|
|
Cancer Res. Author manuscript; available in PMC 2007 January 4. Published in final edited form as: doi: 10.1158/0008-5472.CAN-04-3728. | PMCID: PMC1762912 NIHMSID: NIHMS2295 |
Polymorphisms associated with asthma are inversely related to
glioblastoma multiforme Judith Schwartzbaum,1,2,3* Anders Ahlbom,3 Beatrice Malmer,4 Stefan Lönn,3 Anthony J. Brookes,5 Hani Doss,6 Waldemar Debinski,7 Roger Henriksson,4 and Maria Feychting3 1 Division of Epidemiology and Biometrics, School of Public Health, Ohio State University, Columbus, USA. 2 Comprehensive Cancer Center, Ohio State University, Columbus, Ohio USA 3 Division of Epidemiology, Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 4 Department of Radiation Sciences, Oncology, Umeå University Hospital, Umeå, Sweden 5 Department of Genetics, University of Leicester, England 6 Department of Statistics, Ohio State University, Columbus, USA. 7 Wake Forest University, School of Medicine, Brain Tumor Center of Excellence, Wake Forest, North Carolina, USA. Keywords: Asthma, polymorphisms, glioblastoma multiforme Abbreviations: GBM glioblastoma multiforme, IL interleukin, COX-2 cyclooxygenase 2, OR odds ratio, CI confidence interval, SNP single nucleotide polymorphism, CRP C-reactive protein A reduced risk of primary malignant adult brain tumors is observed among people
reporting asthma, hayfever and other allergic conditions; however, findings may be
attributable to prediagnostic effects of tumors or recall bias. To determine whether
asthma and allergic condition polymorphisms are inversely related to glioblastoma
multiforme (GBM) risk, we conducted a population-based case-control study of 111 GBM
patients and 422 controls. We identified five single nucleotide polymorphisms (SNPS) on
three genes previously associated with asthma (interleukin (IL) 4RA, IL-13, ADAM33) and
one gene associated with inflammation (COX-2). Confirming previous literature, we found
that self-reported asthma, eczema, and fever are inversely related to GBM (e.g., asthma
odds ratio (OR)=0.64, 95% confidence interval (CI), 0.33, 1.25).
In addition, IL-4RA ser478pro TC, CC and IL-4RA gln551arg AG, AA are positively
associated with GBM (OR=1.64, 95% CI=1.05, 2.55;
1.61, 95% CI 1.05, 2.47) while IL-13-1112 CT, TT is negatively associated
with GBM (0.56, 95% CI=0.33, 0.96). Each of these
polymorphism-GBM associations is in the opposite direction of a corresponding
polymorphism-asthma association, consistent with previous findings that self-reported
asthmatics and people with allergic conditions are less likely to have GBM than are
people who do not report these conditions. Because we used germline polymorphisms as
biomarkers of susceptibility to asthma and allergic conditions, our results cannot be
attributed to recall bias or effects of GBM on the immune system. However, our findings
are also consistent with associations between IL-4RA, IL-13 and GBM that are independent
of their role in allergic conditions. Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor
accounting for 23.0% of all primary brain and central nervous system tumors
and 51.9% of all gliomas. The median age at diagnosis is 65 years and the
age-adjusted incidence rate is 3.24/100,000 although it increases to 13.74/100,000 for
ages 65–74. The average five year relative survival rate from time of
diagnosis for GBM is only 3.3 % and is lower for people over age 65 years at
diagnosis (0.3%) ( 1). Although the etiology of this tumor is unknown, there is evidence for a role of
the immune system in GBM growth and development ( 2). In particular, a consistent inverse association between self-reported
allergic conditions and glioma has been recently reported in a cohort and several
case-control studies ( 3– 7). While the cohort study had rather small numbers of cases,
case-control results can be subject to preclinical effects of the tumor on the immune
system or to errors in recall among brain tumor patients who may have cognitive deficits
(depending on tumor lateralization and type of therapy ( 8)). Wiemels et al. take another approach to the question of whether allergic
disease reduces brain tumor risk by comparing serum IgE levels of cases and controls
( 9). Although they find that glioma patients
have lower serum IgE levels than do controls, the possibility that the tumor itself or
its treatment may affect serum IgE levels cannot be excluded. In general, definitive
evidence of associations between immunologic biomarkers and glioma risk must be based on
measurements taken well before the time of tumor diagnosis. To avoid the influence of
