The Role of Environmental Tobacco Smoke in Genetic Susceptibility to Asthma

Thorsten Kurz; Carole Ober

Disclosures

Curr Opin Allergy Clin Immunol. 2004;4(5) 

In This Article

Studies of Genotype, Environmental Tobacco Smoke Exposure and Asthma

There have been relatively few studies to date specifically examining interaction effects between genotype, ETS exposure, and asthma. However, with the recent advances in genotyping technologies and in the analytical tools to study gene-by-environment interactions, it is likely that the number of studies addressing this important area will increase in the future. Two general approaches have been used for examining the relationship between genotype, ETS exposure, and asthma-associated phenotypes, which parallel the approaches used for identifying asthma susceptibility alleles in general.[23,24] The first is a candidate gene approach, using either a case-control or cohort study design. In these studies, genes are selected because they have been associated with asthma (or a related phenotype)[25] or with the metabolism of tobacco smoke.[26,27] The second is a genome-wide approach, in which exposure status is incorporated into a genome-wide screen for asthma (or a related phenotype) to identify loci that contribute to asthma risk in exposed asthmatics only and those that contribute to asthma risk in unexposed asthmatics only. In contrast to the candidate gene approach, the genome-wide approach has the potential to identify novel loci that interact with ETS exposure to influence risk.

Three studies have examined genotype-ETS interaction effects on asthma or atopic phenotypes using a candidate gene approach. One study each examined polymorphisms in the α2-adrenergic receptor (ADRB2) gene,[28,29] the interleukin-10 (IL-10) gene[30*] and the glutathione S-transferase M1 (GSTM1) gene.[31**]

The first study to examine genotype-ETS interactions was by Wang and colleagues.[28] The investigators hypothesized that because cigarette smoking can induce airway inflammation and increase airway responsiveness and because β2-adrenergic receptor is involved in mechanisms for bronchodilation, associations between polymorphisms in the ADRB2 gene and asthma may be more evident among smokers. They used a nested case-control design to assess associations between polymorphisms in ADBR2 and asthma in Chinese subjects, using smoking status (never or ever) as a covariate.[28] They found a significant interaction between genotype and smoking status on asthma risk: among smokers, the asthmatics (n=39) were more than twice as likely as controls (n=23) to have the Arg16/Arg16 genotype (OR 7.81; 95% CI 2.07-29.5; P=0.002). There was no increased risk associated with smoking among individuals with other genotypes at the Gly16Arg and Gln27Glu polymorphisms in ADBR2, suggesting that individuals with the Arg16/Arg16 genotype were particular susceptible to the adverse effects of ETS exposure.

Karjalainen and colleagues[30*] studied three polymorphisms in the promoter region of the IL-10 gene in adult asthmatic patients and controls.[30*] They hypothesized that the high IL-10 producing promoter haplotype, referred to as -1082G/-829C/-592C (GCC), would be reduced among adults with asthma or allergy compared with controls. They did not find a difference between asthmatics and controls with respect to promoter haplotypes, but smoking male controls with impaired lung function - predicted low forced expiratory volume in 1 s (FEV1) - had a modestly significant increase in the frequency of the high IL-10 producing GCC haplotype compared with male controls (P=0.049). However, because their findings were in the opposite direction of what they expected and there were only 35 smoking male controls in this study (20 with the GCC haplotype and 15 with other haplotypes), these results should be interpreted cautiously.

Gilliland and colleagues[31**] investigated the effects of GSTM1 genotype, maternal smoking during pregnancy, and childhood ETS exposure on subsequent development of asthma and wheezing among participants in the Children's Health Study. They hypothesized that GSTM1 plays a role in susceptibility to asthma and wheezing in children exposed to ETS because it is involved in pathways involved in xenobiotic metabolism and antioxidant defenses. They found that the effects of in-utero exposure to maternal smoking (n=462) on asthma and wheezing were largely restricted to children with the GSTM1 null genotype, whereas in-utero exposure was not associated with asthma or wheezing among children with the GSTM1+ genotype (active asthma OR 1.7, 95% CI 1.1-2.8; persistent wheeze OR 2.2, 95% CI 1.3-4.0; interaction P<0.05). They concluded that in-utero exposure to ETS may have gentotype specific effects on asthma risk.

The US National Heart Lung and Blood Institute Lung Health Study is a multicenter randomized clinical trial of over 5000 participants who smoke, and, on enrollment, were between the ages of 35 and 60 years, and had spirometric evidence of moderate lung function impairments.[32] Sandford, Paré, and colleagues have conducted a series of genetic studies in participants in this study to identify genes that may serve as markers for rapid decline in lung function among smokers.[29,33,34,35,36,37] Although these studies do not directly investigate genetic risk factors for asthma, they may identify candidate genes that interact with ETS exposure to increase risk for asthma.

