Professional Documents
Culture Documents
Astm Articol PDF
Astm Articol PDF
Toward a Comprehensive
Set of Asthma Susceptibility
Genes
Yohan Bossé and Thomas J. Hudson
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
171
ANRV299-ME58-12 ARI 28 December 2006 17:36
recruited inflammatory cells (4). The partic- by functional class and subcellular localiza-
ipation of many cell types and their secreted tion. Each gene is represented only once even
by Fordham University on 01/10/13. For personal use only.
molecules constitutes a dynamic network that though several would fit in more than one
constantly shapes the disease over time at category. We attempted to categorize each
both the cellular and the organismal levels. gene according to what we believe is its major
This affects the symptoms of asthma, which role in the pathogenesis of asthma. It should
change throughout life, making genetic and be noted that only published findings are in-
nongenetic risk factors difficult to find (5). cluded, and careful examination in the future
Early genetic epidemiology studies have may reveal evidence against association for
suggested that asthma is in part attributable several genes.
to genetic factors. Findings include (a) a four- Most of the genes investigated so far were
to fivefold increase in asthma prevalence in identified by a candidate gene strategy. In
first-order relatives of an affected individ- this approach, genes are selected based on
ual, (b) greater concordance of the disease their known functions. As a result of current
in monozygotic twin pairs compared to dizy- concepts of asthma pathogenesis, geneticists
gotic twins, and (c) heritability estimates in have studied genes involved in inflammation,
the range of 40%–60% (6). Many research immunoregulation, bronchoconstriction, air-
efforts have sought genetic variants that pre- way remodeling, and mucus secretion. In fact,
dispose to asthma, and after several years of more than half of the genes investigated are
intense investigation, several genes have been involved in inflammation and immunoregu-
identified (7). lation (Figure 1). Genes involved in innate
We present a global view of genes asso- immunity and the metabolism of lipid me-
ciated with asthma and asthma-related phe- diators were also examined, as well as genes
notypes. We then focus on two recently dis- that modify the oxidation of pollutants and
covered asthma susceptibility genes, namely, other environmental exposures, such as glu-
the vitamin D receptor (VDR) and the G tathione S transferase. It is also apparent from
protein–coupled receptor for asthma (GPRA) Figure 1 that most of the genes associated
genes. We address the difficulty of identifying with asthma to date are located in either the
asthma susceptibility genes by highlighting plasma membrane or secreted inflammatory
the inherent complexity of the disease as well molecules. Interestingly, new disease-causing
as some methodological issues. Finally, new mechanisms are also emerging from genetic
methods rendered possible by the comple- studies. An elegant example was recently pro-
tion of the International HapMap Project are vided by Palmer et al. (10). They showed that
DNA variants in the filaggrin (FLG) gene velop airway inflammation, eosinophilia, or
disrupted the skin barrier, allowing allergen airway hyperresponsiveness, despite high im-
sensitization and subsequently promoting the munoglobulin E (IgE) concentrations and el-
Positional cloning:
development of asthma (11). Unanticipated evated Th2 cytokines. a gene-mapping
genes acting far from the lung may thus be In humans, a number of association studies process that localizes
involved in disease predisposition. have investigated VDR and asthma (Table 1). mutations or
A small set of genes was also studied us- Two groups coreported associations between susceptibility alleles
by studying genetic
ing positional cloning approaches, which are VDR genetic variants and asthma-related
markers in high-risk
based on cotransmission of disease pheno- traits (18, 19). In a French-Canadian founder individuals or
types in family members and marker alleles population (18), six single-nucleotide poly- families
that span the human genome (illustrated in morphisms (SNPs) located between intron 2 Genome-wide
green in Figure 1). In this approach, genome- and exon 9, spanning 28 kb of the VDR gene, scan: a
wide scans are first performed to identify were associated with asthma. By sequenc- whole-genome
chromosomal regions within which one or ing the promoter, exons, and surrounding association (or
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
linkage) study of
more disease-predisposing genes lie. Genes regions, Poon et al. excluded novel mis-
random genetic
within such regions become positional candi- sense mutations that could explain the ob- markers to identify
dates and are next examined with a denser col- served association. In a second report (19),
by Fordham University on 01/10/13. For personal use only.