the brain tumor itself on an indicator of susceptibility to asthma or allergic
conditions, we used germline polymorphisms previously associated with asthma and other
allergic conditions as biomarkers of susceptibility. Clearly these genetic variants
cannot be influenced by the presence of a brain tumor. The rationale for using polymorphisms to test the validity of asthma and allergy
self-reports is not their superior sensitivity or specificity to self-report because
most individual polymorphisms are neither sensitive nor specific indicators of complex
diseases ( 10). Furthermore, asthma, and to a
lesser extent allergy, self-reports are relatively sensitive indicators of these
conditions ( 11, 12). Rather, the advantage of using germline polymorphisms as biomarkers of
susceptibility is that, unlike asthma self-report or possibly IgE levels, they cannot be
influenced by presence of glioblastoma multiforme (GBM) and therefore case and control
asthma and allergy measurements are subject to the same degree of error. While this
error may reduce the size of measures of association between asthma or allergic
conditions and GBM, it will not cause the measure of association to change direction, as
may happen when case and control allergic conditions are each measured with a different
degree of error ( 13). From the extensive literature on asthma and allergic condition polymorphisms, we
selected genetic variants that are consistently associated with asthma or allergic
conditions in at least two populations and whose functions relate to either glioma
development or normal brain physiology. Two of the polymorphisms that meet these
criteria are ser478pro and gln551arg on the interleukin (IL)-4 receptor alpha gene
(IL-4RA) ( 14). These IL-4RA polymorphisms are
associated with asthma and allergies in two and eleven studies respectively, each study
based on different populations ( 15). Two
additional polymorphisms consistently associated with asthma and other allergic
conditions are arg130gln ( 16) and -1112 C/T
( 17) on the IL-13 gene. Associations between
these two IL-13 polymorphisms and asthma or allergic conditions have been identified in
nine and four studies respectively ( 15). IL-4 and
IL-13 are cytokines that share immunoregulatory functions and a common IL-4RA chain on
their receptors. They both play a central role in allergy by inducing IgE synthesis and
both can inhibit inflammatory cytokines ( 18,
19). Importantly for the present research,
IL-4 and IL-13 show strong antitumor activity in mice and inhibit proliferation of
astrocytoma and low grade glioma cell lines ( 20,
21). We also looked at the T1 polymorphism of a newly identified asthma gene, ADAM33
( 22), that was found to be associated with
asthma in three different populations ( 22– 24). This gene is a
member of a family of matrix metalloproteases, extracellular proteases that participate
in matrix degradation and glioblastoma invasion ( 25). Finally, the last polymorphism that we evaluated is found on the cyclooxygenase-2
(COX-2) gene (−765GC) and is associated with post-surgical C-reactive
protein levels ( 26). (C-reactive protein is
produced in response to inflammatory cytokines during the acute phase response.)
Although IL-4 and IL-13 function as pro-inflammatory mediators in asthma, allergy and
helminth infection, these cytokines also have anti-inflammatory properties resulting, in
part, from their inhibition of both cell-mediated immune responses ( 27, 28) and COX-2
expression ( 29). In addition, our selection of
the COX-2 gene was based on our previous findings of an inverse association between
non-steroidal anti-inflammatory drug use and GBM ( 30). Glioma and meningioma cases that occurred in Sweden between September 1, 2000
and August 31, 2002 were identified in collaboration with brain tumor treatment
centers. Regional cancer registries were searched approximately every third month
for additional case identification, to make sure that no cases had been missed. This
system was effective in reducing the time between diagnosis and interview as
indicated by the fact that proxy interviews were necessary for only 9%
of glioma and 3% of meningioma cases (a low proportion of proxy
interviews when compared to other brain tumor studies ( 7) ). We restricted our study to the most common type of
adult glioma, GBM, to reduce genetic heterogeneity Controls were randomly selected within strata defined by glioma or meningioma
patients’ age, sex, and geographic region from a continuously updated
population registry. Computer-assisted interviews were conducted by research nurses.
