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Introduction
Asthma is a complex genetic disorder that is highly familial
yet does not follow a simple pattern of inheritance [1,2]. In
order to successfully map asthma susceptibility genes,
several analytic methods will need to be employed and,
ultimately, new methods will need to be developed. Prior to
application of analytic options for detection of linkage from
either a candidate gene or anonymous marker screen,
however, the definition of the phenotype (asthma) has to
be established. While not the focus of this discussion,
inconsistent definition of asthma within a study will introduce misclassification (with accompanying loss of power)
and decrease the likelihood of replication of linkage results
across studies.
The prevalence of asthma appears to be increasing in
most parts of the industrialized world and, with increasing
diagnoses, the number of families with multiple cases of
asthma is also increasing [3,4]. Since the rate of increase in
asthma cases has occurred over a short period of (evolutionary) time, the likely cause of the increase could be due
to either increased diagnosis or increased exposure to
environmental triggers that allow expression of asthma
susceptibility genes. While the gold standard for diagnosis
of asthma is likely a combination of clinical history of
Correspondence: Dr S. R. Rich, Department of Public Health Sciences,
Bowman Gray School of Medicine, Winston-Salem, North Carolina, USA.
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larger, and that the pairs are considered pairwise independent. Thus, as long as the total number of sib pairs is large,
greater than 100, then all affected pairs can be used in the
analyses.
Although sib pair analysis can take place with either
candidate gene or anonymous marker data, the use of
genome screen methods provide increased information in
a multipoint analysis. This approach usually assumes that
the recombination fraction (v) between an asthma susceptibility locus is 0.05 (< 5 cm), corresponding to a locus
between two markers in a 10 cm genome-wide screen. For
genetic markers in a typical screen, the polymorphic information content (PIC) ranges from 0.70 to 0.90; even with
the low end of PIC values, multipoint analysis [11] would
typically result in a significant gain in information. The
critical value for detecting linkage in a genome screen is
usually set at a criteria of 3.6, corresponding to a significance level of 2 10 5 in order to assure a global type I error
rate of 5% [12].
Associated phenotypes
Asthma, as defined by history and bronchial hyperreactivity
(BHR), lends itself to decomposition into component (intermediate) phenotypes, including BHR, atopy, and skin-test
reactivity [13]. Since the individual components of symptoms that comprise asthma may be more common than
asthma, per se, the families ascertained for occurrence of
asthma may contain more members affected with BHR,
atopy, or skin-test reactivity. As power for mapping genes
depends on the number of affected sibling pairs, analysis of
BHR or atopy in families ascertained on the basis of two or
more affected siblings with asthma may have more power
than that associated with asthma.
When families are analysed for asthma and its associated
phenotypes (e.g. BHR and atopy), several outcomes are
possible with respect to regions of interest (Fig. 1). First,
there could be complete concordance for regions of interest
of all phenotypes (asthma, BHR and atopy). While this
event may provide confirmation that the region is of
interest for disease, it is not clear which disease(s) the
region controls. On the other hand, discordance within a
region (significant for asthma but not for BHR and atopy)
suggests importance for the disease, yet concern that there is
no evidence for clearly associated phenotypes.
An alternative to analysis of asthma separately from its
associated phenotypes is the restriction of the asthma
phenotype to those who exhibit asthma, BHR and atopy.
While this approach may provide increased homogeneity of
phenotype, there will also be a decreased number of individuals meeting the more restricted criteria and therefore a
reduction in the number of affected sibling pairs (and
reduced power).
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S. S. Rich
q 1998 Blackwell Science Ltd, Clinical and Experimental Allergy, 28, Supplement 1, 8487
Future prospects
Given the complexity of asthma and its associated phenotypes, the diverse populations under study, and the many
groups of investigators who are leading these studies, it
would appear on the surface that collaboration and combined analyses would not be likely. It should be noted,
however, that collaboration can take place at several levels
using a core set of variables for phenotype definition
(either as a qualitative or quantitative trait) in a joint genetic
analysis, using a core set of genetic markers, or providing a
structure to allow rapid data exchange for replication
studies. The first of these approaches (core variables to
allow joint analysis) would be most flexible, in that differences in results from different populations could not be
attributed to differences in phenotype definition (one group
using a clinical history while another using history and
BHR, for example).
The ultimate success of each investigators endeavours
will be the identification of asthma susceptibility genes in
the target population. It is not clear, given the complexity
of genetic susceptibility and environmental exposure, replication across divergent populations can be expected. It is
also not clear that replication would be likely within an
ethnic group across a divergent geographical region, or
even within the same region, depending upon time of
sampling (seasonality and environmental load) and microexposures that may have macro-effect (such as differences
between dog/cat/house dust mite allergen loads that are
home-specific). In many respects therefore failure to replicate an initial linkage should not necessarily suggest a
falsepositive result. Rather, caution should be taken for
that region, yet it should remain a region of interest.
Standardization of phenotype definition would facilitate
the evaluation of these numerous interesting regions for
asthma susceptibility genes.
References
1 National Institutes of Health. Global strategy for asthma
management and prevention. NHLBI/WHO workshop report.
NIH, Bethesda, MD. Publication no. 953659, 1995.
2 Sibbald B, Horn ME, Gregg I. A family study of the genetic
basis of asthma and wheezy bronchitis. Arch Dis Child 1980;
55:3547.
3 Ninan TK, Russell G. Respiratory symptoms and atopy in
Aberdeen schoolchildren: Evidence from two surveys 25 years
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q 1998 Blackwell Science Ltd, Clinical and Experimental Allergy, 28, Supplement 1, 8487