Twin studies and studies of familial aggregation have demonstrated a significant genetic contribution to asthma. Estimates of the heritability of asthma in twin studies have ranged from 36 to 79%.
To date, 15 groups have reported results of genome-wide linkage analysis for asthma and/or its intermediate phenotypes in 17 distinct populations. Several of these groups have published second-generation surveys with larger numbers of subjects and markers. One of these genome-wide linkage studies for asthma reported only partial results. Fourteen chromosomal regions have shown significant evidence of linkage 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); 2q33 (to eosinophil count); 5q31-q33 (to mite-sensitive asthma); 7p14-p1550 and 7q21 (to total serum IgE level); 11q12-q13 (to atopy)-; 6p21, 12q24,14q24, and 20p1355 (to asthma); and 19p13 and 20q13 (to dust mite allergy).
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. To date, there have been reports 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 popu-lations, 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 clon-ing.’’ 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)-.. to asthma phenotypes are insufficiently understood. Although some replication studies 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 popula-tions. Functional data in rodents and humans provide strong support for a significant role of GPR154 in asthma pathogenesis.
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 Genome-Wide Linkage Analyses
The Collaborative Study on the Genetics of Asthma (CSGA) 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. 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 linkage (maximum log10 of the odds of linkage [LOD], 2.0) between chromosome 11q21 and asthma in African Americans. Following the inclusion of additional markers in the analysis, there was significant evidence of linkage (maximum LOD, 4.4) between chromosome 11q and asthma among African Americans.
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, and modest evidence of linkage (p < 0.01) between two genomic regions (chromosomes 12p and 17p) and atopy. 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
ADAM33: Howard et al 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 al and Slutsky and Zamel. Raby and colleagues 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, asthma, and other asthma-related phenotypes. SNPs in exons of IL4R have been associated with asthma, total serum IgE level, and other asthma-related phenotypes., Burchard and colleagues 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 al 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 al 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 His-panics). 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, asthma,, and total serum IgE level. Donfack et al 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 rodents 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. 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 al 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 al found no association between SNPs in the TLR9 gene and asthma.