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Time to draw breath: asthma-susceptibility genes are identified

Nature Reviews Genetics volume 5, pages 376–387 (2004)Cite this article

Key Points

  • Asthma is a chronic respiratory condition that affects children and adults. Genetic predisposition and environmental factors interact to produce the disease.

  • The multigenic nature of asthma has hampered progress in identifying asthma-susceptibility genes. Genome screens and genetic association studies have provided numerous positional candidate genes for asthma, but the results of replication studies have been variable.

  • The TH2 cytokine signalling pathway is upregulated in asthma and drives the asthma phenotype. The TH2 cytokine gene IL13 is one of the more widely validated asthma positional candidate genes, and its involvement is supported by linkage, genetic association and function studies.

  • Despite the inherent challenges of gene discovery for complex genetic diseases, several groups have provided evidence in support of novel asthma candidate genes.

  • ADAM33 was identified as an asthma-susceptibility gene using positional cloning methodologies. ADAM33 seems to function in airway remodelling.

  • Positional cloning was also used to identify DPP10, a peptidase gene that might be involved in the immunological aspects of asthma.

  • The chromosome 13q14 gene PHF11 was recently identified as a locus for immunoglobulin E levels in asthma.

  • Positional cloning was combined with the power of murine congenics to identify the Tim1 gene, which seems to be involved in the differentiation of TH2 cells.

  • Microarray and genome screen studies in a murine model of asthma intersected at the C5 locus. Functional studies support a key role for C5 in bridging the gap between innate and adaptive immune responses in asthma.

  • Several groups have now progressed from broad linkage regions to asthma-gene identification. The resultant identification of novel genes both confirms our current model of disease pathogenesis and expands our knowledge in new direction

Abstract

The prevalence of complex genetic immune disorders, such as asthma, arthritis and diabetes, has escalated in recent decades. Despite the formidable challenges posed by the identification of susceptibility genes in complex genetic disorders such as these, several groups have now progressed from broad linkage regions to the identification of several positional candidate asthma genes. The insights into disease mechanisms that these recent discoveries might allow will inform the development of new therapeutic strategies for the treatment of asthma and will pave the way for the identification of genes that underlie a diverse array of immunologically mediated disorders.

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Figure 1: Methods of asthma-susceptibility gene discovery.
Figure 2: ADAM33 gene-discovery methods.

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Acknowledgements

We thank the three anonymous reviewers for their critical comments. Grants from the National Heart, Lung, and Blood Institute are gratefully acknowledged.

Author information

Authors and Affiliations

  1. Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, 45229, Ohio, USA

    Marsha Wills-Karp

  2. Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, 48824-1302, Michigan, USA

    Susan L. Ewart

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  1. Marsha Wills-Karp
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Corresponding author

Correspondence to Marsha Wills-Karp.

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DATABASES

Entrez

Abhr1

Abhr2

ADAM33

ADRB2

C5

CD14

DPP10

IL4

IL5

IL9

IL13

PHF11

RCBTB1

SETDB2

OMIM

asthma

HAVCR1

FURTHER INFORMATION

The Molecular Respiratory and Equine Genetics Laboratory

Glossary

ASTHMA

An inflammatory airway disease that is characterized by episodic airway obstruction for which an allergic underpinning is common.

IMMUNOGLOBULIN E

(IgE). Antibody molecules that are characterized by heavy chains and that are involved in allergic reactions.

GENETIC HETEROGENEITY

The production of a similar phenotype by different genes or genetic mechanisms in different kindreds; the occurrence of different gene combinations that cannot be distinguished at the phenotype level.

PHENOCOPY

Environmental conditions that induce a phenotype that is similar to that caused by a gene mutation; in this case, the phenomenon of other pulmonary disorders, such as chronic obstructive pulmonary disease, resembling or masquerading as asthma.

BRONCHIAL HYPER-RESPONSIVENESS

(BHR). Excessive constriction of smooth muscle that surrounds bronchi and bronchioles, resulting in narrowed airway passages and airflow limitation.

SKIN PRICK TESTS

A test for local allergic reactions to intradermal allergen administration.

INTERMEDIATE PHENOTYPES

Objective, quantitative traits that are used as surrogate markers of a complex disease that is open to subjective definition. For asthma, examples include total and specific immunoglobulin E levels, bronchial hyper-responsiveness and skin prick tests.

