ANRV299-ME58-12 ARI 28 December 2006
Toward a Comprehensive
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17:36
Set of Asthma Susceptibility
Genes
Yohan Bossé and Thomas J. Hudson
McGill University and Génome Québec Innovation Center, Montréal, Québec,
Canada; email: tom.hudson@mcgill.ca
Key Words
complex traits, candidate genes, SNP selection, VDR, GPRA
Abstract
Epidemiological and twin studies have demonstrated that asthma
is under genetic and environmental influences. Numerous candi-
date gene association studies as well as genome-wide linkage scans
have followed, aiming to elucidate the genetic architecture under-
lying this complex disease. Several promising asthma susceptibility
genes were identified, and a comprehensive catalogue of these genes
seems a realistic goal within 5 to 10 years. However, a key challenge
is to understand the combination of genes and environmental factors
that gives rise to the disease in a specific individual. Currently, most
of the reports of asthma susceptibility genes are either preliminary
or controversial, with little knowledge about the genetic mecha-
nisms leading to abnormal function of the gene that promotes the
development of asthma. Replications of published associations are
relatively few. Many factors, including the inherent complexity of
asthma as well as methodological issues, can explain these inconsis-
tencies. Promising genetic tools are emerging with the completion
of the International HapMap Project that will increase the scope
of gene-discovery investigations. It is hoped that these tools, com-
bined with validation studies in additional populations, will enable
the creation of a comprehensive catalogue of susceptibility genes for
asthma. Notwithstanding the difficulties in making sense of the vast
amount of new genetic data, we already see the emergence of new
biological pathways of atopy, airway remodeling, and asthma that
may lead to novel therapeutic approaches.
171
ANRV299-ME58-12 ARI 28 December 2006 17:36
INTRODUCTION
Asthma is a heterogeneous respiratory disease
VDR: vitamin D characterized by chronic inflammation of the
receptor airways, reversible bronchoconstriction, air-
GPRA: G way hyperreactivity, eosinophilia, and mucus
protein–coupled hypersecretion. Asthma symptoms include re-
receptor for asthma current episodes of chest tightness, wheez-
HapMap: an ing and breathlessness (1). The prevalence of
international project asthma in western societies has increased sub-
that identified and
stantially in recent decades (2), following sim-
catalogued genetic
variants across the ilar trends observed for other allergic and au-
human genome toimmune disorders (3). The initiation and
progression of asthma are complex and in-
volve the interplay of numerous resident and
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
recruited inflammatory cells (4). The partic-
ipation of many cell types and their secreted
by Fordham University on 01/10/13. For personal use only.
molecules constitutes a dynamic network that
constantly shapes the disease over time at
both the cellular and the organismal levels.
This affects the symptoms of asthma, which
change throughout life, making genetic and
nongenetic risk factors difficult to find (5).
Early genetic epidemiology studies have
suggested that asthma is in part attributable
to genetic factors. Findings include (a) a four-
to fivefold increase in asthma prevalence in
first-order relatives of an affected individ-
ual, (b) greater concordance of the disease
in monozygotic twin pairs compared to dizy-
gotic twins, and (c) heritability estimates in
the range of 40%–60% (6). Many research
efforts have sought genetic variants that pre-
dispose to asthma, and after several years of
intense investigation, several genes have been
identified (7).
We present a global view of genes asso-
ciated with asthma and asthma-related phe-
notypes. We then focus on two recently dis-
covered asthma susceptibility genes, namely,
the vitamin D receptor (VDR) and the G
protein–coupled receptor for asthma (GPRA)
genes. We address the difficulty of identifying
asthma susceptibility genes by highlighting
the inherent complexity of the disease as well
as some methodological issues. Finally, new
methods rendered possible by the comple-
tion of the International HapMap Project are
172 Bossé · Hudson
discussed, which promise to make the search
for asthma genes more efficient and more
comprehensive.
GENES ASSOCIATED WITH
ASTHMA
Figure 1 provides an overview of genes as-
sociated with asthma or asthma-related phe-
notypes (References 8, 9, and 67 contain thor-
ough literature reviews). Genes were included
in the figure if at least one published study
reported a positive association. A total of
120 genes are illustrated and are distributed
by functional class and subcellular localiza-
tion. Each gene is represented only once even
though several would fit in more than one
category. We attempted to categorize each
gene according to what we believe is its major
role in the pathogenesis of asthma. It should
be noted that only published findings are in-
cluded, and careful examination in the future
may reveal evidence against association for
several genes.
Most of the genes investigated so far were
identified by a candidate gene strategy. In
this approach, genes are selected based on
their known functions. As a result of current
concepts of asthma pathogenesis, geneticists
have studied genes involved in inflammation,
immunoregulation, bronchoconstriction, air-
way remodeling, and mucus secretion. In fact,
more than half of the genes investigated are
involved in inflammation and immunoregu-
lation (Figure 1). Genes involved in innate
immunity and the metabolism of lipid me-
diators were also examined, as well as genes
that modify the oxidation of pollutants and
other environmental exposures, such as glu-
tathione S transferase. It is also apparent from
Figure 1 that most of the genes associated
with asthma to date are located in either the
plasma membrane or secreted inflammatory
molecules. Interestingly, new disease-causing
mechanisms are also emerging from genetic
studies. An elegant example was recently pro-
vided by Palmer et al. (10). They showed that
ANRV299-ME58-12 ARI 28 December 2006 17:36
DNA variants in the filaggrin (FLG) gene
disrupted the skin barrier, allowing allergen
sensitization and subsequently promoting the
development of asthma (11). Unanticipated
genes acting far from the lung may thus be
involved in disease predisposition.
A small set of genes was also studied us-
ing positional cloning approaches, which are
based on cotransmission of disease pheno-
types in family members and marker alleles
that span the human genome (illustrated in
green in Figure 1). In this approach, genome-
wide scans are first performed to identify
chromosomal regions within which one or
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
more disease-predisposing genes lie. Genes
within such regions become positional candi-
dates and are next examined with a denser col-
by Fordham University on 01/10/13. For personal use only.
lection of genetic variants. The advantage of
this approach is that it can be applied without
prior knowledge of the biological basis of the
disease or the phenotype under study. The fol-
lowing section discusses examples of recently
discovered asthma susceptibility genes, one
identified by a candidate gene approach and
the other by positional cloning.
Vitamin D Receptor and Asthma
The vitamin D receptor (VDR) is a ligand-
regulated transcription factor that mediates
the effect of the biologically active form of
vitamin D (1,25-dihydroxyvitamin D3). This
ligand-receptor complex regulates a large
number of genes (12) that in turn modulate
various physiological processes, including im-
portant functions of the immune system (13,
14). VDR’s role in the pathogenesis or de-
velopment of asthma is not entirely known,
but its participation is supported by numerous
functional studies. Indeed, VDR is expressed
in immunologically relevant cells (including
dendritic cells, monocytes, and activated B
and T lymphocytes), and treating these cells
with vitamin D has important consequences
for their development and functions (13, 15,
16). Furthermore, VDR-null mice are pro-
tected against experimentally induced asthma
(17). More specifically, these mice fail to de-
velop airway inflammation, eosinophilia, or
airway hyperresponsiveness, despite high im-
munoglobulin E (IgE) concentrations and el-
Positional cloning:
evated Th2 cytokines. a gene-mapping
In humans, a number of association studies process that localizes
have investigated VDR and asthma (Table 1). mutations or
Two groups coreported associations between susceptibility alleles
by studying genetic
VDR genetic variants and asthma-related
markers in high-risk
traits (18, 19). In a French-Canadian founder individuals or
population (18), six single-nucleotide poly- families
morphisms (SNPs) located between intron 2 Genome-wide
and exon 9, spanning 28 kb of the VDR gene, scan: a
were associated with asthma. By sequenc- whole-genome
ing the promoter, exons, and surrounding association (or
linkage) study of
regions, Poon et al. excluded novel mis-
random genetic
sense mutations that could explain the ob- markers to identify
served association. In a second report (19),
chromosomal
significant associations with VDR variants and regions harboring
asthma were found in two independent co- disease-predisposing
genes
horts. Seven candidate genes mapping to the
centromeric region of chromosome 12 were IgE:
immunoglobulin E
screened in the Childhood Asthma Manage-
ment Program (CAMP) study. Only one SNP CAMP: Childhood
Asthma Management
located in the VDR gene demonstrated ev-
Program
idence of association with asthma. To ex-
SNP
clude the possibility that neighboring genes
(single-nucleotide
cause the association, the authors genotyped polymorphism): a
29 SNPs in a 330-kb region surrounding the DNA sequence
VDR gene. None of these SNPs were asso- variant occurring at a
ciated with asthma, leaving VDR as the im- single nucleotide in
the genome; the
plicated gene. Their finding was then tested
most common form
in the Nurses’ Health Study (NHS). In this of genetic
cohort, 4 of the 6 genotyped SNPs within polymorphism
the VDR gene were associated with asthma. NHS: Nurses’
However, a curious observation was that the Health Study
direction of the association was not the same
as in the CAMP study. Indeed, what appeared
to be the protective alleles in the NHS (and
in the French-Canadian population) are the
risk-conferring alleles in the CAMP study.
Taken together, these data suggest that the
VDR locus harbors variants that contribute to
asthma, but the relationship seems complex
and the disease-causing variants are still not
identified.
An earlier investigation had not observed
association with asthma when testing a single
genetic marker at the VDR locus (20). The
www.annualreviews.org • Genetics of Asthma 173
ANRV299-ME58-12 ARI 28 December 2006 17:36