Information collected on allergies included questions about whether the participant
had been diagnosed with asthma, hayfever, or eczema and the length of time these
conditions were present. In addition, data were collected on allergy medication
including type of medication and frequency of use. Although information concerning
type of glioma of individuals who refused to participate was not available to
investigators (to protect nonrespondents’ privacy), we know that of the
499 glioma patients, 73.9% agreed to be interviewed and of the 956
potential controls identified, 66.2% agreed to be interviewed. However,
once interviewed, slightly more controls (66.7%) than GBM cases
(63.8%) consented to having their blood drawn. Statistical Analysis We used unconditional logistic regression to compare case and control
polymorphism prevalence adjusted for age and sex. The variable geographic region
had no influence on our findings so we eliminated it from our regression
models. Genotyping Dynamic Allele-Specific Hybridization (DASH) was performed as previously
described ( 31– 35). For this, two PCR primers and one DASH probe per
target mutation/SNP were designed by means of custom software ( 36) provided by DynaMetrix Ltd (UK). These
oligonucleotides were provided and HPLC purified, by Biomers GmbH (Germany). The
DASH PCRs entailed amplifying 50–90 bp genomic fragments spanning
the variant of interest, with one of the primers carrying a
5′-biotin label. Amplifications were performed in 5uL volume,
containing 1–2ng genomic DNA, 0.38uM biotinylated primer, 0.75uM
non-biotinylated primer, 0.03 units AmpliTaq Gold (PE Biosystems, CA),
10% dimethylsulphoxide, 1 × AmpliTaq Gold Buffer
including 1.5mM of MgCl2 (Applied Biosystems, CA) and 0.2mM each dNTP. Thermal
cycling was conducted on an MBS 384 device (Thermo-Hybaid, Ashford, UK) as
follows; 1 × (10 minutes at 94 C), 35× (15 seconds at 94
C, 30 seconds at annealing temperature). To verify successful amplification,
0.5ul of several randomly chosen samples were examined on a 3.0%
low-melt agarose gel. DASH analysis of the PCR product was conduced on membrane macro-arrays,
using the DASH-2 protocol ( 34). Briefly,
this entailed transferring samples to the membrane array by centrifugation or
robotic gridding ( 37). Resulting
individual arrays with up to 9,600 distinct samples/features were rinsed in 0.1
M NaOH to denature the PCR products, and then exposed to 2ml HE buffer (0.1 M
HEPES, 10mM EDTA, pH 7.9) containing 4nmol of suitable probe, itself
end-labelled with ROX. After heating to 85 C and cooling to room temperature,
the membrane was briefly rinsed in HE buffer. The array was then soaked in 40ml
HE-buffer containing SYBR GreenI dye at 1:20,000 dilution for up to 3 hours.
Using a DASH-2 device (DynaMetrix Ltd, UK), the membrane was taken through a
DASH heating ramp (heating at 3 C/minute from room temperature to 85 C) whilst
fluorescence from the ROX acceptor dye on the probe was monitored. Data were
collected at interval of 0.5 C. Fluorescence changes with temperature (DNA
melting profiles) were used to distinguish different alleles, and this was done
by means of the DASH-2 device software which uses negative derivatives of
fluorescence against temperature to reveal peaks of denaturation rate
(target-probe melting temperatures; Tm) and thereby automatically assign DNA
samples into genotype groups. Finally, a random sample of 15% of all
DNA samples was reassayed and the genotype assignment confirmed. An error rate
of less than one percent was observed. No samples were sequenced since DASH is an extensively validated method
( 31– 35). Quality control data included in the preceding
references confirms the error rate of the method across many different SNPs is
<0.1%. In Table 1 the distributions of age,
sex, and allergic condition variables are shown for interviewed cases and controls
who did and did not consent to having their blood drawn. Overall, results are
similar except when the sample size for a category is small, as is the case for the
variable food allergy among people who did not have their blood drawn. For both
groups there are consistent inverse relationships between self-reported asthma,
eczema, fever during the ten years prior to the interview and GBM. The reason that
cases and controls differ with respect to age (median age for all participants:
cases 56 years, controls 53 years) and sex (for total participants: male cases 59.18