chromosomal
lection of genetic variants. The advantage of significant associations with VDR variants and regions harboring
this approach is that it can be applied without asthma were found in two independent co- disease-predisposing
genes
prior knowledge of the biological basis of the horts. Seven candidate genes mapping to the
disease or the phenotype under study. The fol- centromeric region of chromosome 12 were IgE:
immunoglobulin E
lowing section discusses examples of recently screened in the Childhood Asthma Manage-
discovered asthma susceptibility genes, one ment Program (CAMP) study. Only one SNP CAMP: Childhood
Asthma Management
identified by a candidate gene approach and located in the VDR gene demonstrated ev-
Program
the other by positional cloning. idence of association with asthma. To ex-
SNP
clude the possibility that neighboring genes
(single-nucleotide
cause the association, the authors genotyped polymorphism): a
Vitamin D Receptor and Asthma 29 SNPs in a 330-kb region surrounding the DNA sequence
The vitamin D receptor (VDR) is a ligand- VDR gene. None of these SNPs were asso- variant occurring at a
regulated transcription factor that mediates ciated with asthma, leaving VDR as the im- single nucleotide in
the genome; the
the effect of the biologically active form of plicated gene. Their finding was then tested
most common form
vitamin D (1,25-dihydroxyvitamin D3). This in the Nurses’ Health Study (NHS). In this of genetic
ligand-receptor complex regulates a large cohort, 4 of the 6 genotyped SNPs within polymorphism
number of genes (12) that in turn modulate the VDR gene were associated with asthma. NHS: Nurses’
various physiological processes, including im- However, a curious observation was that the Health Study
portant functions of the immune system (13, direction of the association was not the same
14). VDR’s role in the pathogenesis or de- as in the CAMP study. Indeed, what appeared
velopment of asthma is not entirely known, to be the protective alleles in the NHS (and
but its participation is supported by numerous in the French-Canadian population) are the
functional studies. Indeed, VDR is expressed risk-conferring alleles in the CAMP study.
in immunologically relevant cells (including Taken together, these data suggest that the
dendritic cells, monocytes, and activated B VDR locus harbors variants that contribute to
and T lymphocytes), and treating these cells asthma, but the relationship seems complex
with vitamin D has important consequences and the disease-causing variants are still not
for their development and functions (13, 15, identified.
16). Furthermore, VDR-null mice are pro- An earlier investigation had not observed
tected against experimentally induced asthma association with asthma when testing a single
(17). More specifically, these mice fail to de- genetic marker at the VDR locus (20). The
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
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.
replicate the finding (Table 1). An early study gle SNPs reached significance. One of them is
was conducted in 439 patients with asthma nonsynonymous (rs324981, substitution of Ile
and in 374 control subjects of Korean ori- with Asn at the 107th codon) and was followed
gin (28). Another 311 normal subjects derived up in stage II. At this stage, a similar trend was
from a type 2 diabetes mellitus cohort served observed, although it was not statistically sig-
as a second control group. No association was nificant. However, in the pooled analysis that
observed for asthma, atopy, total serum IgE included subjects of stages I and II, association
levels, and log-transformed PC20 (provoca- with airway hyperresponsiveness was signifi-
tion concentration of methacholine inducing cant. Whether this nonsynonymous SNP has
a 20% fall in forced expiratory volume). Many functional consequence remains to be deter-
reasons can explain this lack of association mined. Finally, a study performed in 188 adult
(29), but genotyping only one SNP in the gene patients with atopic dermatitis and 221 age-
is a likely explanation. The SNP genotyped in and sex-matched controls failed to show as-
the Korean population was initially proposed sociation between GPRA and atopic dermati-
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
by Laitinen et al. (24) as a single tagging SNP tis and related phenotypes (33). No signifi-
for risk and nonrisk haplotypes in the Finnish cant association was observed for IgE levels
and Canadian populations. Because the func- or atopic dermatitis for any of the 7 haplotype
by Fordham University on 01/10/13. For personal use only.