Table 1 Association studies for the vitamin D receptor (VDR) and the G protein–coupled receptor for
asthma (GPRA) genes with asthma-related phenotypesa
Associated
Gene Reference Population n # SNPs Phenotype SNPs Haplotypesb
VDR 18 French-Canadian 223 independent 12 Asthma 6 5/10
families, 1139 Atopy 4 3/10
individuals IgE levels 3
19 CAMP study 582 nuclear families, 7 Asthma 1 2/3
2486 individuals FEV1 /FVC ratio 1
BD 2
FEV1 none
PC20 none
IgE levels none
Eosinophil counts
Nurses’ Health Study 517 cases and 519 6 Asthma 4 2/3
controls
20 German 172 families, 743 1 Asthma none
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

individuals IgE levels none

Eosinophil counts none
Slope none
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22 German 224 pedigrees, 951 13 Asthma 3 1

individuals Slope 3
RAST 2
IgE levels none

GPRA 24 Finnish Kainuu 131 trios 51 IgE levels 43 2/7 (H4, H5)
Finnish North Karelian 31 trios 29 IgE levels Not 1/7 (H7)
mentioned
French Canadian 193 trios 22 Asthma 20 1/7 (H2)
28 Korean 439 cases, 374 controls 1 Asthma none
#1 and 311 controls Atopy none
#2 IgE levels none
PC20 none
30 Western European 3113 children + 800 7 Asthma 1 none
PARSIFAL study and children Sensitization 2 3/7 (H1, H5, H6)
Swedish birth cohort Allergic-asthma 2 2/7 (H1, H5)
study (BAMSE) Allergic- none 1/7 (H3)
rhinoconjunctivitis
31 German 1872 children 7 Asthma 3 1/7
BHR none none
Asthma + BHR 2 1/7
IgE levels 1 none
33 Northern European 188 cases and 221 7 Atopic dermatitis none none
descent controls IgE levels none none
32 Chinese Stage I: 451 cases and 7 PC20 2 none
232 controls
Stage II: 264 cases and 1 PC20 none
241 controls
Combine stage I and 1 PC20 1
stage II FEV1 none
FVC 1
FEV1 /FVC none
IgE levels none
Eosinophil count none
Atopy none

