Genetic polymorphism in allergy and asthma

doi:10.1016/j.coi.2003.09.005

Current Opinion in Immunology

Volume 15, Issue 6, December 2003, Pages 609-613

https://doi.org/10.1016/j.coi.2003.09.005 Get rights and content

Abstract

The impact of genetic factors on the pathogenesis of allergy and asthma is currently an area of intense investigation. Although epidemiological studies find more and more genes that are likely to contribute to allergic inflammation, functional studies of the mechanisms that link genetic variation with dysregulation of gene expression and function are hindered by the high frequency of natural variation. The interplay between genes and environment adds another layer of complexity to the determination of allergic phenotypes. The complexity emerging from these studies warrants novel experimental strategies and bolder conceptual paradigms.

Introduction

The recent advent of high-throughput methods for gene sequencing and genotyping, coupled with a growing interest in functional studies, has resulted in the generation of an impressive amount of data on the genetics of allergy and asthma. Overall, these studies have reiterated the essential role played by genetic factors in the pathogenesis of allergic disease.

Such analyses have resulted in the emergence of three interrelated themes: the heuristic value of genetic studies, which have the power to identify new candidate genes; the remarkable frequency of natural variation even in highly conserved genes; and the interplay between genes and environment. In this review, I discuss each of these three themes.

Section snippets

Uncovering the unexpected: the heuristic value of genetic studies

These days, a common trend in biology is to complement hypothesis-driven research with hypothesis-independent, global types of analysis. In studies of the genetics of asthma and allergy, this means pursuing the identification of putative allergy or asthma susceptibility genes by positional cloning in outbred populations, and then characterizing the associations between patterns of variation in those candidate genes and specific disease phenotypes.

To date, linkage studies have identified more

Genetic variation: so frequent, so deep

Basic immunology is making wider and wider use of animal models based on inbred strains. The genetic manipulations and permutations possible in such models enables a level of experimental elegance that is unattainable in human studies, which accounts for the popularity of this approach. Needless to say, using inbred strains of laboratory animals to model the function and behavior of human genes presupposes fundamental genetic similarities between these animals and humans, as well as within the

Gene–environment interactions: the endotoxin switch

In 1999, a SNP in the CD14 promoter, CD14-159C/T, was found to be associated with increased amounts of soluble CD14 and decreased total serum IgE in the Children Respiratory Study (CRS), a study of an unselected population enrolled at birth in Tucson, Arizona [13]. This work received wide attention, because the role of innate immunity in sensing the environment and regulating adaptive responses was becoming increasingly clear at that time. At the beginning of 2003, another group did not find

Conclusions

Far from simplifying our understanding of the pathogenesis of allergic disease, the advances in the genetic studies of asthma and allergy discussed above highlight a situation of remarkable complexity that warrants novel approaches. Haplotypes, rather than single SNPs, will have to be evaluated. New strategies will be needed to tease out the mechanisms through which natural variation has an impact on gene expression and/or function. Animal models will have to be improved to recapitulate better

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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of special interest
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of outstanding interest

Acknowledgements

The author was supported by grants PO1HL67672 and RO1HL66391 from the National Institutes of Health, and by the Program for Genomic Applications Innate Immunity in Heart, Lung and Blood Disease (U01-HL66803) from the National Heart, Lung and Blood Institute.