tional causality of this SNP is not demon- tagging SNPs proposed by Laitinen et al. (24).
strated, it is likely to represent a marker in In summary, GPRA and asthma appear to be
linkage disequilibrium (LD) with the func- associated in all large replication studies using
tional variant. This is called an indirect asso- several SNPs that tag the locus, but the causal
ciation and arises by the existent correlations variants and their mechanisms remain to be
among neighbor genetic variants. In practice, elucidated.
the functional allele that will be in LD with an
individual tagging SNP or haplotype can dif-
fer between populations, which may explain COMPLEXITY OF FINDING
the lack of association in the Korean popula- ASTHMA SUSCEPTIBILITY
tion. This was the case in two large European GENES
population samples where the particular tag- Experience with other candidate genes for
ging SNP taken individually showed no as- asthma (and other complex diseases) has
sociation with asthma or other intermediate taught us not to be too enthusiastic about
phenotypes, whereas other SNPs and haplo- early positive findings. In fact, as the num-
types were significantly associated (30, 31). ber of association studies increases, it becomes
These two reports together involved close to clear that the initial report overestimates the
6000 children and strongly supported GPRA importance of the gene (34). The story of
as a susceptibility gene for asthma. However, it ADAM33, the first asthma gene identified by
is noticeable that the pattern of SNPs or hap- positional cloning (35), is a perfect example
lotypes association differs between the stud- of a strong initial finding and inconsistencies
ies. This suggests that the genetic mechanism in subsequent studies (36). Reassuringly, a re-
associated with aberrant function of this gene cent meta-analysis confirmed the association
is likely to be complex, and in order to capture between ADAM33 and asthma (37). How-
this underlying complexity it is important to ever, the later study also demonstrated the
investigate multiple polymorphisms. A third importance of large sample sizes (1299 cases
study also confirmed a role of GPRA in genetic and 1665 controls as well as 4561 individu-
predisposition to asthma (32). This two-stage als in family studies) for testing asthma can-
study was conducted in a Chinese popula- didate genes. Whether other positional can-
tion. In stage I, no haplotypes were associated didate genes for asthma, namely PHF11 (38),
with airway hyperresponsiveness, but two sin- DPP10 (39), CYFIP2 (40), and HLA-G (41)
(illustrated in green in Figure 1), will have or bronchial hyperresponsiveness per se but is
such encouraging follow-up still needs to be associated with nocturnal asthma and asthma
seen. What is more certain, with the dramatic severity (45). The second meta-analysis found
ADRB2 :
increase in the use of association studies (42), no effect of this allele on asthma susceptibility β2-adrenergic
is that many research groups will try to repli- in adults but jarringly found a recessive pro- receptor
cate these findings. tective effect in children (44). Therefore, even
The β2 -adrenergic receptor (ADRB2) in the context of meta-analysis, the effect of
gene can serve to illustrate what happens to this variant is unclear. There are unavoidable
asthma susceptibility genes if standards for and avoidable reasons for such discrepancies
conducting and reporting association stud- in genetic association studies. Finding a ge-
ies are not established. Indeed, more than 30 netic association between genetic variants and
studies have examined whether genetic vari- asthma or asthma-related phenotypes is not
ants, mostly Arg16Gly and Gln27Glu, in the straightforward, as it is influenced by the in-
ADRB2 gene alter the susceptibility or the herent complexity of the disease and method-
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
Genetic Time
variants
Interacting and dynamic network affecting the
Complexity of asthma development and progression of asthma at any given
time throughout an individual’s life
Methodological issues
Genetic Environmental
-Phenotype definition component component
-Lack of power Unknown number -Allergen exposures
of alleles
-Genotyping errors -Lifestyle
-Population stratification Unknown number
of genes -Medications
-Multiple testing without
appropriate corrections -Other environmental
Genetic background factors
-Publication bias (epistasis)
-Allele approach instead of a
gene-based approach
Influence many cell types affecting immune and
-Incomplete genetic inflammatory responses, which can sometimes be
information compensated by redundant mechanisms
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).