%, male controls 48.02 %) is that we include controls who
were initially matched to age and sex of all glioma and meningioma cases (see
Methods Section). | Table 1Demographic variables and age- and sex-adjusted self-reported
physician-diagnosed asthma and allergic condition and inflammation variables
from population-based Swedish case-control study of glioblastoma (more ...) |
The second column of Table 2 shows
previously reported associations between five polymorphisms and asthma ( 14, 16,
17, 22). Column 3 contains results from the present study for associations of
these same polymorphisms with GBM. For each SNP, odds ratios for asthma that are
greater than or less than the null value (OR= 1.0) correspond to odds
ratios for GBM that are greater than or less than the null value. However, because
reference categories that we use for the two diseases differ, our findings indicate
that these asthma susceptibility polymorphisms have opposite relationships with
asthma and GBM. For example, individuals with the TT polymorphism for the IL-4RA
ser478pro SNP appear to be more susceptible to asthma and less susceptible to GBM
than are individuals with the TC or CC variants. Also reported at the bottom of the
second column are maximum levels of C-reactive protein after coronary by-pass
surgery stratified on alleles of the COX-2 -765GC polymorphism ( 26). The odds ratio characterizing the association
between the COX-2 polymorphism and GBM indicates that higher post-surgical levels of
C-reactive protein, perhaps indicating a stronger acute phase inflammatory response,
are associated with a greater risk of GBM. | Table 2Sex- and age-adjusted associations between asthma polymorphisms and
glioblastoma multiforme (GBM) from population based Swedish case-control
study (2000–2002), and comparisons with previously published
(more ...) |
Further details describing associations between each of the six
polymorphisms and GBM are reported in columns 4–8 of Table 2. The genotype distribution of GBM cases and
controls is shown together with the same distributions for asthma cases and controls
from previous literature. For each of the first five polymorphisms, if GBM and
asthma cases and controls are ranked by the percentage having the most common
polymorphism, GBM and asthma cases are at the extremes and controls lie between
them. For example, for the IL-13 -1112 C/T polymorphism, 84% of GBM
cases have the CC genotype, while only 58% of asthma cases are in this
category. This pattern is reversed for IL-4RA ser478pro where a gradient from GBM
(59% TT genotype) to asthma cases (77% TT genotype) can be
seen. The order of these percentages does not change when people reporting asthma or
other allergic conditions are excluded from the GBM case group (not shown). GBM
asthma and control genotype distributions are similar, except those for the ADAM33,
T1 SNP ( 22). These distributions remain
similar when people with asthma or other allergic conditions are excluded from the
GBM control group (not shown). In the previously reported
effect of the interaction between IL-4RA ser478pro and IL-13 -1112 C/T on asthma
risk is shown ( 14). Consistent with findings
in Table 2, GBM odds ratios are inversely
associated with previously reported asthma odds ratios. Although we find no similar
interaction in the present study among GBM controls (the middle bar labeled 4 is not
higher than the sum of middle bars labeled 2 and 3), asthma genotype odds ratios in
our sample are similar to those previously reported. However, there is little
additional evidence of associations between individual asthma susceptibility
polymorphisms reported in Table 2 and
self-reported asthma, hayfever, fever, or any of the allergic conditions shown in
Table 1 among controls in our data (not
shown). Nor did our findings change when asthma or allergic condition variables were
stratified on age at onset or duration of disease. Using previously identified polymorphisms as biomarkers of susceptibility to
asthma, we found an association between three of these biomarkers (IL-4RA ser478pro
TC, CC, IL-4RA gln551arg AG, AA, and IL-13 -1112 CT, TT) and GBM. In addition, as
predicted by both previous epidemiologic and asthma susceptibility polymorphism
literature ( 3– 7, 14, 16, 17,
22, 26, 38), odds ratios for GBM were the
inverse of those for asthma. Ours is the first study to suggest the validity of the
