JRSM >
Volume 95, Number 1 >
Pp. 14-17
Department of Primary Health Care and General Practice, Imperial College of Science, Technology and Medicine: Charing Cross Campus, St Dunstan's Road, London W6 8RP, UK
 | INTRODUCTION |
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 TOP INTRODUCTION FAMILIAL STUDIESGENE MAPPING STUDIESCONCLUSIONSREFERENCES |
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Asthma is a condition characterized by reversible airflow obstruction and lower airway hyper-responsiveness, which results in episodic cough, wheeze and shortness of breath5. Inflammation of the nasal passages, manifesting as sneezing, nasal blockage and itchy rhinorrhoea, is the symptom complex known as rhinitis6. Eczema is the commonest cause of dermatitis in developed countries and affects approximately 20% of the general population7. The distribution of eczematous lesions varies with age, the face and trunk being most affected in infants whereas the flexor aspects of the limbs are typically affected in older children and adults. Advances in our understanding of the immunobiology of these disorders have shown them to have a common pathophysiological basis—an exaggerated and inappropriate IgE-mediated inflammation in response to allergen exposure—referred to as atopy8. The absence of objective and reliable criteria for defining either atopy or the atopic allergic conditions (eczema, rhinitis and asthma) has been and continues to be a major obstacle to establishing the genetic basis of atopic disorders.
This review is based in the main on articles retrieved by searching Medline, EMBASE and OMIM (Online Mendelian Inheritance in Man) electronic databases. Key websites of possible relevance were also searched9, including those of the British Society for Human Genetics10, the European Society for Human Genetics11, and the Human Mutation Database12. Allergy and genetic texts were consulted, and the analysis was helped by personal contacts with several experts on human genetics.
| FAMILIAL STUDIES |
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TOPINTRODUCTIONFAMILIAL STUDIESGENE MAPPING STUDIESCONCLUSIONSREFERENCES |
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Studies in twins are a good way to disentangle genetic and environmental factors in families, and early work in small numbers showed that concordance rates for atopic disorders were higher for monozygotic (MZ) than for dizygotic (DZ) twins14. These findings were replicated in several larger studies conducted in various population groups. The most notable was Edfors-Lubs's study of 7000 Swedish twin pairs, in which the MZ versus DZ concordance rates were: asthma 19.0% vs 4.8%; rhinitis 21.4% vs 13.6%; eczema 15.4% vs 4.5%16. Work by Hanson and colleagues, comparing serum IgE levels in MZ and DZ twins reared together and apart, was another landmark in familial studies: MZ twins had consistently stronger correlation coefficients for serum total IgE than did DZ twins17. In addition, MZ twins showed over 70% concordance for specific IgE response to one or more common aeroallergens; however, the finding that almost one-third of MZ twins were discordant indicated that sensitization through environmental exposure was also aetiologically important.
Segregation analysis
Segregation analysis, or the study of trait distributions in families, has
often been a key step in elucidating the genetic basis for disease, allowing
testing to see whether the pattern of phenotype distribution within families
is consistent with a known genetic
model18. But in
common multifactorial and heterogeneous disorders this can be a hazardous
undertaking. Results to date from such studies have been inconsistent and
confusing. Using complex segregation analysis techniques for studying IgE
concentrations in 173 families, Gerard and colleagues concluded that the
regulatory locus for IgE occupied two alleles, with the dominant allele
suppressing persistently high levels of
IgE19. The
observation that 90% of atopic asthmatics in 239 members of forty nuclear
families had an atopic parent led Cookson and Hopkin to suggest a dominant
model of inheritance for propensity to produce an exaggerated IgE
response20. Other
Mendelian models proposed have included autosomal recessive inheritance,
autosomal dominant inheritance with incomplete penetrance, codominance, and
dominant inheritance through the maternal
line21. Opinion has
lately converged on the view that several genes interact to determine
liability to disease (polygenic inheritance). Empirical support for this
suggestion comes from the findings of Xu and colleagues, who, studying serum
total IgE data in 92 Dutch families, found that two-locus segregation analysis
gave a better fit than did a one-locus
model22.