with each gene effect depending on an un- studies of asthma (48). Indeed, the criteria
known number of alleles or groups of alle- to define asthma (physician’s diagnosis, pa-
les (haplotypes). In addition, different genes tient self-report, combined or not with arbi-
may affect different populations having dif- trary thresholds from objective measures such
ferent genetic backgrounds or environmen- as methacholine challenges) differ widely be-
tal exposures. In some circumstances, a gene tween studies, making comparisons challeng-
with a small individual effect may make a ing. In addition, the phenotype can be de-
substantial contribution to the manifestation fined using affection status based on a discrete
of asthma by interacting with a second gene binary scale (affected or unaffected) or by
(epistasis) or an environmental factor (gene- studying quantitative disease-related pheno-
environment interaction). Gene-gene and types, such as bronchial hyperresponsiveness
gene-environment interactions are currently and serum IgE levels. Despite their close rela-
difficult to test but are likely to be important tionships, these phenotypes do not match each
in the context of asthma and other complex other exactly (49). On top of that, the genetic
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
traits (46, 47). The joint actions of multiple and etiological heterogeneity of asthma im-
genes and environmental factors are mediated plies that similar phenotypes can result from
through primary biochemical (mRNA ex- different factors (phenocopies). This reality
by Fordham University on 01/10/13. For personal use only.
deviated from Hardy-Weinberg equilibrium What should be the basic genetic com-
was higher among SNPs showing positive as- ponent to be considered for association with
sociation than among those showing nega- complex diseases such as asthma? New per-
Tag SNP:
tive association. This example demonstrates spectives are emerging in the literature (58). single-nucleotide
the serious consequence of poor-quality geno- Historically, the allele, genotyped at a single polymorphism that is
types and the importance of good genotyp- variant, was the basic unit of analysis. Nowa- correlated with a
ing practices. Population stratification occurs days, with the increasing availability of SNPs neighbor variant and
serves as a proxy for
when case and control subjects have unin- and the use of the LD-based approach of as-
a neighboring (not
tentionally been drawn from different ethnic sociation, the focus has shifted toward haplo- genotyped) variant
groups (51). Any trait that has a higher fre- types. Neale & Sham (58) argue elegantly that
Transmission
quency in a particular ethnic group will have performing replication studies at the level of disequilibrium test:
a positive association with any genetic markers SNPs or haplotypes is problematic, and sug- a joint test of linkage
having higher allele frequencies in that same gest moving toward a gene-based approach. and association.
ethnic group. Two solutions have been pro- In this approach, all the variants in the gene Allele transmission is
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
tracked from
posed to prevent these false positive associa- are considered jointly, and the gene itself is the
heterozygous parents
tions. First, by typing several dozen random basic unit of analysis. After all, the gene is the to single probands;
markers, one can empirically detect and cor- true unit of interest, particularly when there
by Fordham University on 01/10/13. For personal use only.
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
interpreting the data properly are key to less- developed in the next decades. So far, genetic
ening the vicious cycle of irreproducibility. research in asthma has produced new leads for
Moreover, researchers should take advantage therapeutic intervention. For example, both
of the new tools rendered possible by the com- VDR and GPRA, described in this review, are
pletion of the International HapMap Project. targets for small molecules (27, 66). Indeed,
These tools can substantially raise the qual- isoform-specific activation of GPRA-A is now
ity of association studies by guiding SNP se- possible with a peptide called Neuropeptide
lection so as to capture most of the genetic S, which is known to inhibit cell growth
variation at loci of interest. in vitro (27). Likewise, more refined thera-
It has become clear that many loci con- peutic agents having cell-context-dependent
tribute to the expression of asthma. How this activity are being evaluated for VDR (66).
genetic knowledge will be used for the molec- The advances in asthma genetic research are
ular classification of the disease or its pre- likely to become clinically apparent in the near
vention and treatment are key issues to be future.
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
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).
LITERATURE CITED
1. National Asthma Education and Prevention Program. 2002. Expert panel report: Guide-
lines for the diagnosis and management of asthma update on selected topics—2002. J.