consistently observed inverse association between self-reported asthma and GBM
because we used biomarkers that cannot be altered by the presence of GBM. By basing
our selection of polymorphisms on strong a-priori epidemiologic and
genetic evidence ( 2), we reduce the risk of
false-positive results which so often characterize the genetic polymorphism
literature ( 39). However, because the
individual polymorphisms that we identified are not related to self-reported asthma
or allergic conditions among controls in our data, our results may reflect a
relationship between IL-4RA, IL-13 and GBM that is independent of their role in
asthma and other allergic conditions. Asthma is an inflammatory disease of lung airways that may or may not have
an allergic component. Here we define allergy as immune reactions to common
environmental proteins characterized by elevated IgE levels and distinguished by
allergic symptoms from atopy. Although asthma and other allergic conditions such as
hayfever are clinically distinct, they are genetically linked. For example, the AG
and AA genotypes of the IL-13 arg130gln polymorphism are associated with atopy,
allergen-specific IgE, and asthma ( 16). A
further manifestation of this genetic association among allergic conditions is that
within the same family individuals may have allergic diseases of different target
organs such as asthma, hayfever, and eczema ( 40). Because of this genetic link, inferences from our findings can be
extended from asthma to other allergic conditions. Possible reasons for our failure to find expected associations between
individual polymorphisms and allergic conditions among controls include both the
relatively small numbers of controls reporting asthma or allergic conditions and
misclassification of these conditions. In most case-control studies of asthma, all
study participants (including controls) are actively screened for asthma by
spirometry, reversibility to albuterol or bronchial responsiveness testing to
albuterol, e.g., ( 24). While in the present
study asthma and other allergic conditions are identified only by self-report of
physician diagnosis. Errors in measurement of allergic conditions may also explain
the reason for relatively weak associations between allergic conditions ( Table 1, measured with error) and GBM as
opposed to relatively strong associations between allergic disease susceptibility
polymorphisms ( Table 2, measured with little
error) and GBM ( 41). Additional evidence for an association between allergic conditions and GBM
includes the findings of Weimels et al. that glioma cases have lower serum IgE
levels than do controls ( 9), however, their
findings need to be validated with prospectively collected data. Perhaps related to
the role of allergic disease in the etiology of GBM, are findings from a clinical
trial of an IgE blocking drug for asthmatics (Omalizumab) that show a higher rate of
solid tumors in the treatment group compared to the control group (rate ratio for
solid tumors excluding non-melanoma skin cancer, 3.8, 95% CI 0.9, 34.3 )
( 42). Whether brain tumors are included
among the solid tumors identified is not known. In addition because the number of
tumors found is relatively small (Omalizumab group, n=16, control group,
n=5), random allocation of study participants may not have equally
distributed individuals with differing prior risks of cancer to the treatment and
control groups. It is also possible that IL-4RA and IL-13 play a role in GBM development
that is independent of their roles in asthma and allergic conditions. The function
of IL-4 and IL-13 in brain tumor growth has been the subject of several
investigations. Barna et al. found that 3 normal astrocytic, 2 low-grade astrocytoma
and 3 out of 4 GBM cell lines that she evaluated express IL-4Ralpha receptors.
However, IL-4 suppresses DNA synthesis and cell proliferation only in the normal
astrocytic and low-grade astrocytoma cell lines but not in the GBM cell lines ( 21). Their results suggest that IL-4 may
interfere with progression from lower to higher grade glioma but may have no role in
de novo glioblastomas ( 43). Saleh et al. attribute the growth-inhibiting properties of mouse IL-4
on implanted C6 glioma cell lines to its ability to promote eosinophil infiltration
and to inhibit angiogenesis. Furthermore, Saleh et al. observe that implantation of
C6 cell gliomas that produce IL-4 retrovirus are rapidly eradicated in rats ( 44, 45).