An additional layer of complexity comes from the increasing evidence that inheritance of atopic disorders is end-organ specific—i.e. for the skin (eczema), nose (rhinitis) and airways (asthma)23. The possibility is thus raised that, although inheritance of an exaggerated IgE response may underlie all these conditions, separate genes predispose to specific clinical manifestations of the allergic phenotype.
| GENE MAPPING STUDIES |
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TOPINTRODUCTIONFAMILIAL STUDIESGENE MAPPING STUDIESCONCLUSIONSREFERENCES |
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Positional cloning analysis
The first evidence for linkage of atopy to a specific chromosomal region
was made in 1989 when Cookson and colleagues detected linkage disequilibrium
with the D11S97 marker implicating chromosome
11q1324. Seven
families were studied in total and a maximum LOD score of 5.6 was obtained
(LOD score is the logarithm of the odds ratio of the probability of observing
such a family if the genes are linked compared with the probability of
observing such a family if the genes are not linked; a score of > 3 is
generally considered to provide evidence of linkage). In this dataset, a large
part of the score came from a single family, and attempts at replication have
yielded inconsistent results. Positive linkages have been noted in studies
conducted in the Netherlands, Germany, Japan, and Australia, for
example25; but a
large British study, in which atopy was characterized as a continuous
variable, produced no evidence of linkage at this
site26.
Another region of intense interest is chromosome 5q, which contains several candidate genes for atopy including those that encode for cytokines known to be important in pathogenesis (IL-3, IL-4, IL-5, IL-9, IL-12, IL-13) as well as those that encode for the ß2-adrenergic receptor, the corticosteroid receptor and the granulocyte-macrophage colony-stimulating factor. Marsh and colleagues reported linkage of 5q markers with atopy in a US Amish population27 and Meyers et al.28 have replicated their findings in a group of Dutch families; but not all groups have been as successful25. Linkages have been found with several other loci including chromosomes 13q, 12q and 6p, although replication has again proved problematic. So far, four genome-wide screening studies for atopic disorders have been reported, and together they implicate a total of thirteen chromosomes (1, 4, 5, 6, 7, 11, 12, 13, 14, 16, 17, 19 and 21); however, replication has been possible only with respect to chromosomes 4, 7, 11 and 1625.
Why has replication proved so troublesome? Clearly there are inherent difficulties in studying complex genetic disorders in which environmental factors are also important29. Biases in the selection of subjects and a failure to correct for multiple testing will increase the possibility of type 1 errors; and type 2 errors will be fostered by disagreement amongst reserach teams on definitions of atopy and atopic allergic conditions, and by the small sample sizes frequently used. Another important factor, yet to be resolved, is the question of a significant LOD29. Conventional cut-off values of > 3 for detecting significance at the 5% level are likely to generate many false-positive linkages when complex genetic disorders are studied. For example, Daniels et al., in their genome screen of eighty nuclear families with 300 markers spaced at approximately 10% recombination, opted for a significance level of 0.1%; nonetheless, Monte Carlo simulations indicated that 1.6 false-positive linkages were to be expected from the data30. The American Collaborative Study on the Genetics of Asthma used a significance level of 1%, and this almost certainly explains the unexpectedly large number of linkages detected31.
Candidate genes
Characterization of many of the inflammatory mediators crucial to
pathogenesis, and the sequencing and cloning of several of the responsible
genes, has made possible the testing of candidate genes for atopy. The
principal difficulty herein is that the list of candidate genes is very long.
Barnes and Page, for example, estimate that over a hundred inflammatory
mediators may be involved in the pathogenesis of asthma alone, implicating a
similar number of candidate
genes32.
A comprehensive review of the candidate genes thus far considered empirically is beyond the scope of this paper. Suffice it to say that associations have been detected with several genes of interest including most notably the cytokines encoded for on chromosome 5q (see above) and the FceR1B gene on chromosome 11q13 that codes for the beta-chain of the high-affinity IgE receptor gene33. Mutations of the latter could conceivably lead to increased signal transduction after allergen binds to IgE. One such mutation, Leu-181, has been shown to be associated with atopy and asthma in some populations but not others. Another substitution in this gene results in an aminoacid substitution (Glu237Gly) in the region encoding for the cytoplasmic tail of the protein, and this too is associated with positive skin tests and childhood asthma in some population groups25.
| CONCLUSIONS |
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TOPINTRODUCTIONFAMILIAL STUDIESGENE MAPPING STUDIESCONCLUSIONSREFERENCES |
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| Acknowledgments |
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| REFERENCES |
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TOPINTRODUCTIONFAMILIAL STUDIESGENE MAPPING STUDIESCONCLUSIONSREFERENCES |
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