ATOPY

A genetically determined state of hypersensitivity to environmental allergens that is detected by increased serum immunoglobulin E and/or positive dermal allergen tests.

T CELL

Lymphoid-derived white blood cells that are responsible for cell-mediated immunity.

TH2 CELLS

A subset of T-helper cells that produce IL-4, IL-5 and other cytokines and that stimulate B cells to produce antibodies.

TH1 CELLS

A subset of T-helper cells that produce interferon-γ (and other cytokines) and that activate macrophages.

CYTOKINES

Hormone-like low-molecular-weight proteins that are involved in the regulation and cell-to-cell communication of the immune system, haematopoiesis and inflammation.

CHEMOKINE

(Also known as chemotactic cytokines). A group of polypeptides that share a 4-cysteine structure and induce chemotaxis, or directed migration, of leukocyte subsets.

TH0 CELLS

Naive T-helper cells before antigen stimulation, that can differentiate into TH1 or TH2 cells.

CANDIDATE GENE

A gene that logically relates to the phenotype of interest on the basis of the general understanding of disease mechanisms.

ASSOCIATION STUDIES

A study design to test whether genetic variants occur more frequently in cases than in controls.

TRANSMISSION DISEQUILIBRIUM TEST

(TDT). A joint test of linkage and association in which allele transmission is tracked from heterozygous parents to single probands, and the alleles that are not transmitted are used as controls.

LINKAGE ANALYSIS

A method for tracking the transmission of genetic information across generations to identify the map location of genetic loci on the basis of co-inheritance of genetic markers and discernable phenotypes in families.

SINGLE NUCLEOTIDE POLYMORPHISMS

(SNPs). Bi-allelic (typically) base-pair substitutions, which are the most common forms of genetic polymorphism.

GENE TARGETING

Molecular manipulation of genes that results in overexpression or gene deletion.

LOD SCORE

A statistical estimate of whether two loci are likely to lie near each other on a chromosome and are therefore likely to be inherited together. A LOD score of three or more is generally taken to indicate that the two loci are close.

ASCERTAINMENT SCHEME

The method that is used to find or select subjects for inclusion in a genetic study.

PROBAND

(Also known as the index case). The affected person that identifies a family for study.

POSITIONAL CANDIDATE GENES

A subset of candidate genes that are located in regions of the genome that contain susceptibility loci for the phenotype of interest, as identified by genetic studies.

BACTERIAL ARTIFICIAL CHROMOSOME

(BAC). A research tool that is used to clone large fragments of chromosomal DNA.

HAPLOTYPE

A set of closely linked genetic markers present on one chromosome that tend to be inherited together (not easily separable by recombination). Some haplotypes might be in linkage disequilibrium.

PAC

(P1-derived artificial chromosome). A vector that is used to clone DNA fragments of 100–300 kb insert size (average at 150 kb) in Escherichia coli cells. Based on the bacteriophage P1 genome.

PARASYMPATHETIC GANGLIA

Groups of cholinergic nerve cell bodies of the autonomic nervous system that receive input fibres from the visceral motor neurons.

B CELLS

White blood cells of lymphoid origin that differentiate on activation into antibody-secreting plasma cells.

CONGENIC

A breeding scheme that is used to move a defined segment of genomic material onto the genetic background of a different strain; produced by repeatedly crossing a donor strain that contains a gene or genomic region of interest to a recipient inbred strain that lacks the gene or trait.

MACROPHAGES

Large mononuclear phagocytic cells that are important in innate immunity as antigen-presenting cells and as effector cells in humoral and cell-mediated immunity.

QUANTITATIVE TRAIT LOCUS ANALYSIS

A technique for identifying genes that influence polygenic traits that vary between individuals in a continuous fashion.

INNATE IMMUNE RESPONSE

Components of the immune system that constitute the immediate, first line of defence against antigens. Pathogen recognition is mediated by pattern-recognition receptors.

COMPLEMENT

Nine serum proteins that are activated in sequence by an antigen, forming an antigen–antibody compound (symbol 'C'). It is part of the non-specific immune system that generally deals with bacterial infections.

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Wills-Karp, M., Ewart, S. Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 5, 376–387 (2004). https://doi.org/10.1038/nrg1326

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