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Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory.
Association of interleukin 6 single nucleotide polymorphisms with allergic rhinitis
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Currently, there is no doubt that genetic predisposition has a major role in the pathogenesis of the disease [1,2,8]. These genetic factors not only affected its development, but also its severity and treatment [9,10]. Proinflammatory cytokines are emphasized as important mediators of the inflammatory response in allergic rhinitis and bronchial asthma [11], while their single nucleotide polymorphisms (SNPs) have been investigated in a number of diseases [12–16].
Allergic rhinitis (AR) is a polygenic inflammatory disorder of the nasal mucosa with an increasing prevalence worldwide. As interleukin 6 (IL-6) seems to be involved in development of allergic disorders, such as allergic rhinitis, this study was performed to evaluate the association of two promotor variants of IL-6 gene in the AR.
Ninety eight patients with AR were enrolled in this study. Genotyping was done for two polymorphisms in a promoter region of IL-6 gene (G/C at −174, rs1800795 and G/A at −597, rs1800797), using a PCR sequence-specific-primers method.
Patients homozygous for the G allele of rs1800795 in IL-6 had a 3.35-fold risk of having AR than those with the C allele. AA genotype in rs1800797 of IL-6 was associated with the increased risk of developing AR. G/G haplotype for IL-6 (rs1800795, rs1800797) was significantly higher in the patient group. In some subgroups of patients, there were significant relationships between IgE levels, eosinophil count, eosinophil percentage, nature of sensitivity and persistency of disease and these two variants.
We found that two promotor variants in IL-6, especially rs1800795, were predisposing factors for AR with a negative heterosis pattern. These SNPs could also affect the clinical parameters, the nature of sensitivity and persistency of the disease in some subgroups of the patients.
Association between Interleukin-27 gene polymorphisms and susceptibility to allergic rhinitis
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Furthermore, AR is a known risk factor for comorbid conditions such as asthma, rhinosinusitis, nasal polyposis, and sleep disorders, resulting in important medical and social problems [3,4]. Over the last two decades, the pathogenesis of AR has been widely studied and genetic factors are thought to be major players affecting the development, severity and treatment of AR [5,6]. It has been reported that numerous loci and candidate genes show associations with AR [7,8].
Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. Interleukin-27 (IL-27), a novel IL-12 family member, has recently been reported to play a role in some immune-related disorders. This study was performed to evaluate the potential association of IL-27 polymorphisms with AR in a Chinese Han population.
A case-control study was performed in 445 Chinese AR patients and 691 healthy controls. Three SNPs in the IL-27p28 gene, including rs153109, rs17855750 and rs181206, were detected using a polymerase chain reaction–restriction fragment length polymorphism assay (PCR–RFLP).
A significantly increased prevalence of the rs153109 TT genotype and the T allele was found in AR patients, while a decreased prevalence of the CT and CC genotypes and the C allele was found. For rs153109, the TT genotype and the T allele were significantly associated with the risk of AR, but the CT and CC genotypes and the C allele decreased the risk of AR; for rs17855750, the TT genotype and T allele were risk factors for AR, and the GT genotype and G allele provided protection. TTT and TTC haplotypes in the IL-27p28 gene were positively correlated with AR, while CGT, CTC and CTT haplotypes were associated with a significantly decreased risk of AR.
This study indicates that IL-27p28 polymorphisms rs153109 and rs17855750 are likely involved in AR susceptibility, making them potentially useful genetic biomarkers for AR susceptibility in the Chinese Han population.
Gene polymorphisms of Interleukin-4 in allergic rhinitis and its association with clinical phenotypes
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Furthermore, they release more mediators responsible for the late phase of allergic reactions and systemic component of AR [11]. Behind this scene, genetic factors are major players affecting development, severity and treatment of AR [13,14]. Several susceptibility loci were identified as a result of extensive studies.
Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. T-helper (Th)2 cytokines seems to have major roles behind the scene of unpleasant symptoms resulted from AR. Expression of interleukin (IL)-4 and its receptor could be affected by single nucleotide polymorphisms (SNPs). This study assessed the effect of 4 genetic variants within genes of IL-4 and IL-4R in AR.
Allele frequencies of one IL-4R variant (rs1801275) and three SNPs of IL-4 (rs2243248, rs2243250, and rs2070874) were investigated in 98 patients with AR, compared to a group of controls, using PCR sequence-specific-primers (PCR-SSP) method.