a
Abbreviations: BD, bronchodilator response [(postbronchodilator FEV1 – prebronchodilator FEV1 )/prebronchodilator FEV1 ]; BHR, bronchial
hyperresponsiveness; CAMP, Childhood Asthma Management Program; PARSIFAL, Prevention of Allergy Risk factors for Sensitization In
children related to Farming and Anthroposophic Lifestyle; RAST, radioallergosorbent test; Slope, slope of the dose-response curve of the
methacholine challenge.
b
Haplotypes showing significant associations are summarized by the ratio between the number of significant haplotypes and the number of
haplotypes tested. The names of the significant haplotypes, as labeled by the authors, are in parentheses.

174 Bossé · Hudson

ANRV299-ME58-12 ARI 28 December 2006 17:36

only protein-modifying SNP (the Fok I re- G Protein-Coupled Receptor

striction site) of VDR was genotyped in that for Asthma
study. This polymorphism changes the trans-
Recently, Laitinen et al. (24) identified GPRA PC20 : provocation
lation initiation codon, and its putative func- concentration of
(also called GPR154) as a susceptibility gene
tionality makes it attractive. However, geno- methacholine
for asthma. Their search on chromosome 7p
typing only Fok I was insufficient to capture all inducing a 20% fall
was initiated by a genome-wide linkage scan
genetic information in the VDR region (21). A in forced expiratory
that showed evidence of linkage between ge- volume
subsequent study, conducted in an expanded
netic markers located within this region and
sample of the same population, studied 13 LD (linkage
asthma-related traits (25, 26). Using a hier- disequilibrium):
SNPs in the VDR with asthma, bronchial
archical genotyping design in three different nonrandom
hyperresponsiveness, and serum IgE levels association of alleles
population samples, they converged toward
(22). Although no VDR variants were over- at two or more loci
a 133-kb risk-conferring region containing
or undertransmitted to children with asthma, RAST:
GPRA, which belongs to the G protein-
three SNPs showed preferential transmis- radioallergosorbent
coupled receptor family. The structure of the
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

sion to unaffected children, raising the pos- test

gene allows varying protein isoforms owing to
sibility of a protective effect. Positive asso- Allelic imbalance:
alternative splicing. The two main transcripts,
ciations with unaffected children were also unequal expression
by Fordham University on 01/10/13. For personal use only.

labeled A and B, have alternative 3 exons that

observed with bronchial hyperresponsiveness of both transcripts of
generate proteins of 371 and 377 amino acids, a gene in a
and the sum score of all specific IgE serum
respectively. Immunohistochemical staining heterozygous sample
levels measured using the radioallergosor-
of bronchial, gut, and skin sections has shown Haplotype: a
bent test (RAST). This example illustrates
that the A isoform is predominantly detected combination of
the importance of genotyping a sufficient alleles at different
in smooth muscle cells, whereas the B iso-
number of genetic variants in a gene region markers along the
form is predominantly expressed in epithe-
before claiming the presence or absence of same chromosome
lial cells. A distinctive pattern of expression
association. or haploid DNA
was observed by comparing bronchial biop- molecule
The mechanism by which genetic vari-
sies of asthmatic patients and controls. The B
ants in VDR are associated with asthma is
isoform is highly expressed in airway smooth
still under investigation. However, recent
muscle cells of asthmatic patients but not ex-
findings have demonstrated that VDR dis-
pressed in controls. In addition, the B isoform
plays differential allelic expression (23). Us-
is expressed in epithelial cells of both asth-
ing lymphoblastoid cell lines and sequence-
matics and controls, but the staining is much
based allelic imbalance, it was demonstrated
stronger in asthmatics. The same authors
that cis-acting regulatory variants affected the
tested the regulation of the mouse ortholog
expression of VDR. Combining this finding
GPRA mRNA in a model of ovalbumin-
with the association study results (18) reveals
induced lung inflammation. They found that
that the highly expressed haplotype is over-
GPRA mRNA in the lung is significantly up-
transmitted to asthmatic individuals (in the
regulated in sensitized mice compared with
French-Canadian population and the NHS)
controls. Taken together, these data support
whereas the less expressed haplotype is un-
the involvement of GPRA in the pathogenesis
dertransmitted (Figure 2). It is thus tempt-
of asthma. However, the biochemical mecha-
ing to speculate that differential levels of
nisms that link GPRA to asthma are still poorly
VDR transcript caused by regulatory vari-
understood. Recent findings pinpoint the
ants alter the global transcriptional activity
joint actions of aberrant isoform expression
of the nuclear receptor and by this mecha-
in relevant tissues and the specific inhibitory
nism modulate downstream genes involved in
effect of isoform A on cell growth (27).
inflammation, immunoregulation, and airway
Since the earlier report by Laitinen et al.
remodeling.
(24), many research groups have attempted to

