Susceptibility to allergic diseases may result from the inheritance of many mutated genes, but unfortunately, as in many other complex diseases, any of the specific biochemical abnormalities occurring at the cellular level that cause disease in allergic diseases are not known, although most of the genetic studies on allergic diseases have focused on the molecular pathways involved in pathogenesis. By studying the genetic basis of the disease, its mutated genes and abnormal gene products can be identified by the abnormal phenotypes that result from them. Identifying the genes responsible for these disease phenotypes can contribute to a better understanding of the basis of the pathogenesis of these diseases, and genetic studies of allergic diseases have deepened our understanding of the diseases in many ways. Zhang Yuan, Department of Nasal Allergy, Tongren Hospital, Beijing, China
(i) The importance of environmental stimulation: gene-environment interactions
Allergic diseases are the result of environmental stimuli directed at genetically susceptible individuals. Inhalation and ingestion of environmental factors have been hypothesized to be an important contributor to asthma, including allergens, diet, respiratory viruses, airborne pollutants, smoking, endotoxins, and occupational exposures. Recent gene-environment studies have focused on functional SNP loci of candidate genes that are predicted to potentially play an important role in the identification of environmental events and in the regulation of environmental exposures. With this aim, studies in gene-environment interactions have led to a deeper understanding of the pathogenesis of allergic diseases, such as asthma and atopic dermatitis, and their severity and progression.
Pattern recognition receptors, such as CD14 and toll-like receptor (TLR)4, are thought to recognize and clear bacterial endotoxins by activating a range of natural host immune responses, and their SNP variants can alter the biological function of these receptors and can influence the origin of asthma during development when the immune system is developing. In a case-control and family-based study, Smit et al. found that in atopic individuals, polymorphisms in CD14, TLR4 and other TLR genes could alter the association with asthma risk, especially for patients living in rural areas. In a study on farm living environment, Bieli et al. observed that some specific alleles in the promoter region of the CD14 gene may be protective factors for asthma and allergic diseases in individuals who consume farm milk on a long-term basis.
Exposure and sensitization against house dust mite antigens (e.g. Der p 1) have been recognized as risk factors for atopy and asthma.Sharma et al. found a correlation between altered single nucleotide polymorphisms in the TGF-β1 gene (TGFB1) and asthma phenotype (airway hyperresponsiveness and worsening of asthma), while this correlation could be modified by the degree of dust mite exposure, suggesting that it may be affected by the TGFB1 gene polymorphisms may be immunomodulated to varying degrees. Other studies have found that house dust mite exposure modifies the association between IL10 gene polymorphisms and asthma and between dendritic cellCassociated nuclear protein 1 (DCNP1) polymorphisms and house dust mite specific IgE. Although these findings were not validated, they provide us with preliminary evidence of gene-environment-allergen interactions.
The effect of air pollution on asthma susceptibility may also be modulated by polymorphisms in genes encoding inflammatory cytokines and metabolic enzymes. Recently, polymorphisms in the arginase gene (arginase, ARG), a gene involved in the nitrosative stress response, were investigated by Salam et al. They observed that a haplotype interaction in the ARG1 gene occurs between childhood ozone exposure and the risk of asthma. The glutathione-s-transferase polymorphism may also influence the risk of asthma from ambient air pollution during childhood, especially when controlling for ozone concentrations as well as diesel exhaust particulate matter. In addition, the association of environmental tobacco levels and childhood asthma risk with altered SNPs in the TNF-a gene (TNFA) and chromosome 17q21 region also demonstrates gene-environment interactions.
Although data on the role of gene-environment in asthma continue to emerge, the challenge of conventional research now lies in combining molecular, clinical and epidemiological data on asthma with a view to discovering more refined mechanisms of gene-environment interactions and thus facilitating personalized interventions for asthma patients. In addition, the application of genetic epidemiology may offer a real opportunity to address the drawback of purely causal inference that exists in observational epidemiology. Epidemiological studies of environmental exposures may reveal spurious etiologies of diseases due to behavioral, physiological, and socioeconomic factors that are associated with both exposure and disease endpoints. One solution is to use Mendel’s principle of randomization, where the inheritance of one trait does not depend on the inheritance of other traits.
(ii) Discovery of new models of pathogenesis
Figure 2. Susceptibility genes for allergic diseases
(Cited in Genetics of allergic disease. Allergy Clin Immunol, 2010, 125(2 Suppl 2):S81-94)
Genetic studies of allergic diseases have clearly shown that the factors influencing atopic predisposition are different from those influencing the disease process, however, these disease factors need to interact with atopy to trigger the disease. For example, in asthmatics, bronchial stenosis is mostly triggered by an allergic response to inhaled allergens with eosinophilic inflammation in the lungs, but in some individuals with “asthma susceptibility genes” but not atopic conditions, asthma is triggered by other exposures, such as toluene diisocyanate. These atopic immune response genes and tissue-specific factors also apply to other clinical manifestations of atopy, such as rhinitis and atopic dermatitis. We can divide these genes that contribute in allergic diseases into four clusters, see Figure 2.
