. Hanis, CL, Hewett-Emmett, D, Bertin, TK, et al Origins of US Hispanics: implications for diabetes. Diabetes Care 1991;14,618-627[Abstract]
  24. Parra, EJ, Marcini, A, Akey, J, et al Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 1998;63,1839-1851[CrossRef][ISI][Medline]
  25. Rosenberg, NA, Pritchard, JK, Weber, JL, et al Genetic structure of human populations. Science 2002;298,2381-2385[Abstract/Free Full Text]
  26. Romualdi, C, Balding, D, Nasidze, IS, et al Patterns of human diversity, within and among continents, inferred from biallelic DNA polymorphisms. Genome Res 2002;12,602-612[Abstract/Free Full Text]
  27. Stephens, JC, Schneider, JA, Tanguay, DA, et al Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001;293,489-493[Abstract/Free Full Text]
  28. Homa, DM, Mannino, DM, Lara, M Asthma mortality in US: Hispanics of Mexican, Puerto Rican, and Cuban heritage, 1990–1995. Am J Respir Crit Care Med 2000;161,504-509[Abstract/Free Full Text]
  29. Holguin, F, Mannino, DM, Anto, J, et al Country of birth as a risk factor for asthma among Mexican Americans. Am J Respir Crit Care Med 2005;171,103-108[Abstract/Free Full Text]
  30. Leon, PE, Raventos, H, Lynch, E, et al The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A 1992;89,5181-5184[Abstract/Free Full Text]
  31. Ridker, PM, Miletich, JP, Hennekens, CH, et al Ethnic distribution of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. JAMA 1997;277,1305-1307[Abstract]
  32. Choudhry, S, Ung, N, Avila, PC, et al Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am J Respir Crit Care Med 2005;171,563-570[Abstract/Free Full Text]
  33. Duffy, DL, Martin, NG, Battistutta, D, et al Genetics of asthma and hay fever in Australian twins. Am Rev Respir Dis 1990;142,1351-1358[ISI][Medline]
  34. Nieminen, MM, Kaprio, J, Koskenvuo, M A population-based study of bronchial asthma in adult twin pairs. Chest 1991;100,70-75[CrossRef][ISI][Medline]
  35. Edfors-Lubs, ML Allergy in 7000 twin pairs. Acta Allergol 1971;26,249-285[ISI][Medline]
  36. Hopp, RJ, Bewtra, AK, Watt, GD, et al Genetic analysis of allergic disease in twins. J Allergy Clin Immunol 1984;73,265-270[ISI][Medline]
  37. Lubs, ML Empiric risks for genetic counseling in families with allergy. J Pediatr 1972;80,26-31[CrossRef][ISI][Medline]
  38. Koeppen-Schomerus, G, Stevenson, J, Plomin, R Genes and environment in asthma: a study of 4 year old twins. Arch Dis Child 2001;85,398-400[Abstract/Free Full Text]
  39. Greally, M, Jagoe, W, Greally, J The genetics of asthma. Ir Med J 1982;75,403-405[ISI][Medline]
  40. Dold, S, Wjst, M, von Mutius, E, et al Genetic risk for asthma, allergic rhinitis, and atopic dermatitis. Arch Dis Child 1992;67,1018-1022[Abstract]
  41. Longo, G, Strinati, R, Poli, F, et al Genetic factors in nonspecific bronchial hyperreactivity: an epidemiologic study. Am J Dis Child 1987;141,331-334[Abstract]
  42. Jenkins, MA, Hopper, JL, Giles, GG Regressive logistic modeling of familial aggregation for asthma in 7,394 population-based nuclear families. Genet Epidemiol 1997;14,317-332[CrossRef][ISI][Medline]
  43. Sibbald, B, Horn, ME, Brain, EA, et al Genetic factors in childhood asthma. Thorax 1980;35,671-674[Abstract]
  44. Daniels, SE, Bhattacharrya, S, James, A, et al A genome-wide search for quantitative trait loci underlying asthma. Nature 1996;383,247-250[CrossRef][Medline]
  45. Collaborative Study on the Genetics of Asthma.. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 1997;15,389-392[CrossRef][ISI][Medline]
  46. Ober, C, Cox, NJ, Abney, M, et al Genome-wide search for asthma susceptibility loci in a founder population: the Collaborative Study on the Genetics of Asthma. Hum Mol Genet 1998;7,1393-1398[Abstract/Free Full Text]
  47. Wjst, M, Fischer, G, Immervoll, T, et al A genome-wide search for linkage to asthma: German Asthma Genetics Group. Genomics 1999;58,1-8[CrossRef][ISI][Medline]
  48. Yokouchi, Y, Nukaga, Y, Shibasaki, M, et al Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31–q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics 2000;66,152-160[CrossRef][ISI][Medline]
