Genetic variants in IL-4, IL-13, and IL-4Rα genes have been linked to asthma and related phenotypes in various populations. In this study, we analyzed the effects of genetic variants and haplotypes in these genes in an African-American asthmatic cohort. We also examined the effects of gene–gene interaction between SNPs that showed an association with asthma or asthma-related phenotyes. One genetic variant in the IL-13 gene was significantly associated with post-FEV1 and bronchodilator responsiveness. Another variant in the IL-4Rα gene was associated with post-FEV1. Two SNPs, which were modestly correlated with baseline lung function independently of each other, interacted to significantly affect this phenotype. Although our results from the interaction analysis were consistent with our results from the single SNP analysis, neither SNP reached statistical significance in association with pre-FEV1 alone. Both polymorphisms may have modestly contributed to baseline lung function individually, but the effect was more pronounced when the SNPs interacted in our cohort.
Our results show that genetic variants in IL-13 and IL-4Rα genes may interact to affect baseline lung function in African-American subjects with asthma. Interaction between genetic variants in these genes has previously been shown to influence asthma susceptibility in several populations. In a study by Chan and colleagues, the IL-4Rα (A+4679G) allele was shown to interact with the IL-13 (R130Q) allele to influence asthma risk in a Chinese cohort (15
). Similarly, Howard and associates' report on Dutch subjects with asthma demonstrated an interaction between the IL-13 (C−1112T) and IL-4Rα (C+22656T) alleles for asthma susceptibility (14
). Although the SNPs that interacted in our cohort differed from those of Chan and colleagues or Howard and coworkers, our results suggest that interaction between IL-13 and IL-4Rα genes may play a role in lung function in our population as well. It has been suggested that replication of complex genetic associations may be more informative on a genewide level as opposed to the individual SNP level, especially among different populations (24
). To our knowledge, this study is the first to test the effects of gene–gene interaction between IL-4, IL-13, and IL-4Rα genes and asthma in an African-American population.
Gene–gene interaction between IL-4 and IL-4Rα and asthma has been demonstrated in several populations (25
). Because no significant or moderately significant associations were found for IL-4 SNPs in our population, we did not test for interaction between this gene and IL-4Rα. It is still possible, however, that there was an interaction between these two genes, but the effects were not detectable via single SNP analysis. Although we may have been underpowered due to sample size, our sample size of 264 cases and 176 control subjects is comparable to other genetic association studies for these genes. Finally, the interaction with IL-4Rα could be with alternative SNPs in the IL-4 gene, which were not analyzed in our study.
Although our results were globally consistent with previous studies of gene–gene interactions, our results were not entirely consistent with studies of individual SNPs. For example, polymorphisms in the IL-4 gene, in particular the C−589T and C−33T alleles, have been linked to asthma and related phenotypes in some studies (5
), but not in others (26
). One or both of these promoter SNPs has been linked to asthma, total serum IgE levels, or allergy in white (5
) and Japanese (28
) populations. In contrast, we did not find any associations between IL-4 SNPs and asthma (pre- or post-FEV1
), drug responsiveness, or total serum IgE. However, our results were fairly consistent with Basehore and colleagues' study of 168 African-American subjects with asthma and 269 African-American control subjects (5
). Basehore and coworkers genotyped 11 IL-4 SNPs (including C−589T, C−33T, and A+8427A) in white, African-American, and Hispanic populations; 9 of the 11 SNPs were significantly associated with an asthma-related phenotype in whites. However, only one of these SNPs (G+3017T), which was not genotyped in our population, was associated with an asthma-related phenotype in African Americans or Hispanics. Likewise, Donfack and colleagues (10
) found associations between C−589T and/or C−33T and asthma-related phenotypes in Europeans and Hutterites, but not in African Americans. We have previously reported an association between the IL-4 C−589T allele and baseline FEV1
in whites but not in African Americans (9
). These studies may suggest that, although polymorphisms in the IL-4 gene may be significant contributors to asthma in whites, their effects may be attenuated in African Americans. Alternatively, SNPs in the IL-4 gene may not themselves be biological contributors to asthma but may be in LD with other SNPs that are biological contributors to asthma in whites, but not in African Americans. Furthermore, Basehore and colleagues noted that IL-4 G+3017T SNP was in LD with at least three other SNPs.
In contrast to our results for the IL-4 gene, we found evidence of association between a promoter SNP (A−646G) in the IL-13 gene and post-FEV1
and drug response, and a trend for association with baseline lung function. SNPs in the promoter region of the IL-13 gene have been associated with various asthma-related phenotypes in other studies. Donfack and colleagues described an association between a two-SNP haplotype containing IL-13 (C−1112T) and IL-4 (G+3017T), and allergic sensitization to molds in an African-American population (10
). This result confirmed the results of a study by van der pouw Kraan and colleagues, who found an association between IL-13 (C−1112T) and allergic asthma in another population (referred to as −1055 in van der pouw Kraan and colleagues' study) (13
It has been shown that soluble IL-4R protein levels are found in higher concentrations in patients with asthma than in healthy control subjects, lending support to a possible role in the pathogenesis of asthma (29
). Genetic variants in IL-4Rα have been examined several times in association studies for asthma (14
) and other related phenotypes (6
), although findings were not consistent (31
). In our population, two SNPs in the IL-4Rα gene (A+4679G and C+22656T) showed a trend of association with pre-FEV1
. Patients with asthma with the minor allele at IL-4Rα (A+4679G) or the major allele at IL-4Rα (C+22656T) had lower baseline lung function.
We have previously demonstrated that genetic and pharmacogenetic associations for asthma vary among different racial and ethnic groups (18
). This has been confirmed for other diseases as well (18
). For example, a meta-analysis has shown that the impact of apolipoprotein (APO)-E4 on Alzheimer's disease varies by race (32
). Although there are many potential explanations for these observations, one possibility is that there are unique racial and ethnicity-specific modifiers (genetic and environmental) that attenuate or accentuate genetic risk factors.
In this study, we were able to replicate findings of gene–gene interaction between IL-13 and IL-4Rα and asthma-related phenotypes, which has been shown in other populations. However, we were unable to replicate previous single SNP associations with these phenotypes. One possible explanation is that genetic associations may be affected by differing LD patterns between ethnic groups (e.g., Africans typically have less LD when compared with other populations). The differences in LD between racial groups can be exploited to identify putative disease-causing genetic variants. Specifically, examination of SNP associations across multiple ethnic groups may reveal precisely which SNPs are consistently observed to be associated in the different populations, regardless of LD pattern. For example, in cloning the phenylthiocarbamide (PTC) bitter-taste gene, three different amino acid substitutions were observed to be associated with taste blindness (33
). Although there was strong to complete LD among these SNPs in most populations, it was also observed that studies of Africans could disentangle the effects of individual SNPs because of reduced LD in this group. Similar such examples have been provided in the association study of adult macular degeneration (34
). Such findings underscore the importance of studying multiple ethnic and racial groups in genetic association studies.