Aller. Clin. Immunol. 110:S141–219
2. Beasley R. 2002. The burden of asthma with specific reference to the United States. J.
Aller. Clin. Immunol. 109:S482–89
3. Bach JF. 2002. The effect of infections on susceptibility to autoimmune and allergic dis-
eases. N. Engl. J. Med. 347:911–20
4. Bousquet J, Jeffery PK, Busse WW, et al. 2000. Asthma. From bronchoconstriction to
airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 161:1720–45
5. Carroll W. 2005. Asthma genetics: pitfalls and triumphs. Paediatr. Respir. Rev. 6:68–74
6. Manian P. 1997. Genetics of asthma: a review. Chest 112:1397–408 8. Comprehensive
7. Wills-Karp M, Ewart SL. 2004. Time to draw breath: asthma-susceptibility genes are review of genetic
association studies
identified. Nat. Rev. Genet. 5:376–87 of asthma and
8. Hoffjan S, Ober C. 2002. Present status on the genetic studies of asthma. Curr. atopy, updated in
Opin. Immunol. 14:709–17 References 9 and
9. Hoffjan S, Nicolae D, Ober C. 2003. Association studies for asthma and atopic diseases: a 67.
comprehensive review of the literature. Respir. Res. 4:14
10. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. 2006. Common loss-of-
10. Successful
function variants of the epidermal barrier protein filaggrin are a major predisposing application of a
factor for atopic dermatitis. Nat. Genet. 38:441–46 genetic study that
11. Hudson TJ. 2006. Skin barrier function and allergic risk. Nat. Genet. 38:399–400 identified a gene
12. Wang TT, Tavera-Mendoza LE, Laperriere D, et al. 2005. Large-scale in silico and involved in atopic
microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol. dermatitis.
Endocrinol. 19:2685–95
13. Hayes CE, Nashold FE, Spach KM, Pedersen LB. 2003. The immunological functions of
the vitamin D endocrine system. Cell Mol. Biol. (Noisy-le-grand) 49:277–300
14. Cantorna MT, Zhu Y, Froicu M, Wittke A. 2004. Vitamin D status, 1,25-dihydroxyvitamin
D3, and the immune system. Am. J. Clin. Nutr. 80:1717S–20S
15. Shalita-Chesner M, Koren R, Mekori YA, et al. 1998. 1,25-Dihydroxyvitamin D3 enhances
degranulation of mast cells. Mol. Cell Endocrinol. 142:49–55
16. Lemire JM, Archer DC, Beck L, Spiegelberg HL. 1995. Immunosuppressive actions of
1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J. Nutr. 125:1704S–
8S
17. Wittke A, Weaver V, Mahon BD, et al. 2004. Vitamin D receptor-deficient mice fail to
develop experimental allergic asthma. J. Immunol. 173:3432–36
18. Poon AH, Laprise C, Lemire M, et al. 2004. Association of vitamin D receptor genetic
variants with susceptibility to asthma and atopy. Am. J. Respir. Crit. Care Med. 170:967–
73
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
19. Raby BA, Lazarus R, Silverman EK, et al. 2004. Association of vitamin D receptor gene
polymorphisms with childhood and adult asthma. Am. J. Respir. Crit. Care Med. 170:1057–
65
by Fordham University on 01/10/13. For personal use only.
20. Vollmert C, Illig T, Altmuller J, et al. 2004. Single nucleotide polymorphism screening and
association analysis—exclusion of integrin beta 7 and vitamin D receptor (chromosome
12q) as candidate genes for asthma. Clin. Exp. Aller. 34:1841–50
21. Nejentsev S, Godfrey L, Snook H, et al. 2004. Comparative high-resolution analysis of
linkage disequilibrium and tag single nucleotide polymorphisms between populations in
the vitamin D receptor gene. Hum. Mol. Genet. 13:1633–39
22. Wjst M. 2005. Variants in the vitamin D receptor gene and asthma. BMC Genet. 6:2
23. Pastinen T, Ge B, Gurd S, et al. 2005. Mapping common regulatory variants to human
haplotypes. Hum. Mol. Genet. 14:3963–71
24. Laitinen T, Polvi A, Rydman P, et al. 2004. Characterization of a common susceptibility
locus for asthma-related traits. Science 304:300–4
25. Laitinen T, Daly MJ, Rioux JD, et al. 2001. A susceptibility locus for asthma-related traits
on chromosome 7 revealed by genome-wide scan in a founder population. Nat. Genet.