Consistent with Saleh et al.’s results, Volpert et al. show that IL-4
blocks corneal neovascularization by fibroblast growth factor in mice as well as
inhibiting the migration of cultured bovine and human microvascular cells ( 46). However, because IL-4 is species-specific
the above findings may not be directly applicable to human disease. IL-13 shares the IL-4R alpha signaling receptor chain with IL-4, and like
IL-4, inhibits astrocyte and low grade astrocytoma proliferation but does not
inhibit GBM cell proliferation ( 20). In
addition, Shin et al. found that IL-13 controls brain inflammation by inducing death
of activated microglia (major inflammatory cells of the central nervous system)
( 47). Further evidence for a role of
IL-13 in GBM development or growth comes from the overexpression of IL-13Ralpha2
receptors in glioblastoma tissue ( 48, 49). The role of these receptors in GBM cells
is to inhibit IL-13 and IL-4 dependent signal transduction ( 50). Not only do IL-4 and Il-13 not inhibit cell growth in GBM (as they appear to
do in lower grade gliomas) but also IL-4 or IL-13 stimulation of IL-4RA contributes
to the pathogenesis of GBM cells ( 51). In
addition, Madhankumer and Debinski find that IL-13 stimulates a signaling cascade
that increases the oncogenic potential of GBM cells ( 52). There is also extensive evidence indicating that IL-13
downregulates antitumor response by indirectly suppressing production of cytotoxic T
cell production e.g., ( 53). (Although these
effects have not been observed for brain tumors, they may be in the future.) As a
consequence, Berzofsky et al. have suggested a possible benefit of IL-13 withdrawal
as a means of both increasing anti-tumor immunity and the efficiency of vaccines
( 54). There are also proposals that
asthma and allergic conditions be prevented or treated by inhibiting IL-13
production ( 55, 56). Our findings of an inverse association between IL-4RA and IL-13
polymorphisms, and GBM suggest that IL-13 withdrawal therapies to treat allergic
conditions may interfere with possible tumor-inhibiting effects of this cytokine in
the brain. However, if these tumor inhibiting effects occur early in GBM development
then perhaps reducing endogenous IL-13 production after GBM development may still be
beneficial. Further research should include investigation of additional allergy
susceptibility polymorphisms, use of biomarkers of allergic conditions measured
before GBM diagnosis and validation of asthma and allergic condition self-reports.
Overall, one of the goals of subsequent research should be to determine whether
allergic conditions per se or their related cytokines affect GBM risk. The authors thank Arthur E. Varner, M.D. for his helpful comments. This research was
supported by grants from the United States National Cancer Institute (R03CA103379),
the Swedish Council for Working Life and Social Research, the Swedish Cancer
Society, the Swedish Research Council, the European Union Fifth Framework Program,
and the International Union against Cancer (UICC). 1. CBTRUS. Statistical Report: Primary Brain Tumors in
the United States, 1995–1999.: Central Brain Tumor Registry of the
United States, 2002. 2. Fisher JL, Schwartzbaum JA, Wrensch M, Berger MS.
Evaluation of epidemiologic evidence for primary adult brain tumor risk factors
using Evidence-Based Medicine. Review of Neurological Surgery by Evidence-Based
Medicine Standards: S Karger AG, 2005. 3. Schlehofer B, Blettner M, Becker N, Martinsohn C, Wahrendorf J. Medical risk factors and the development of brain tumors. Cancer. 1992;69:2541–47. [PubMed] 4. Schlehofer B, Blettner M, Preston-Martin S, et al. Role of medical history in brain tumour development. Results from
the international adult brain tumour study. Int J Cancer. 1999;82:155–60. [PubMed] 5. Wiemels JL, Wiencke JK, Sison JD, Miike R, McMillan A, Wrensch M. History of allergies among adults with glioma and controls. Int J Cancer. 2002;98:609–15. [PubMed] 6. Brenner AV, Linet MS, Fine HA, et al. History of allergies and autoimmune diseases and risk of brain
tumors in adults. Int J Cancer. 2002;99:252–9. [PubMed] 7. Schwartzbaum J, Jonsson F, Ahlbom A, et al. Cohort studies of association between self-reported allergic
conditions, immune-related diagnoses and glioma and meningioma risk. Int J Cancer. 2003;106:423–8. [PubMed] 8. Scheibel RS, Meyers CA, Levin VA. Cognitive dysfunction following surgery for intracerebral glioma:
influence of histopathology, lesion location, and treatment. J Neurooncol. 1996;30:61–9. [PubMed] 9. Wiemels JL, Wiencke JK, Patoka J, et al. Reduced immunoglobulin E and allergy among adults with glioma
compared with controls. Cancer Res. 2004;64:8468–73. [PubMed] 10. Becker KG. The common variants/multiple disease hypothesis of common complex
genetic disorders. Med Hypotheses. 2004;62:309–17. [PubMed] 11. Annesi-Maesano I, Didier A, Klossek M, Chanal I, Moreau D, Bousquet J. The score for allergic rhinitis (SFAR): a simple and valid
assessment method in population studies. Allergy. 2002;57:107–14. [PubMed] 12. Toren K, Brisman J, Jarvholm B. Asthma and asthma-like symptoms in adults assessed by
questionnaires. A literature review Chest. 1993;104:600–8. 13. Rothman K, Greenland S. Modern Epidemiology:
Lippincott–Raven Publishers, 1998. 14. Howard TD, Koppelman GH, Xu J, et al. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch
population with asthma. Am J Hum Genet. 2002;70:230–6. [PubMed] 15. Hoffjan S, Nicolae D, Ober C. Association studies for asthma and atopic diseases: a
comprehensive review of the literature. Respir Res. 2003;4:14. [PubMed] 16. Heinzmann A, Mao XQ, Akaiwa M, et al. Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet. 2000;9:549–59. [PubMed] 17. Howard TD, Whittaker PA, Zaiman AL, et al. Identification and association of polymorphisms in the
Interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol. 2001;25:377–384. [PubMed] 18. Holgate ST. The epidemic of allergy and asthma. Nature. 1999;402:B2–4. [PubMed] 19. Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282:2258–61. [PubMed] 20. Liu H, Jacobs BS, Liu J, et al. Interleukin-13
sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic
glia and low-grade astrocytoma differ from malignant glioma. Cancer Immunol
Immunother 2000;49. 21. Barna BP, Estes M, Pettay J, Iwasaki K, Zhou P, Barnett GH. Human astrocyte growth regulation: interleukin-4 sensitivity and
receptor expression. J Neuroimmunol. 1995;60:75–81. [PubMed] 22. Van Eerdewegh P, Little RD, Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial
hyperresponsiveness. Nature. 2002;418:426–30. [PubMed] 23. Werner M, Herbon N, Gohlke H, et al. Asthma is associated with single-nucleotide polymorphisms in
ADAM33. Clin Exp Allergy. 2004;34:26–31. [PubMed] 24. Howard TD, Postma DS, Jongepier H, et al. Association of a disintegrin and metalloprotease 33 (ADAM 33)
gene with asthma in ethnically diverse populations. J Allergy Clin Immunol. 2003;112:717–22. [PubMed] 25. Nakada M, Okada Y, Yamashita J. The role of matrix metalloproteinases in glioma invasion. Front Biosci. 2003;8:e261–9. [PubMed] 26. Papafili A, Hill MR, Brull DJ, et al. Common promoter variant in Cyclooxygenase-2 represses gene
expression:Evidence of role in acute-phase inflammatory response. Atheroscler Thromb Vasc Biol. 2002;22:1631–36. 27. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–56. [PubMed] 28. Mentink-Kane MM, Wynn TA. Opposing roles for IL-13 and IL-13 receptor alpha 2 in health and
disease. Immunol Rev. 2004;202:191–202. [PubMed] 29. Saito A, Okazaki H, Sugawara I, Yamamoto K, Takizawa H. Potential action of IL-4 and IL-13 as fibrogenic factors on lung
fibroblasts in vitro. Int Arch Allergy Immunol. 2003;132:168–76. [PubMed] 30. Sivak-Sears N, Schwartzbaum J, Miike R, Moghadassi M, Wrensch M. Case-control study of non-steroidal anti-inflammatory drug use
and glioblastoma multiforme. Am J of Epidemiol. 2004;159:1131–1139. [PubMed] 31. Howell WM, Jobs M, Gyllensten U, Brookes AJ. Dynamic allele-specific hybridisation: A new method for scoring
single nucleotide polymorphisms. Nature Biotech. 1999;17:87–88. 32. Prince JA, Feuk L, Howell WM, et al. Robust and accurate single nucliotide polymorphism genotyping by
dynamic allele-specific hybridization (DASH) design. Criteria and assay validation Genome Research. 2001;11:152–62. 33. Howell WM, Jobs M, Brookes AJ. iFRET: an improved fluorescence system for DNA-melting analysis. Genome Res. 2002;12:1401–7. [PubMed] 34. Jobs M, Howell WM, Stromqvist L, Mayr T, Brookes AJ. Dash-2: Flexible, low-cost, and high-throughput SNP genotyping by
dynamic allele-specific hybridication on membrane arrays. Genome Research. 2003;13:916–924. [PubMed] 35. Sawyer SL, Howell WM, Brookes AJ. Scoring
insertion-deletion polymorphisms by dynamic allele-specific hybridization.