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ANRV299-ME58-12
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ARI 28 December 2006 17:36
replicate the finding (Table 1). An early study
was conducted in 439 patients with asthma
and in 374 control subjects of Korean ori-
gin (28). Another 311 normal subjects derived
from a type 2 diabetes mellitus cohort served
as a second control group. No association was
observed for asthma, atopy, total serum IgE
levels, and log-transformed PC20 (provoca-
tion concentration of methacholine inducing
a 20% fall in forced expiratory volume). Many
reasons can explain this lack of association
(29), but genotyping only one SNP in the gene
is a likely explanation. The SNP genotyped in
the Korean population was initially proposed
by Laitinen et al. (24) as a single tagging SNP
for risk and nonrisk haplotypes in the Finnish
and Canadian populations. Because the func-
tional causality of this SNP is not demon-
strated, it is likely to represent a marker in
linkage disequilibrium (LD) with the func-
tional variant. This is called an indirect asso-
ciation and arises by the existent correlations
among neighbor genetic variants. In practice,
the functional allele that will be in LD with an
individual tagging SNP or haplotype can dif-
fer between populations, which may explain
the lack of association in the Korean popula-
tion. This was the case in two large European
population samples where the particular tag-
ging SNP taken individually showed no as-
sociation with asthma or other intermediate
phenotypes, whereas other SNPs and haplo-
types were significantly associated (30, 31).
These two reports together involved close to
6000 children and strongly supported GPRA
as a susceptibility gene for asthma. However, it
is noticeable that the pattern of SNPs or hap-
lotypes association differs between the stud-
ies. This suggests that the genetic mechanism
associated with aberrant function of this gene
is likely to be complex, and in order to capture
this underlying complexity it is important to
investigate multiple polymorphisms. A third
study also confirmed a role of GPRA in genetic
predisposition to asthma (32). This two-stage
study was conducted in a Chinese popula-
tion. In stage I, no haplotypes were associated
with airway hyperresponsiveness, but two sin-
176 Bossé · Hudson
gle SNPs reached significance. One of them is
nonsynonymous (rs324981, substitution of Ile
with Asn at the 107th codon) and was followed
up in stage II. At this stage, a similar trend was
observed, although it was not statistically sig-
nificant. However, in the pooled analysis that
included subjects of stages I and II, association
with airway hyperresponsiveness was signifi-
cant. Whether this nonsynonymous SNP has
functional consequence remains to be deter-
mined. Finally, a study performed in 188 adult
patients with atopic dermatitis and 221 age-
and sex-matched controls failed to show as-
sociation between GPRA and atopic dermati-
tis and related phenotypes (33). No signifi-
cant association was observed for IgE levels
or atopic dermatitis for any of the 7 haplotype
tagging SNPs proposed by Laitinen et al. (24).
In summary, GPRA and asthma appear to be
associated in all large replication studies using
several SNPs that tag the locus, but the causal
variants and their mechanisms remain to be
elucidated.
COMPLEXITY OF FINDING
ASTHMA SUSCEPTIBILITY
GENES
Experience with other candidate genes for
asthma (and other complex diseases) has
taught us not to be too enthusiastic about
early positive findings. In fact, as the num-
ber of association studies increases, it becomes
clear that the initial report overestimates the
importance of the gene (34). The story of
ADAM33, the first asthma gene identified by
positional cloning (35), is a perfect example
of a strong initial finding and inconsistencies
in subsequent studies (36). Reassuringly, a re-
cent meta-analysis confirmed the association
between ADAM33 and asthma (37). How-
ever, the later study also demonstrated the
importance of large sample sizes (1299 cases
and 1665 controls as well as 4561 individu-
als in family studies) for testing asthma can-
didate genes. Whether other positional can-
didate genes for asthma, namely PHF11 (38),
DPP10 (39), CYFIP2 (40), and HLA-G (41)
ANRV299-ME58-12 ARI 28 December 2006 17:36
(illustrated in green in Figure 1), will have
such encouraging follow-up still needs to be
seen. What is more certain, with the dramatic
increase in the use of association studies (42),
is that many research groups will try to repli-
cate these findings.
The β2 -adrenergic receptor (ADRB2)
gene can serve to illustrate what happens to
asthma susceptibility genes if standards for
conducting and reporting association stud-
ies are not established. Indeed, more than 30
studies have examined whether genetic vari-
ants, mostly Arg16Gly and Gln27Glu, in the
ADRB2 gene alter the susceptibility or the
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
severity of asthma and asthma-related pheno-
types (43). The overwhelming body of con-
flicting results is difficult to summarize. Re-
by Fordham University on 01/10/13. For personal use only.
cent meta-analyses have tried to synthesize
this conflicting literature (44, 45). The first
of these reports found that the Gly16 allele
does not contribute to asthma susceptibility
Genetic association studies
Genetic
variants
Complexity of asthma
Methodological issues
-Phenotype definition
-Lack of power
-Genotyping errors
-Population stratification
-Multiple testing without
appropriate corrections
-Publication bias
-Allele approach instead of a
gene-based approach
-Incomplete genetic
information
Asthma or
asthma-related
phenotypes
Figure 3
Genetic association studies attempt to establish a linear relationship between genetic variants and asthma
or asthma-related phenotypes (left panel ). However, the genotype-phenotype relationship is not
straightforward to establish and is affected by two broad categories of factors, namely, the inherent
complexity of asthma (right panel ) and methodological issues (see text).
or bronchial hyperresponsiveness per se but is
associated with nocturnal asthma and asthma
severity (45). The second meta-analysis found
ADRB2 :
no effect of this allele on asthma susceptibility β2-adrenergic
in adults but jarringly found a recessive pro- receptor
tective effect in children (44). Therefore, even
in the context of meta-analysis, the effect of
this variant is unclear. There are unavoidable
and avoidable reasons for such discrepancies
in genetic association studies. Finding a ge-
netic association between genetic variants and
asthma or asthma-related phenotypes is not
straightforward, as it is influenced by the in-
herent complexity of the disease and method-
ological issues (Figure 3).
Inherent Complexity of Asthma
The right-hand panel of Figure 3 illustrates
the complexity of asthma itself. Asthma is
influenced by an unknown number of genes,
Inherent complexity of asthma
Time
Interacting and dynamic network affecting the
development and progression of asthma at any given
time throughout an individual’s life
Genetic Environmental
component component
Unknown number -Allergen exposures
of alleles
-Lifestyle
Unknown number
of genes -Medications
-Other environmental
Genetic background factors
(epistasis)
Influence many cell types affecting immune and
inflammatory responses, which can sometimes be
compensated by redundant mechanisms
Affected subclinical phenotypes and risk factors:
bronchoconstriction, mucus secretion,
hyperreactivity, IgE levels, airway structure
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ANRV299-ME58-12
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ARI 28 December 2006 17:36
with each gene effect depending on an un-
known number of alleles or groups of alle-
les (haplotypes). In addition, different genes
may affect different populations having dif-
ferent genetic backgrounds or environmen-
tal exposures. In some circumstances, a gene
with a small individual effect may make a
substantial contribution to the manifestation
of asthma by interacting with a second gene
(epistasis) or an environmental factor (gene-
environment interaction). Gene-gene and
gene-environment interactions are currently
difficult to test but are likely to be important