In these studies, approximately 284 participants (range 282-286) showing a fast decline in lung function over five years and approximately 306 participants (range 305-308) with a slow decline in lung function over five years were selected for genotyping. The rapid decliners had a decrease in FEV1 of 153.7±2.62 ml/year and the slow or non-decliners had a decrease in FEV1 of 14.9±1.51 ml/year. They compared genotype and/or haplotype frequencies between these two groups at (1) loci involved in oxidative stress and detoxification of tobacco smoke substances (GSTM1, GSTT1, GSTP1, heme oxygenase 1 (HMOX1) and microsomal epoxide hydrolase (EPHX1))[34,37]; (2) genes encoding proteolytic enzymes with roles in tissue remodeling and repair (matrix metalloproteinase (MMP1), MMP9, MMP12, and α1-antitrypsin (AAT))[34,36]; (3) the ADRB2 locus[29]; (4) genes encoding cytokines and their receptors that have been associated with chronic obstructive pulmonary disease in human or animal studies (interleukin-13 (IL-13), interleukin-13 receptor α-chain (low-affinity) (IL13RA1), interleukin-4 receptor α-chain (IL4RA), tumor necrosis factor-α (TNFA), lymphotoxin-α precursor (LTA))[33,34] or with inflammation (interleukin-1β (IL1B), interleukin-1 receptor agonist (IL1RN))[35]; and (5) other genes previously associated with chronic obstructive pulmonary disease (vitamin D binding protein (VDBP)).[34]

Using a nearly identical design in each study they reported associations between rapid decline in lung function and (1) combinations of genotypes in GSTM1, GSTP1 and GSTT1 (P=0.03), (2) haplotypes comprised of variants in IL1B and IL1RN (P=0.0005), (3) genotypes at MMP1 (P=0.02) and haplotypes comprised of variants in MMP1 and MMP12 (P=0.0007), (4) heterozygosity for the Gln27Glu polymorphism in ADBR2 (P=0.0007), (5) genotype at the IL4RA locus (P=0.043) and combinations of genotypes at the IL-13 and IL4RA locus (P=0.050 and 0.041), (6) genotype at AAT (P=0.03), and (7) haplotypes at EPHX1 (P=0.03). None of the other tested loci showed an association with decline in lung function.

Because of the large number of comparisons performed in these studies, these results should be interpreted cautiously, as noted by the authors. In particular, the modest associations (0.01<P<0.05) reported at most loci could be type I errors. Moreover, the significant results reported for haplotypes at the GST and at the interleukin-1 (IL-1) loci are likely to be anticonservative because the investigators did not account for the fact that the haplotype frequencies were estimated and not directly observed.[35,36] Overall, therefore, these combined studies suggest that some of the loci examined may have minor effects on decline in lung function in smokers. Finally, it should be noted that these studies do not directly test for interactions between genotype and ETS exposure because they did not include non-smokers in their studies. However, they identify a number of loci that might be reasonable candidates for studies directly assessing interaction effects with ETS exposure on asthma risk.

Taking a very different approach to identifying genes that interact with ETS exposure to influence asthma susceptibility, Colilla et al. [38**] incorporated information on exposure to ETS during infancy into a genome-wide linkage study. They hypothesized that asthmatic children who were exposed to ETS in infancy may have different genetic susceptibilities than asthmatic children who were not exposed to ETS during infancy. Moreover, they suggested that inclusion of information on exposure to ETS may improve the ability to detect linkage signals for asthma. They reclassified the asthmatics in 144 families into those who were exposed and those who were not exposed to ETS. They then conducted genome scans separately for each phenotype, 'ETS-exposed asthma' and 'non-ETS-exposed asthma', including only families that had at least two related asthmatic individuals with same childhood exposure. The evidence for linkage in three chromosomal regions (1p, 5q, and 17p) increased in the analysis of 51 exposed families (191 affected individuals). The increase from the baseline analysis in the 144 families was significant for the linkages on 1p (P=0.034) and 17q (P=0.017), as assessed by a permutation test. In addition, the evidence for linkage in three chromosomal regions (1q, 6p and 9q) increased in the 77 unexposed families (243 affected individuals), with regions on 1q and 9q showing a significant increase from baseline (P=0.002 and P=0.009, respectively). They concluded that different genes may be contributing to asthma susceptibility in children exposed to ETS compared with unexposed children and that the inclusion of environmental risk factors in linkage analyses could help to target new candidate susceptibility genes for asthma.

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