First, there is a group of genes that are directly involved in regulating responses to environmental exposures. These include genes encoding components of the natural immune system that interact with the degree of microbial exposure to modify the risk of allergic immune responses, such as CD14 and TLR4, genes encoding components of the lipopolysaccharide response pathway. other environmental response genes, including detoxification enzymes such as glutathione-s-transferase genes modulate the effects of exposure factors including oxidant stress (e.g. smoking and air pollution).
A second major cluster includes genes identified by non-hypothetical genomic strategies, primarily involving signaling pathway genes that maintain epithelial barrier integrity at the mucosal surface and the immune system of the epithelium after environmental exposure. For example, polymorphisms in the intermediate filament-aggregating protein (Filaggrin, FLG) gene, which directly affects skin barrier function, are not only associated with the risk of developing atopic dermatitis, but also increase atopic sensitization. Genes encoding chitin play an important role in modulating allergic inflammation in asthmatics, while having high levels of expression in the epithelium and selectively activating macrophages. the PCDH1 gene, an important member of the cell adhesion molecule family, is expressed in the bronchial epithelium and has been shown to be a susceptibility gene for airway hyperreactivity.
A third group of genes is involved in immunomodulatory responses and includes IL13, IL4RA, STAT6, TBX21 (encoding a T-box transcription factor), HLAG and GATA3, which are responsible for the regulation of Th1/Th2 differentiation and effector function, and others, including IRAKM and PHF11 genes, which can regulate allergic disease occurring in end organs ( respiratory tract, skin and nasal cavity) in the inflammatory response.
This last group of genes is responsible for determining the tissue response to chronic inflammation, such as airway remodeling. They include the ADAM33 gene, expressed in fibroblasts and smooth muscle cells, the PDE4D gene, expressed in smooth muscle and inflammatory cells, and the COL29A1 gene, which encodes a novel collagen expressed in the skin and strongly associated with atopic dermatitis.
Thus, the recognition that genetic variation in genes involved in the regulation of the atopic immune response is not the only or major determinant of susceptibility to allergic disease has reinforced the importance of local tissue response factors and epithelial susceptibility factors in the pathogenesis of allergic disease. This may be the greatest contribution of the genetic studies that have been conducted to the study of allergic diseases, and it is expected that new therapeutic strategies targeting the most critical pathways in disease pathogenesis will be developed in the future.
(iii) Sensitization and process: the role of FLG in atopic dermatitis and asthma
Atopic dermatitis often represents the first clinical manifestation of atopic disease in childhood and suggests a high subsequent risk of developing persistent asthma. Current studies of the FLG gene have shown a correlation between early childhood eczema and the subsequent development of asthma, due in part to enhanced sensitization to allergens resulting from defects in epithelial barrier function. In 2006, Smith et al. reported that loss-of-function mutations in the FLG gene cause ichthyosis vulgaris, a severe skin dysfunction characterized by dry skin with ichthyotic scaling and a predisposition to atopic dermatitis, and is associated with asthma. 2282del4) carriers can develop severe ichthyosis vulgaris, whereas those with heterozygous mutations develop only mild disease.
Subsequently, these mutations have also been shown to be associated with atopic dermatitis, asthma, and allergy. The hypothesis that defective epithelial barrier function caused by mutations in the FLG gene, through skin exposure to allergens, triggers a systemic allergic response and initiates the natural course of the allergic reaction (atopic march) was recently confirmed by the analysis of a mouse with a spontaneous recessive mutation in the lamellar tail, a phenotype previously shown to result from a shift mutation in the murine FLG gene. The topical application of antigens in such mutant pure mice can lead to enhanced skin antigen uptake and the resulting antigen-specific IgE and IgG antibody responses.
(iv) The importance of early life
There is consensus that tests of phenotypes, including atopy and asthma, such as cord blood immune response, respiratory function, and bronchial hyperresponsiveness, are predictive of the development of subsequent allergic disease in the neonatal period. Fetal growth retardation has also been shown to be associated with lung damage in childhood. In addition to this, it is likely that there is an interaction between atopy and lung development. Numerous genetic studies have confirmed the impact of early life development in allergic diseases, for example, a genome-wide positional cloning study in 2001 identified ADAM33 as an asthma susceptibility gene and its polymorphisms were associated with asthma susceptibility and airway hyperresponsiveness (but not atopy or serum IgE concentration). Furthermore, the selective expression of the ADAM33 gene in airway smooth muscle cells and fibroblasts is highly suggestive that alterations in its activity may cause functional abnormalities in the aforementioned cells, which are critical for airway hyperresponsiveness as well as reconstitution. As in the adult airways, multiple ADAM33 protein isoforms are present in the human embryonic lung, and testing at 8 to 12 weeks revealed that polymorphisms in ADAM33 correlate with several assays of lung function early in life, a finding that, although not yet validated, suggests that variants in this gene may determine lung development in utero or early in life. Recently, Bouzigon et al. reported that single nucleotide polymorphisms encoding the ORMDL3 gene region, located on chromosome 17q21, were associated with asthma, and a validation study found that single nucleotide polymorphisms encoding the ORMDL3 gene region, located on chromosome 17q21, were associated with early-onset (<4 years of age) asthma, but not late-onset asthma, further supporting the importance of early life for the importance of asthma onset. Furthermore, after correcting for cigarette exposure, they found that the risk of early-onset asthma was 2.9-fold higher in children with cigarette exposure than with cigarette exposure.