in the context of asthma and other complex
traits (46, 47). The joint actions of multiple
genes and environmental factors are mediated
through primary biochemical (mRNA ex-
pression and stability, splicing/isoforms, etc.)
and cellular processes that affect immune
and inflammatory responses. Many cell types
and their secreted signaling molecules, often
acting redundantly, are implicated in these
responses and subsequently affect the pheno-
typic measures of disease states, such as bron-
choconstriction, mucus secretion, reactivity
of the airway, IgE levels, and airway structure.
An extra layer of complexity emerges from the
fact that all the above factors, both genetic
and nongenetic, exist in a dynamic and epi-
genetic network. This complex network acts
at the biochemical, cellular, and organismal
levels and involves feedback information that
constantly shapes the network and many pro-
cesses that are relevant to asthma pathology.
Finally, this network operates throughout the
lifetime of an individual, making the asthma
status changeable with age. Thus, the corre-
lations between genetic variants and asthma
are also changeable with time and should not
be analyzed and interpreted as constant, as
genetic association studies treat them.
Methodological Issues
The left-hand panel of Figure 3 summa-
rizes the methodological issues that compli-
cate data interpretation still further. Pheno-
type definitions vary among different genetic
178 Bossé · Hudson
studies of asthma (48). Indeed, the criteria
to define asthma (physician’s diagnosis, pa-
tient self-report, combined or not with arbi-
trary thresholds from objective measures such
as methacholine challenges) differ widely be-
tween studies, making comparisons challeng-
ing. In addition, the phenotype can be de-
fined using affection status based on a discrete
binary scale (affected or unaffected) or by
studying quantitative disease-related pheno-
types, such as bronchial hyperresponsiveness
and serum IgE levels. Despite their close rela-
tionships, these phenotypes do not match each
other exactly (49). On top of that, the genetic
and etiological heterogeneity of asthma im-
plies that similar phenotypes can result from
different factors (phenocopies). This reality
unavoidably creates a lot of inconsistencies in
the results. In addition, asthma is a moving tar-
get in that a large proportion of children with
asthma outgrow their symptoms over time,
whereas some individuals develop asthma only
in adulthood (50). Thus, the affection sta-
tus of asthma can change throughout the
life of an individual, causing unavoidable
misclassification.
The validated genetic factors involved in
asthma appear to have rather modest effect
sizes. “Asthma mutations” with large individ-
ual effects are likely to be rare; the genetic
component of the disease is more likely to be
polygenic (many genetic variants, each with
a small effect). Finding such variants requires
large sample sizes, which are not used in most
reported studies. Indeed, it is known that mul-
tiple association studies have generated con-
flicting findings because of insufficient power
(51).
Discrepancies between association studies
can also result from poor genotyping quality
or population stratification. Genotyping er-
ror is an underappreciated problem. A sum-
mary of genetic association studies for various
traits performed in the year 2000 indicated
that 12% of studied SNPs showed deviation
from Hardy-Weinberg equilibrium, suggest-
ing genotyping error (52). More disturbing
is the fact that the proportion of SNPs that
ANRV299-ME58-12 ARI 28 December 2006 17:36
deviated from Hardy-Weinberg equilibrium
was higher among SNPs showing positive as-
sociation than among those showing nega-
tive association. This example demonstrates
the serious consequence of poor-quality geno-
types and the importance of good genotyp-
ing practices. Population stratification occurs
when case and control subjects have unin-
tentionally been drawn from different ethnic
groups (51). Any trait that has a higher fre-
quency in a particular ethnic group will have
a positive association with any genetic markers
having higher allele frequencies in that same
ethnic group. Two solutions have been pro-
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
posed to prevent these false positive associa-
tions. First, by typing several dozen random
markers, one can empirically detect and cor-
by Fordham University on 01/10/13. For personal use only.
rect for stratification (53). Second, one can use
family-based study design and the transmis-
sion disequilibrium test, which are immune
to false positives caused by ethnic admixture
(54).
Lack of reproducibility of genetic associa-
tions can also be attributed to analytical meth-
ods and interpretation of the data. Nowa-
days, many research groups test multiple
polymorphisms, multiple genes, and multi-
ple phenotypes. In addition, haplotypes, gene-
gene testing, and gene-environment testing
are also performed with the hope of find-
ing the right genetic model. Although there
are obvious benefits, there is also a cost
when performing numerous additional statis-
tical tests, as significance thresholds need to be
adjusted.
Interpretation problems also arise when
results from the literature are summarized.
There is a clear publication bias toward posi-
tive findings that is not unique to gene associ-
ation studies (55). Researchers are less eager
to publish negative results, and this feeling
is amplified by the knowledge that journals
and editors are unreceptive to such data (56).
The Genetic Association Database (57) is an
interesting solution to cope with this prob-
lem, but investigators need to be more active
in submitting their negative results.
What should be the basic genetic com-
ponent to be considered for association with
complex diseases such as asthma? New per-
Tag SNP:
spectives are emerging in the literature (58). single-nucleotide
Historically, the allele, genotyped at a single polymorphism that is
variant, was the basic unit of analysis. Nowa- correlated with a
days, with the increasing availability of SNPs neighbor variant and
serves as a proxy for
and the use of the LD-based approach of as-
a neighboring (not
sociation, the focus has shifted toward haplo- genotyped) variant
types. Neale & Sham (58) argue elegantly that
Transmission
performing replication studies at the level of disequilibrium test:
SNPs or haplotypes is problematic, and sug- a joint test of linkage
gest moving toward a gene-based approach. and association.
In this approach, all the variants in the gene Allele transmission is
tracked from
are considered jointly, and the gene itself is the
heterozygous parents
basic unit of analysis. After all, the gene is the to single probands;
true unit of interest, particularly when there
the alleles that are
are no well-characterized functional polymor- not transmitted are
phisms. Genotyping only the specific SNP used as controls
showing association in the original study is Admixture: the
problematic because the frequency of these mixture of two or
more ancestral
SNPs and the strength of LD between them
populations within a
are likely to be disparate across diverse hu- single group
man populations. In contrast, the position, se-
quence, and function of genes are highly con-
sistent across populations.
The gene-based approach is also more
likely to capture complex patterns of associ-
ation. The VDR and GPRA genes presented
above are good example of genes that show
complex patterns of association: (a) In both
cases, no single SNP or haplotype was as-
sociated across all populations tested; (b) the
risk SNPs or haplotypes were not the same
in different populations; and (c) associated
SNPs do not appear to act at the amino
acid level. This complex pattern of associa-
tion is not unique to VDR and GPRA and
applies to many of the genes associated with
asthma (59, 60). Research conducted in the
past few years has revealed novel mechanisms
by which gene function may be disturbed (61).
The emerging picture suggests that complex
traits are likely to possess complex patterns
of gene association and that comprehensive
studies will be essential to capture this genetic
complexity.
www.annualreviews.org • Genetics of Asthma 179
ANRV299-ME58-12 ARI 28 December 2006 17:36