28:87–91
26. Daniels SE, Bhattacharrya S, James A, et al. 1996. A genome-wide search for quantitative
trait loci underlying asthma. Nature 383:247–50
27. Vendelin J, Pulkkinen V, Rehn M, et al. 2005. Characterization of GPRA, a novel G
protein-coupled receptor related to asthma. Am. J. Respir. Cell Mol. Biol. 33:262–70
28. Shin HD, Park KS, Park CS. 2004. Lack of association of GPRA (G protein-coupled
receptor for asthma susceptibility) haplotypes with high serum IgE or asthma in a Korean
population. J. Aller. Clin. Immunol. 114:1226–27
29. Postma DS, Koppelman GH. 2005. Confirmation of GPRA: a putative drug target for
asthma. Am. J. Respir. Crit. Care Med. 171:1323–24
30. Melen E, Bruce S, Doekes G, et al. 2005. Haplotypes of G protein-coupled receptor 154
are associated with childhood allergy and asthma. Am. J. Respir. Crit. Care Med. 171:1089–
95
31. Kormann MS, Carr D, Klopp N, et al. 2005. G-protein-coupled receptor polymorphisms
are associated with asthma in a large German population. Am. J. Respir. Crit. Care Med.
171:1358–62
32. Feng Y, Hong X, Wang L, et al. 2006. G protein-coupled receptor 154 gene polymorphism
is associated with airway hyperresponsiveness to methacholine in a Chinese population. J.
Aller. Clin. Immunol. 117:612–17
33. Veal CD, Reynolds NJ, Meggitt SJ, et al. 2005. Absence of association between asthma and
high serum immunoglobulin E associated GPRA haplotypes and adult atopic dermatitis.
J. Invest. Dermatol. 125:399–401
34. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. 2001. Repli-
34. Extensive
cation validity of genetic association studies. Nat. Genet. 29:306–9 review highlighting
35. Van Eerdewegh P, Little RD, Dupuis J, et al. 2002. Association of the ADAM33 gene with important
asthma and bronchial hyperresponsiveness. Nature 418:426–30 methodological
36. Raby BA, Weiss ST. 2004. ADAM33: where are we now? Am. J. Respir. Cell Mol. Biol. issues related to
association studies.
31:1–2
37. Blakey J, Halapi E, Bjornsdottir US, et al. 2005. Contribution of ADAM33 polymorphisms
to the population risk of asthma. Thorax 60:274–76
38. Zhang Y, Leaves NI, Anderson GG, et al. 2003. Positional cloning of a quantitative trait
locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat.
Genet. 34:181–86
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
39. Allen M, Heinzmann A, Noguchi E, et al. 2003. Positional cloning of a novel gene influ-
encing asthma from chromosome 2q14. Nat. Genet. 35:258–63
40. Noguchi E, Yokouchi Y, Zhang J, et al. 2005. Positional identification of an asthma sus-
by Fordham University on 01/10/13. For personal use only.
ceptibility gene on human chromosome 5q33. Am. J. Respir. Crit. Care Med. 172:183–
88
41. Nicolae D, Cox NJ, Lester LA, et al. 2005. Fine mapping and positional candidate studies
identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am. J. Hum. Genet.
76:349–57
42. Casci T. 2002. Free associations. Nat. Rev. Genet. 3:904
43. Holloway JW, Yang IA. 2005. Beta2-adrenergic receptor polymorphism and asthma: true
or false? J. Aller. Clin. Immunol. 115:960–62
44. Thakkinstian A, McEvoy M, Minelli C, et al. 2005. Systematic review and meta-analysis
of the association between β2 -adrenoceptor polymorphisms and asthma: a HuGE review.
Am. J. Epidemiol. 162:201–11
45. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. 2005. Meta-analysis of the associ-
ation of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J. Aller. Clin.
