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Discovering susceptibility genes for asthma and allergy

Key Points

  • Asthma and asthma-related traits are complex diseases with strong genetic and environmental components.

  • Association and genome-wide linkage studies have identified numerous candidate genes that are associated with asthma-related traits and are involved in innate immunity, T helper 2 cell differentiation and effector functions, epithelial cell biology and lung function.

  • The phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context.

  • Despite the achievements of asthma genetics, the identification of all the genes involved in disease, the replication of genotype–phenotype associations across populations, and the interactions of genes with environmental and developmental factors, and with one another, still represent formidable challenges.

  • The development of novel, powerful tools for gene discovery, such as genome-wide association studies, and a closer integration with biology, should help asthma geneticists to overcome these challenges.

Abstract

Asthma and asthma-related traits are complex diseases with strong genetic and environmental components. Rapid progress in asthma genetics has led to the identification of several candidate genes that are associated with asthma-related traits. Typically the phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context. Despite the achievements made in asthma genetics formidable challenges remain. The development of novel, powerful tools for gene discovery, and a closer integration of genetics and biology, should help to overcome these challenges.

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Figure 1: Susceptibility genes for asthma and asthma-related traits.
Figure 2: Susceptibility genes for asthma and asthma-related traits.
Figure 3: Distinct variants of IL13 may synergize and increase susceptibility to allergic inflammation.
Figure 4: Gene–environment interactions in human populations.
Figure 5: Effects of gene–gene interactions on asthma susceptibility.
Figure 6: Steps in the genome-wide association study that led to the identification of ORMDL3 as an asthma gene.

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DATABASES

OMIM

Asthma

atopic dermatits

inflammatory bowel disease

ichthyosis vulgaris

Netherton's syndrome

dbSNP

rs1800925

rs1801275

rs1805010

rs1805015

rs1881457

rs1295686

rs20541

rs2243250

rs2303067

rs2569190

rs324011

rs847

rs4696480

FURTHER INFORMATION

Donata Vercelli's homepage

International HapMap Project

Seattle SNPs

The Single Nucleotide Polymorphism database

Glossary

Atopy

The propensity of an individual to develop allergic diseases, such as asthma, atopic dermatitis, food allergy or hay fever. It is defined operationally by elevations in serum levels of IgE reactive with allergens or by skin-test reactivity to allergens.

Population structure

Any deviation from the ideal state of a single population in which every individual has the same chance of mating with every other.

Single nucleotide polymorphisms

(SNPs). Variations in DNA sequence in which one of the four nucleotides is substituted for another (for example, C for A). SNPs are the most frequent type of polymorphism in the genome.

Tag SNP

A single nucleotide polymorphism (SNP) that is correlated with a neighbouring variant, which serves as a proxy for that (not genotyped) variant.

TH2 cells

CD4+ T helper (TH) cells differentiated along a pathway that leads to coordinated expression of IL-4, IL-13 and IL-5. TH2 cells and their cytokine products are central mediators of allergic inflammation.

Positional cloning

The process of systematically identifying mutations or susceptibility alleles by studying genetic markers in families or high-risk individuals.

Pattern recognition receptors

Proteins expressed by innate immune cells that detect molecules associated with microbial pathogens or cellular stress.

Quantitative-trait locus

A polymorphic locus that contains alleles that differentially affect the expression of a continuously distributed phenotypic trait (for example, total serum IgE levels).

Microsatellites

Polymorphic DNA loci that consist of repeating units of 1–4 bp in length.

Linkage disequilibrium map

Map of non-random associations between alleles at two or more loci.

Haplotype

A combination of alleles at different markers located on the same chromosome in a specific genomic region.

MicroRNAs

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

Epigenetics

The study of heritable changes in gene function that occur without a change in the DNA sequence.

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Vercelli, D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 8, 169–182 (2008). https://doi.org/10.1038/nri2257

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