NEW TOOLS FOR ASSOCIATION method can reduce the genotyping burden on
STUDIES the order of 60%–80%.
Contemporary genetic association stud-
A truly comprehensive genetic association
ies need to take advantage of these new
study must consider all putative causal alleles
approaches. These resources, used properly,
in the gene of interest or in the entire human
can substantially increase the information
genome if resources are available. Until re-
obtained from association studies. As men-
cently, this was practically impossible. With
tioned, a portion of the conflict among asso-
the completion of the International HapMap
ciation results in the literature is attributable
Project (62), it is now possible to target a large
to incomplete genetic information at studied
proportion of the genetic variation across the
genes. These new tools have the potential to
genome, either directly or indirectly (via LD).
resolve this methodological issue by allowing
HapMap is a freely available reference panel
researchers to appropriately select their SNPs
of genotype data from different worldwide
prior to genotyping. In addition, it is tempt-
populations (http://www.hapmap.org). This
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

ing to speculate that complex patterns of as-

resource can be used to guide the design of
sociations, suspected in complex diseases, are
disease association studies and prioritization
more likely to be detected when all the ge-
by Fordham University on 01/10/13. For personal use only.

of SNP genotyping assays. With this dataset,

it is possible to study genetic variants for any
locus of interest. The HapMap dataset has
clearly demonstrated the existence of correla-
tions between nearby variants. By taking ad-
vantage of these correlations, one can select
informative SNPs (tagging SNPs) that pro-
vide information about neighboring variants
that are not genotyped. Only a small fraction
of SNPs need to be genotyped to capture the
full information in a specific region. If a causal
variant is not genotyped, its effect can be indi-
rectly tested with the correlated tag SNP that
has been genotyped.
Many tag selection methods have been de-
veloped. Each of them exploits the knowledge
of the redundancy among SNPs to reduce the
cost of genotyping without losing informa-
tion. Most of these methods use pairwise LD
to select tagging SNPs in a single-marker ap-
proach. In this situation, untyped SNPs are
represented by one tag SNP at a specific r2
threshold defined by the user (this thresh-
old is often arbitrarily set to 0.8). Tag SNPs
can also be combined to form haplotypes that
are even better correlated with putative causal
variants. Recently, it was shown that such
multimarker approaches can increase tagging
efficiency without compromising power (63).
In fact, compared with genotyping the com-
plete set of SNPs, this aggressive tagging
netic information contained in a specific gene
is captured.
The single-gene approach described above
can also be extended to the entire genome.
Genome-wide association scans are emerging
as powerful tools to identify genes involved
in complex diseases. On the basis of phase
I HapMap data, it was shown that approxi-
mately 250,000 to 500,000 SNPs are required
to capture all common SNPs in human pop-
ulations (62). Although these numbers appear
impressive, current technologies can evaluate
more than 500,000 SNPs simultaneously (64,
65). By selecting SNPs properly, we can now
interrogate the entire genome in one assay.
These promising tools will certainly have a
major impact on our understanding of the ge-
netic basic of complex diseases such as asthma.
CONCLUSION
We addressed in this review the complexity of
finding asthma susceptibility genes. A large
part of the difficulty is clearly attributable
to the inherent complexity of the disease.
However, a substantial part is attributable to
methodological issues. By meticulously defin-
ing asthma phenotypes and designing stud-
ies with sufficient statistical power, investi-
gators can substantially increase their chance
of success. Avoiding spurious association and