Immunol. 115:963–72
46. Kabesch M. 2005. Candidate gene association studies and evidence for gene-by-gene in-
teractions. Immunol. Aller. Clin. North Am. 25:681–708
47. Ober C, Thompson EE. 2005. Rethinking genetic models of asthma: the role of environ-
mental modifiers. Curr. Opin. Immunol. 17:670–78
48. Koppelman GH, Meijer GG, Postma DS. 1999. Defining asthma in genetic studies. Clin.
Exp. Aller. 29(Suppl. 4):1–4
49. Holloway JW, Beghe B, Holgate ST. 1999. The genetic basis of atopic asthma. Clin. Exp.
Aller. 29:1023–32
50. Barbee RA, Murphy S. 1998. The natural history of asthma. J. Aller. Clin. Immunol.
102:S65–72
51. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. 2002. A comprehensive
51. Extensive
review of genetic association studies. Genet. Med. 4:45–61 review highlighting
52. Xu J, Turner A, Little J, et al. 2002. Positive results in association studies are associated important
with departure from Hardy-Weinberg equilibrium: hint for genotyping error? Hum. Genet. methodological
111:573–74 issues related to
association studies.
53. Pritchard JK, Rosenberg NA. 1999. Use of unlinked genetic markers to detect population
stratification in association studies. Am. J. Hum. Genet. 65:220–28
54. Spielman RS, McGinnis RE, Ewens WJ. 1993. Transmission test for linkage disequilib-
58. Perspective
article describing rium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J.
the gene-based Hum. Genet. 52:506–16
approach to 55. Knight J. 2003. Negative results: null and void. Nature 422:554–55
replicate 56. Lawrence PA. 2003. The politics of publication. Nature 422:259–61
association
57. Becker KG, Barnes KC, Bright TJ, Wang SA. 2004. The genetic association database. Nat.
findings.
Genet. 36:431–32
58. Neale BM, Sham PC. 2004. The future of association studies: gene-based analysis
61. Reviews and replication. Am. J. Hum. Genet. 75:353–62
complex 59. Weiss LA, Lester LA, Gern JE, et al. 2005. Variation in ITGB3 is associated with asthma
mechanisms of and sensitization to mold allergen in four populations. Am. J. Respir. Crit. Care Med. 172:67–
gene disregulation 73
leading to disease;
highlights difficulty
60. Malerba G, Pignatti PF. 2005. A review of asthma genetics: gene expression studies and
of identifying recent candidates. J. Appl. Genet. 46:93–104
Annu. Rev. Med. 2007.58:171-184. Downloaded from www.annualreviews.org
causal variants. 61. Kleinjan DA, van Heyningen V. 2005. Long-range control of gene expression:
emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76:8–32
62. Altshuler D, Brooks LD, Chakravarti A, et al. 2005. A haplotype map of the human
by Fordham University on 01/10/13. For personal use only.
62. Summarizes
HapMap results; genome. Nature 437:1299–320
demonstrates how 63. de Bakker PI, Yelensky R, Pe’er I, et al. 2005. Efficiency and power in genetic
HapMap can be association studies. Nat. Genet. 37:1217–23
used to guide 64. Syvanen AC. 2005. Toward genome-wide SNP genotyping. Nat. Genet. 37:S5–10
genetic association
65. Engle LJ, Simpson CL, Landers JE. 2006. Using high-throughput SNP technologies to
studies.
study cancer. Oncogene 25:1594–601
66. Ma Y, Khalifa B, Yee YK, et al. 2006. Identification and characterization of noncalcemic,
63. Describes an tissue-selective, nonsecosteroidal vitamin D receptor modulators. J. Clin. Invest. 116:892–
aggressive tagging 904
approach to
67. Ober C, Hoffjan S. 2006. Asthma genetics 2006: the long and winding road to gene
capture the genetic
information of a discovery. Genes Immun. 7:95–100
genomic region by
genotyping a
minimal set of
SNPs.
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.
SPINK5
GSTM1 NAT2 Nucleus NOS1 CD14
TLR10
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.
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).
Annual Review of
Medicine
Contents
v
Contents ARI 30 November 2006 12:12
vi Contents
Contents ARI 14 December 2006 17:24
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
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