  49. Dizier, MH, Besse-Schmittler, C, Guilloud-Bataille, M, et al Genome screen for asthma and related phenotypes in the French EGEA study. Am J Respir Crit Care Med 2000;162,1812-1818[Abstract/Free Full Text]
  50. Laitinen, T, Daly, MJ, Rioux, JD, et al A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet 2001;28,87-91[CrossRef][ISI][Medline]
  51. Xu, X, Fang, Z, Wang, B, et al A genomewide search for quantitative-trait loci underlying asthma. Am J Hum Genet 2001;69,1271-1277[CrossRef][ISI][Medline]
  52. Haagerup, A, Bjerke, T, Schiotz, PO, et al Asthma and atopy: a total genome scan for susceptibility genes. Allergy 2002;57,680-686[CrossRef][ISI][Medline]
  53. Hakonarson, H, Bjornsdottir, US, Halapi, E, et al A major susceptibility gene for asthma maps to chromosome 14q24. Am J Hum Genet 2002;71,483-491[CrossRef][ISI][Medline]
  54. Xu, J, Postma, DS, Howard, TD, et al Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 2000;67,1163-1173[ISI][Medline]
  55. Van Eerdewegh, P, Little, RD, Dupuis, J, et al Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418,426-430[CrossRef][Medline]
  56. Ferreira, MA, O’Gorman, L, Le Souef, P, et al Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13. Am J Hum Genet 2005;77,1075-1085[CrossRef][ISI][Medline]
  57. Evans, DM, Zhu, G, Duffy, DL, et al Major quantitative trait locus for eosinophil count is located on chromosome 2q. J Allergy Clin Immunol 2004;114,826-830[CrossRef][ISI][Medline]
  58. Pillai, SG, Chiano, MN, White, NJ, et al A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p. Eur J Hum Genet 2006;14,307-316[CrossRef][ISI][Medline]
  59. Huang, SK, Mathias, RA, Ehrlich, E, et al Evidence for asthma susceptibility genes on chromosome 11 in an African-American population. Hum Genet 2003;113,71-75[CrossRef][ISI][Medline]
  60. Xu, J, Meyers, DA, Ober, C, et al Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three US populations: Collaborative Study on the Genetics of Asthma. Am J Hum Genet 2001;68,1437-1446[CrossRef][ISI][Medline]
  61. Mathias, RA, Freidhoff, LR, Blumenthal, MN, et al Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families. Genet Epidemiol 2001;20,340-355[CrossRef][ISI][Medline]
  62. Blumenthal, MN, Langefeld, CD, Beaty, TH, et al A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma. Hum Genet 2004;114,157-164[CrossRef][ISI][Medline]
  63. Ober, C, Tsalenko, A, Willadsen, S, et al Genome-wide screen for atopy susceptibility alleles in the Hutterites. Clin Exp Allergy 1999;29,11-15[ISI][Medline]
  64. Koppelman, GH, Stine, OC, Xu, J, et al Genome-wide search for atopy susceptibility genes in Dutch families with asthma. J Allergy Clin Immunol 2002;109,498-506[CrossRef][ISI][Medline]
  65. Brasch-Andersen, C, Tan, Q, Borglum, AD, et al Significant linkage to chromosome 12q24.32-q24.33 and identification of SFRS8 as a possible asthma susceptibility gene. Thorax 2006;61,874-879[Abstract/Free Full Text]
  66. Lander, E, Kruglyak, L Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995;11,241-247[CrossRef][ISI][Medline]
  67. Postma, DS, Meyers, DA, Jongepier, H, et al Genomewide screen for pulmonary function in 200 families ascertained for asthma. Am J Respir Crit Care Med 2005;172,446-452[Abstract/Free Full Text]
  68. Daniels, SE, Bhattacharrya, S, James, A, et al A genome-wide search for quantitative trait loci underlying asthma. Nature 1996;383,247-250[CrossRef][Medline]
  69. Nicolae, D, Cox, NJ, Lester, LA, et al Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet 2005;76,349-357[CrossRef][ISI][Medline]
  70. Blumenthal, MN, Ober, C, Beaty, TH, et al Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA). Genes Immun 2004;5,226-231[CrossRef][ISI][Medline]
  71. Silverman, EK, Palmer, LJ Case-control association studies for the genetics of complex respiratory diseases. Am J Respir Cell Mol Biol 2000;22,645-648[Free Full Text]
  72. Colhoun, HM, McKeigue, PM, Smith, GD Problems of reporting genetic associations with complex outcomes. Lancet 2003;361,865-872[CrossRef][ISI][Medline]