180 Bossé · Hudson

ANRV299-ME58-12 ARI 28 December 2006 17:36

interpreting the data properly are key to less-
ening the vicious cycle of irreproducibility.
Moreover, researchers should take advantage
of the new tools rendered possible by the com-
pletion of the International HapMap Project.
These tools can substantially raise the qual-
ity of association studies by guiding SNP se-
lection so as to capture most of the genetic
variation at loci of interest.
It has become clear that many loci con-
tribute to the expression of asthma. How this
genetic knowledge will be used for the molec-
ular classification of the disease or its pre-
vention and treatment are key issues to be
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
developed in the next decades. So far, genetic
research in asthma has produced new leads for
therapeutic intervention. For example, both
VDR and GPRA, described in this review, are
targets for small molecules (27, 66). Indeed,
isoform-specific activation of GPRA-A is now
possible with a peptide called Neuropeptide
S, which is known to inhibit cell growth
in vitro (27). Likewise, more refined thera-
peutic agents having cell-context-dependent
activity are being evaluated for VDR (66).
The advances in asthma genetic research are
likely to become clinically apparent in the near
future.

ACKNOWLEDGMENTS
by Fordham University on 01/10/13. For personal use only.

Y. Bossé is the recipient of a fellowship award from the Canadian Institutes of Health and
Research. T.J. Hudson is the recipient of a Clinician-Scientist Award in Translational Research
by the Burroughs Wellcome Fund and an Investigator Award from the Canadian Institutes of
Health Research. Y. Bossé and T.J. Hudson are members of the Allergy, Genes and Environment
Network (AllerGen).

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184 Bossé · Hudson

 HI-RES-ME58-12-Bosse.qxd 12/8/06 08:11 PM Page C-1

G protein-coupled receptor
Transcription regulator SCGB1A1
(CC10/CC16)
Transmembrane receptor IL1RN
IL15 SCGB3A2 INFG
(IL1RA)
IL12B (UGRP1)
Nuclear receptor
IL5 IL18
Growth factor IL13 VCAM1
IL4 IL10
Phosphatase IFNGR1 HAVCR1
SELP
IL1B IL3
(TIM1)
IL8RA ITGB3
Transporter TNF IL1A IFNGR2
IL5RA IL4R HAVCR2
Ion channel LTA (TIM3)
CSF2 HLA-G
LTα ICOS
(GM-CSF) IL13RA1
Peptidase IL12RB1 ACP1 CTLA4 MS4A2
Cytokine CCL2 IL8 IL1RL1 (FCER1B)
IKBKAP
CCL5 CYFIP2 HLA-DPB1
Enzyme (IKAP)
(RANTES) TBX21 HLA-DQB1
CCL11 (T-bet)
Other CCR3
(eotaxin) STAT4 HLA-DQA1
STAT3 IRF1 AICDA
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

CCL24
CXCR3 VDR HLA-DRB1
CCL26 CCR5 IRF2
STAT6 TRA@
CXCL12 GATA3 PHF11 (TCRA/D) TAP1
ESR1
by Fordham University on 01/10/13. For personal use only.

CRHR1 CARD4 TLR2 TLR4

MIF
(NOD1)
CFTR
CLCA1 FLG CARD15 TLR6 TLR9
MUC7 GSTT1 DEFB1

SPINK5
GSTM1 NAT2 Nucleus NOS1 CD14
TLR10

KLK7 GSTP1 NOS3 C3

(SCCE) DAP3 COX2 PGDS NOS2A C3AR1
CMA1
Cytoplasm
ALOX5 LTC4S
HNMT ACE C5

ADAM33 KCNS3 CHRM3

DPP10 CYSLTR2 PTGER2 EDNRA
GPR154
(GPRA)
Plasma
CYSLTR1
PTGDR
ADRB2 AGT
SERPINA3
(AACT)
TGFB1
Membrane
TBXA2R GPR44
ALOX5AP (CRTH2)
(FLAP) EDN1
TIMP1
CHIA Extracellular
PLA2G7
(PAFAH)
Space

Figure 1
Genes associated with asthma and atopy phenotypes are categorized by function and subcellular localizations. All of these genes
have been reported to be associated with asthma or asthma-related phenotypes in at least one published study. Ober &
Hoffjan’s (67) comprehensive review of the literature provides complete references. Node shapes and subcellular localizations
are taken from the Ingenuity System (http://www.ingenuity.com). Genes identified by positional cloning studies are in green.
Red nodes indicate that an FDA-approved drug acts against the gene product. Genes are labeled with official Entrez Gene sym-
bols, and common alias names are shown in parentheses for some genes.

www.annualreviews.org ● Genetics of Asthma C-1

 HI-RES-ME58-12-Bosse.qxd 12/8/06 08:11 PM Page C-2

Expression
Haplotype

Asthma

Levels
VDR
Risk
Regulation of
genes involved in
A G C A C Susceptibility
inflammation,
immunoregulation
A T G G Protective and airway
remodeling
rs1544410

rs3782905
rs2239185

rs2239179
(BsmI)
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

B
9 8 65 3 2 1c 1b 1d 1e 1f
7 4 1a
by Fordham University on 01/10/13. For personal use only.

C
46520 46540 46560 46580 46600 46620

Chromosome 12 (kbp)

Figure 2
Putative mechanism of association between vitamin D receptor (VDR) and asthma. (a) Genetic association studies have identi-
fied susceptibility (red) and protective (blue) haplotypes for asthma in the VDR gene. Representative SNPs that distinguish both
haplotypes are shown. Subsequent functional assays (23) have demonstrated that the susceptibility haplotype correlates with rela-
tively higher VDR expression than the protective haplotype. Accordingly, vitamin D target genes involved in asthma
processes may be regulated differently in individuals carrying different combinations of haplotypes. (b) The VDR gene consists
of 14 exons labeled 1a to 1f and 2 to 9. Untranslated exons are represented by grey bars; translated exons are in dark blue.
Positions of the SNPs defining the haplotypes are shown. (c) A 106-kb region showing the location of the VDR gene on chro-
mosome 12, illustrated on the same scale as (b).