Homozygosity for the C allele of rs2243250 in IL-4 was significantly overrepresented in the patient group. CC genotype in rs2070874 significantly was correlated with AR. GG/CC/CC and TT/TT/TT (rs2243248, rs2243250, and rs2070874) haplotypes in the IL-4 gene had a significant negative correlation with AR.
SNPs in IL-4 are associated with AR and could change the clinical picture of the disease in patients.
Common variants of the neuropeptide expressing tachykinin genes and susceptibility to asthma: A case-control study
2010, Journal of Neuroimmunology
Since tachykinins appear to be involved in the pathogenesis of allergic asthma, we investigated a possible association between 28 single nucleotide polymorphisms of the tachykinin genes TAC1, TAC3 and TAC4, and asthma susceptibility. A case–control study was conducted on 102 patients and 100 healthy subjects from the Canary Islands (Spain). A significant association with asthma was observed for two SNPs: rs2291855 in the TAC3 gene conferring asthma protection (Odds ratio [OR]: 0.46; 95% Confidence Interval [CI]: 0.22–0.97; P = 0.038), and rs4794068 in the TAC4 gene associated with an increased risk for asthma (OR: 1.94; 95% CI: 1.06–3.54; P = 0.03). The present study represents a preliminary step in elucidating the association between tachykinin gene polymorphisms and asthma susceptibility.
Progress in understanding postnatal immune dysregulation in allergic disease
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It is well recognized that the effect of host-environmental interactions can depend on genetic polymorphisms and that the effects of functional TLR polymorphisms 39 (and other microbial recognition pathways 40) vary with the level of microbial exposure 39. These complex interactions may explain some of the inconsistencies between studies performed in different environmental contexts 41. In a separate cohort we have also performed the first longitudinal study of these responses (to TLR2-TLR9) during the first 5 years of life.
It is increasingly unlikely that allergic disease is the result of isolated immune defects, but rather the result of altered gene activation patterns in intricate immune networks. This appears to be driven by complex environmental changes, including microbial exposure, diet, and pollutants, which are known to modify immune development in early life, beginning in pregnancy. The first models showing possible epigenetic mechanisms for these effects are beginning to emerge. This review focuses on recent advances in our knowledge of the consequent effects on postnatal immune development, highlighting recognized differences in children with and without allergies. Although we characterized essential differences in longitudinal T-cell development more than 10 years ago, new technologies using whole genome microarrays are now being used to examine for differential gene expression in T cells from individuals with allergies. We have also recently performed the first comprehensive study of the longitudinal development of innate toll-like receptor responses in children with and without allergies during the first 5 years of life, identifying significant differences in these pathways as well. Finally, although there are preliminary differences in regulatory T-cell function at birth, longitudinal studies are limited by difficulties isolating these cells in sufficient numbers from young children for functional studies. Thymic tissue isolated during cardiac surgery is a rich source of regulatory T-cell function in children and may provide further avenues for assessing differences in maturation of these cells in individuals with allergies. To further understand the pathogenesis of these altered patterns of immune response, future research needs to encompass the complexity of gene-environmental interactions, which confer individual susceptibility to environmental exposures.

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Genetic polymorphism in allergy and asthma

Abstract

Introduction

Section snippets

Uncovering the unexpected: the heuristic value of genetic studies

Genetic variation: so frequent, so deep

Gene–environment interactions: the endotoxin switch

Conclusions

References and recommended reading

Acknowledgements

Eur. Cytokine Netw.

Nature

J. Immunol.

J. Exp. Med.

An internet linkage and mutation database for the complex phenotype asthma

Bioinformatics

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Nature

Identification and characterization of novel mouse and human ADAM33s with potential metalloprotease activity

Gene

Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma

Nat. Genet.

A genome-wide search for quantitative trait loci underlying asthma

Nature

Linkage and association of atopic asthma to markers on chromosome 13 in the Japanese population

Hum. Mol. Genet.

Positive association to IgE levels and a physical map of the 13q14 atopy locus

Eur. J. Hum. Genet.

The PHD finger: implications for chromatin-mediated transcriptional regulation

Trends Biochem. Sci.