  73. Ober, C, Hoffjan, S Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006;7,95-100[CrossRef][ISI][Medline]
  74. Laitinen, T, Polvi, A, Rydman, P, et al Characterization of a common susceptibility locus for asthma-related traits. Science 2004;304,300-304[Abstract/Free Full Text]
  75. Zhang, Y, Leaves, NI, Anderson, GG, et al Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003;34,181-186[ISI][Medline]
  76. Allen, M, Heinzmann, A, Noguchi, E, et al Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 2003;35,258-263[CrossRef][ISI][Medline]
  77. Lind, DL, Choudhry, S, Ung, N, et al ADAM33 is not associated with asthma in Puerto Rican or Mexican populations. Am J Respir Crit Care Med 2003;168,1312-1316[Abstract/Free Full Text]
  78. Raby, BA, Silverman, EK, Kwiatkowski, DJ, et al ADAM33 polymorphisms and phenotype associations in childhood asthma. J Allergy Clin Immunol 2004;113,1071-1078[CrossRef][ISI][Medline]
  79. Shin, HD, Park, KS, Park, CS Lack of association of GPRA (G protein-coupled receptor for asthma susceptibility) haplotypes with high serum IgE or asthma in a Korean population. J Allergy Clin Immunol 2004;114,1226-1227[CrossRef][ISI][Medline]
  80. Howard, TD, Postma, DS, Jongepier, H, et al Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol 2003;112,717-722[CrossRef][ISI][Medline]
  81. Slutsky, AS, Zamel, N Genetics of asthma: the University of Toronto Program; University of Toronto Genetics of Asthma Research Group. Am J Respir Crit Care Med 1997;156,S130-S132[Abstract/Free Full Text]
  82. Rosenwasser, LJ, Klemm, DJ, Dresback, JK, et al Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Aller 1995;25(suppl),74-78[CrossRef]
  83. Kabesch, M, Tzotcheva, I, Carr, D, et al A complete screening of the IL4 gene: novel polymorphisms and their association with asthma and IgE in childhood. J Allergy Clin Immunol 2003;112,893-898[CrossRef][ISI][Medline]
  84. Tanaka, K, Sugiura, H, Uehara, M, et al Lack of association between atopic eczema and the genetic variants of interleukin-4 and the interleukin-4 receptor alpha chain gene: heterogeneity of genetic backgrounds on immunoglobulin E production in atopic eczema patients. Clin Exp Allergy 2001;31,1522-1527[CrossRef][ISI][Medline]
  85. Noguchi, E, Shibasaki, M, Arinami, T, et al Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy 1998;28,449-453[CrossRef][ISI][Medline]
  86. Zhu, S, Chan-Yeung, M, Becker, AB, et al Polymorphisms of the IL-4, TNF-{alpha}, and Fc{epsilon} RIß genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med 2000;161,1655-1659[Abstract/Free Full Text]
  87. Beghe, B, Barton, S, Rorke, S, et al Polymorphisms in the interleukin-4 and interleukin-4 receptor {alpha} chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 2003;33,1111-1117[CrossRef][ISI][Medline]
  88. Sandford, AJ, Chagani, T, Zhu, S, et al Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000;106,135-140[CrossRef][ISI][Medline]
  89. Burchard, EG, Silverman, EK, Rosenwasser, LJ, et al Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma. Am J Respir Crit Care Med 1999;160,919-922[Abstract/Free Full Text]
  90. Novak, N, Kruse, S, Kraft, S, et al Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte immunophenotyping and single nucleotide polymorphisms of the interleukin-4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic dermatitis. J Invest Dermatol 2002;119,870-875[CrossRef][ISI][Medline]
  91. Mitsuyasu, H, Izuhara, K, Mao, XQ, et al Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma. Nat Genet 1998;19,119-120[CrossRef][ISI][Medline]
  92. Izuhara, K, Yanagihara, Y, Hamasaki, N, et al Atopy and the human IL-4 receptor {alpha} chain. J Allergy Clin Immunol 2000;106,S65-71[ISI][Medline]
  93. Takabayashi, A, Ihara, K, Sasaki, Y, et al Childhood atopic asthma: positive association with a polymorphism of IL-4 receptor alpha gene but not with that of IL-4 promoter or Fc {epsilon} receptor I ß gene. Exp Clin Immunogenet 2000;17,63-70[CrossRef]