What is the role of genetics in occupational asthma?
table to a particular occupational environment, and not to
stimuli encountered outside the workplace . There are two
types of OA, which are caused by two distinct mechanisms:
immunological and nonimmunological. The former appears
after a latency period and is induced by an immunoglobulin
(Ig)E-dependent mechanism (triggered by most high- and
some low-molecular-weight agents) or an IgE-independent
mechanism (triggered by most low-molecular-weight agents).
The latter type of OA is characterised by the absence of a
of a respiratory irritant at work or outside the workplace .
ccupational asthma (OA) is a disease characterised by
variable airflow limitation and/or airway hyper-
responsiveness, due to causes and conditions attribu-
Although the exact cause of OA is not yet known, in general
OA, similarly to nonoccupational asthma, may be caused by
complex interactions between genes and the environment,
including gene–environment, gene–gene, gene–gene–environ-
ment, and gene–environment–environment interactions .
What, then, is the role of genetics in subjects with OA? And
where should research focus attention?
Addressing the second of these questions, asthma genetics has
received much attention and has made much progress in
recent decades. Importantly, the multifactorial pathogenesis of
asthma has been recognised. That is, genetic research has
shown that asthma behaves as a complex disease, and that it is
not caused by single gene mutations . These findings have
opened important challenges for researchers. Among these
challenges are identifying the genes involved in the disease,
determining the mechanisms underlying the phenotype
heterogeneity of the disease, and understanding how develop-
mental and environmental factors interact with genetic
determinants to affect disease susceptibility.
Another challenge is that many associations found in studies
on the genetics of asthma have not been replicated in multiple
populations. Why? What is the problem with genetics
research? One reasonable explanation is put forward by OBER
and THOMPSON : instead of considering a negative study as
evidence against a gene contributing to risk, it might be more
effective to consider why the gene is contributing to risk in
some populations but not in others. As an example, the HLA-
DQB1*0501 allele confers susceptibility to developing specific
IgEs against organic acid anhydrides , but the same allele is
protective for the low-molecular-weight agents diisocyanates
and plicatic acid [6, 7], suggesting that different affinities for
the corresponding specific class-II molecules exist.
The lack of important associations and the inability to replicate
results in genetic studies on asthma could also be due to the
fact that most studies do not take into account the contribution
from the environment. Environmental factors include the in
endotoxin and inhaled aeroallergen exposure, tobacco smoke,
diet, viral infections, exposure to sensitisers (types and levels of
Another reason that genetic studies have not come up with
important associations may be that epigenetics is the link
between our genes and the environment [3, 8]. With this term,
we define stable and heritable changes in gene expression that
do not involve changes in DNA sequences . Epigenetic
mechanisms include DNA methylation, histone deacetylation
and other modes of chromatin remodelling. They provide a
means for the selective expression of a specific allele from one
chromosome whereas the allele present on the partner
chromosome remains silenced .
Because of the recent focus on asthma genetics, genetic testing
has been recommended for screening and for monitoring
patients. These recommendations raise ethical concerns about
the use of genetic tests and about how implementation should
be expanded. Thus, the ethical question is: what is the
appropriate role of genetics in OA?
There is no consensus of opinion about ethics; nevertheless,
ethical issues must be considered. Theoretically, genetic testing
could be used beneficially, for pre-employment decisions,
employee placement, job replacement or relocation, and risk
avoidance including implementation of control measures for
harmful exposures in the workplace. However, caution is
needed. Among the criteria required to perform genetic testing
on workers, the first is that a genetic test for a specific condition
a low incidence of both false-positives and false-negatives. In
addition, the test must search for a gene that is sufficiently
far, associations found in OA are modest with low odds ratios,
indicating that genetic testing alone is not advisable for
measuring risk for OA [13–15]. Furthermore, because asthma is
a complex disease, caused by multiple genetic and environ-
mental factors, informationobtainedtodate bya singlegene test
SUPPORT STATEMENT: This work was supported by the Ministry of University and Scientific
Research, Associazione per la Ricerca e la Cura dell’Asma (ARCA; Padova, Italy) and the Consorzio
Ferrara Ricerche (Ferrara, Italy).
STATEMENT OF INTEREST: None declared.
CORRESPONDENCE: C.E. Mapp, Dipartimento di Medicina Clinica e Sperimentale, Universita ` degli
Studi di Ferrara, Via Fossato di Mortara 64 B, 44100 Ferrara, Italy. Fax: 39 0532205066. E-mail:
Eur Respir J 2009; 33: 459–460
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EUROPEAN RESPIRATORY JOURNAL
VOLUME 33 NUMBER 3
cannot be recommended .
In addition to genetic testing being as yet unreliable, even
reliable genetic testing would carry the risk of genetic
discrimination, including loss of employment, promotion,
insurance and healthcare . Genetic discrimination and
misuse of genetic information exist and are manifested in
many social institutions, particularly in the health and life
insurance industries . More vigilance is needed in order to
avoid creating a new social underclass based on genetic
discrimination, the so-called ‘‘asymptomatic ill’’ .
What, then, can be done? One suggestion is that identifying
genes of interest based on relevant exposures, rather than on
disease outcomes, may be more useful in clarifying gene–
environment–disease interactions. Thus, there is heightened
interest in the possibility that gene–environment interactions
may be effective for understanding the mechanisms involved
in occupational asthma. Unfortunately, we are not there yet.
There is another issue: are we overemphasising the role of
genes in disease causation? If the answer is yes, by doing this
are we underestimating the role of environmental factors in
disease causation? The answer is probably yes.
So, what comes next? Genes or environment? I can sum up my
thinking by offering five points for consideration: 1) indivi-
duals are not just DNA codes; 2) environmental and occupa-
tional exposures must be taken into account in genetic studies
on OA; 3) reducing the exposure at the workplace is a priority;
4) collaborative studies between different research institutes
and government agencies should be promoted with the aim of
improving genetic testing in OA; and 5) researchers should
always keep always in mind that OA is a preventable disease.
Genetics has the potential to do great good, although to date, it
has had limited benefits for occupational asthma. Genetic
discrimination, misuse of genetic information, and shifting the
responsibility for a safe workplace from the employer to the
employee should be avoided.
Theauthor thanksM. Zeiger (Cardiovascular Research Institute,
University of California San Francisco, San Francisco, CA, USA)
for fine work throughout the revision of this manuscript.
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