C-2 Bosse Hudson ●

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Annual Review of
Medicine

Volume 58, 2007

Contents

The Drug Development Crisis: Efficiency and Safety

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Idiosyncratic Toxicity: A Convergence of Risk Factors

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William W. Stead p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p35
Schizophrenia: New Pathological Insights and Therapies
L. Fredrik Jarskog, Seiya Miyamoto, and Jeffrey A. Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Cardiac Resynchronization Treatment of Heart Failure
Ayesha Hasan and William T. Abraham p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63
New Approaches in the Therapy of Cardiomyopathy in Muscular
Dystrophy
Elizabeth M. McNally p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p75
Acute Ischemic Stroke: Overview of Recent Therapeutic
Developments
Nijasri Suwanwela and Walter J. Koroshetz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89
Use of Stents to Treat Intracranial Cerebrovascular Disease
Philip M. Meyers, H. Christian Schumacher, Kurenai Tanji,
Randall T. Higashida, and Louis R. Caplan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Kidney Disease and Cardiovascular Risk
Marcello Tonelli and Marc A. Pfeffer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 123
Cardiovascular Risks of Antiretroviral Therapies
Kristin Mondy and Pablo Tebas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 141
Airway Surface Dehydration in Cystic Fibrosis: Pathogenesis
and Therapy
Richard C. Boucher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 157

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 Contents ARI 30 November 2006 12:12

Toward a Comprehensive Set of Asthma Susceptibility Genes

Yohan Bossé and Thomas J. Hudson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Does Anti-IgE Therapy Help in Asthma? Efficacy and Controversies
Pedro C. Avila p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
Advances in the Treatment of Prostate Cancer
Mark Pomerantz and Philip Kantoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 205
Immunotoxin Treatment of Cancer
Ira Pastan, Raffit Hassan, David J. FitzGerald, and Robert J. Kreitman p p p p p p p p p p p p p p p 221
NSAIDs and Cancer Prevention: Targets Downstream of COX-2
Yong I. Cha and Raymond N. DuBois p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 239
The Multiple Endocrine Neoplasia Syndromes
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

Vipul T. Lakhani, Y. Nancy You, and Samuel A. Wells p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 253

Cancer Stem Cells: Models and Concepts
by Fordham University on 01/10/13. For personal use only.

Piero Dalerba, Robert W. Cho, and Michael F. Clarke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 267

Stem Cells and Chronic Lung Disease
Brigitte N. Gomperts and Robert M. Strieter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 285
Progress and Potential for Regenerative Medicine
Geoffrey C. Gurtner, Matthew J. Callaghan, and Michael T. Longaker p p p p p p p p p p p p p p p p p 299
The Leading Edge of Stem Cell Therapeutics
Ilyas Singec, Rahul Jandial, Andrew Crain, Guido Nikkhah, and Evan Y. Snyder p p p p p 313
New Reagents on the Horizon for Immune Tolerance
E. William St. Clair, Larry A. Turka, Andrew Saxon, Jeffrey B. Matthews,
Mohamed H. Sayegh, George S. Eisenbarth, and Jeffrey Bluestone p p p p p p p p p p p p p p p p p p p p 329
T Cell Costimulation: A Rational Target in the Therapeutic
Armamentarium for Autoimmune Diseases and Transplantation
Flavio Vincenti and Michael Luggen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 347
A Human Monoclonal Antibody Cocktail as a Novel Component of
Rabies Postexposure Prophylaxis
John de Kruif, Alexander B.H. Bakker, Wilfred E. Marissen, R. Arjen Kramer,
Mark Throsby, Charles E. Rupprecht, and Jaap Goudsmit p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Why Hasn’t Eliminating Acute Rejection Improved Graft Survival?
JogiRaju Tantravahi, Karl L. Womer, and Bruce Kaplan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
End-Stage Renal Disease Measures of Quality
Jonathan Himmelfarb and Alan S. Kliger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 387
Inflammatory Bowel Disease Genetics: Nod2
Judy H. Cho and Clara Abraham p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 401

vi Contents
 Contents ARI 14 December 2006 17:24

New Therapeutic Approaches for Multiple Sclerosis

Philip L. De Jager and David A. Hafler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417
Cytokine Therapy for Crohns Disease: Advances in Translational
Research
Theresa T. Pizarro and Fabio Cominelli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 433
Chemokine Antagonists as Therapeutics: Focus on HIV-1
Athe M.N. Tsibris and Daniel R. Kuritzkes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 445
Current Concepts in AIDS Pathogenesis: Insights from the
SIV/Macaque Model
Andrew A. Lackner and Ronald S. Veazey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 461
Macular Degeneration
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org

Edwin M. Stone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 477

Targeting VEGF-A to Treat Cancer and Age-Related Macular
by Fordham University on 01/10/13. For personal use only.

Degeneration
Napoleone Ferrara, Robert D. Mass, Claudio Campa, and Robert Kim p p p p p p p p p p p p p p p p p p 491

Indexes

Cumulative Index of Contributing Authors, Volumes 54–58 p p p p p p p p p p p p p p p p p p p p p p p p p p p 505

Cumulative Index of Chapter Titles, Volumes 54–58 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 509

Errata

An online log of corrections to Annual Review of Medicine chapters (if any, 1997 to the
present) may be found at http://med.annualreviews.org/errata.shtml

Contents vii