Biotechniques 2003;35:292–6, 298. 36. Fredman D, Jobs M, Stromqvist L, Brookes AJ. DFold: PCR design that minimizes secondary structure and
optimizes downstream genotyping applications. Hum Mutation. 2004;24:1–8. 37. Jobs M, Howell WM, Brookes AJ. Creating assays by centrifugation. Biotechniques. 2002;32:1322–1229. [PubMed] 38. Sawaya R, Ramo OJ. Systemic and thromboembolic
effects of meningiomas. In: Al-Mefty O, ed. Meningiomas. New York: Raven Press,
Ltd., 1991:137–144. 39. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N. Assessing the probability that a positive report is false: an
approach for molecular epidemiology studies. J Natl Cancer Inst. 2004;96:434–42. [PubMed] 40. Abbas AK, Lichtman AH, Pober JS. Cellular and
molecular immunology. London: W. B. Saunders Company, 1997. 41. Vineis P. A self-fulfilling prophecy: are we underestimating the role of
the environment in gene-environment interaction research? Int J Epidemiol. 2004;33:945–6. [PubMed] 42. Genentech. Briefing Document on Safety (BLA STN
1039760/0): Omalizumab (Xolair) for treatment of allergic asthma.,
2003. 43. Louis DN. A molecular genetic model of astrocytoma histopathology. Brain Pathol. 1997;7:755–64. [PubMed] 44. Saleh M, Davis ID, Wilks AF. The paracrine role of tumor-derived mIL-4 on tumour-associated
endothelium. Int J Cancer. 1997;72:664–72. [PubMed] 45. Saleh M, Wiegmans A, Malone Q, Stylli SS, Kaye AH. Effect of in-situ retroviral interleukin-4 transfer on
established intracranial tumors. J Natl Cancer Inst. 1999;91:438–45. [PubMed] 46. Volpert OV, Fong T, Kock AE, et al. Inhibition of angiogenesis by interleukin 4. J Exp Med. 1998;188:1039–46. [PubMed] 47. Shin WH, Lee D-Y, Keun WP, et al. Microglia expressing interleukin-13 undergo cell death and
contribute to neuronal survival in vivo. Glia. 2004;46:142–152. [PubMed] 48. Debinski W, Gibo D, Mintz A. Epigenetics in high-grade astrocytomas: opportunities for
prevention and detection of brain tumors. Ann N Y Acad Sci. 2003;983:232–42. [PubMed] 49. Debinski W, Miner R, Leland P, Obiri NI, Puri RK. Receptor for Interleukin (IL) 13Does Not Interact with IL4 but
Receptor for IL4 Interacts with IL13 on Human Glioma Cells. J Biol Chem. 1996;271:22428–22433. [PubMed] 50. Rahaman SO, Sharma P, Harbor PC, Aman MJ, Vogelbaum MA, Haque SJ. IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor
of IL-4-dependent signal transduction in glioblastoma cells. Cancer Res. 2002;62:1103–9. [PubMed] 51. Rahaman SO, Vogelbaum MA. IL-4 potentiates persistent activation of STAT3 in glioblastoma
multiforme cells: cause and consequence. Neuro-oncol. 2004;6:344. 52. Madhankumar AB, Debinski W. Structural requirements for interleukin 13 to bind to
IL13Ralpha2, a tumor-associated receptor. Neuro-Oncology. 2004;6:343. 53. Terabe M, Park JM, Berzofsky JA. Role of IL13 in regulation of anti-tumor immunity and tumor
growth. Cancer Immunol Immunother. 2004;53:79–85. [PubMed] 54. Berzofsky JA, Terabe M, Oh S, et al. Progress on new vaccine strategies for the immunotherapy and
prevention of cancer. J Clin Invest. 2004;113:1515–25. [PubMed] 55. Ichinose M, Barnes PJ. Cytokine-directed therapy in asthma. Curr Drug Targets Inflamm Allergy. 2004;3:263–9. [PubMed] 56. Kumar RK, Herbert C, Webb DC, Li L, Foster PS. Effects of anticytokine therapy in a mouse model of chronic
asthma. Am J Respir Crit Care Med. 2004;170:1043–8. [PubMed]
|
The publisher's final edited version of this article is available free at 
