Advances in genome sequencing and the completion of the Human Genome Project have allowed
scientists to use genome-wide association studies (GWAS) in attempts to
identify certain disease-causing genes. While many candidate genes have been
described for hay fever, each search appears to reveal additional candidates.
It has become clear that hay fever is a complex disease, driven by genetics and
environmental exposures, both pre- and postnatal. Because of this complexity,
atopy does not follow a Mendelian
model of inheritance, like eye or hair color.
To perform GWAS, researchers collect blood or tissue
samples from individuals with the disease of interest and from symptom-free control
subjects. In many allergy studies, the controls are within the same family,
which helps tease apart genetic differences that might actually contribute to
disease. This is helpful because 300,000 to 1 million
changes in the DNA are tested. These changes called single nucleotide
polymorphisms (SNPs), a type of mutation that indicates a single change in the
DNA base pair. If certain SNPs appear more frequently in the individuals with
the disease, they are said to be associated with that disease. Additional DNA
sequencing is performed to determine the exact change, and then ideally that SNP
is studied in the lab to understand the consequence of the change on cellular
function.
A few notable candidate genes have been identified as
associated with hay fever or with higher levels of circulating IgE antibodies,
as we learned is a hallmark of atopy. Cytokines are the main signaling
molecules that trigger activation of B cells to produce IgE antibodies, and not
surprisingly, people with
hay fever have mutations in genes that encode for cytokines or regulate their
production. Also associated with hay fever are changes that enhance and stabilize
the IgE receptor on mast cells and basophils, contributing to more intense
symptoms. Genes responsible for airway smooth muscle contractions, contributing
to cough and wheeze, are also implicated. SNPs have been identified in the
genes encoding chemical
mediators that cause ongoing symptoms such as leukotrienes, and in the
specialized effector cells involved later in allergic inflammation response,
such as eosinophils.
These are just a few examples of genes; dozens of others
are being studied to learn exactly how they contribute to hay fever.
Furthermore, some genes are only associated with allergies in the context of
specific environments, further complicating the identification of true
disease-causing genes. One clue that environmental factors influence allergies comes
from studies of twins. Twin studies have
shown that between monozygotic (identical) twins there is on average a 65% (range,
42-82%) chance that if one twin has allergies, the other will also have them.
Between dizygotic (fraternal) twins, there is on average a 33% concordance rate
(range 15-52%).
Some differences in twins are obvious, but other differences like allergies require epidemiological studies to tease apart. |
If Strachan’s hypothesis is correct, the Bates family should be allergen-free. |
The “hygiene hypothesis” developed into a much broader “microflora hypothesis”
which proposes that urbanization and a Western lifestyle limits our exposure to
bacteria, viruses and parasites in general. Clean water, increased Cesarean
sections, reduction in breastfeeding, increased antibiotic and antibacterial
use, and reduced exposure to farm animals have limited our exposure to our microbial “old
friends”. According to this idea, these “old friends” have evolved with us to
the point where we require them for proper immune function.
“The Wonder Years” cast knew that we get by with a little
help from our friends.
The diversity of our
microbiome is decreasing, which may have detrimental effects on general
health and the efficiency of our immune system. W. Parker proposed the term “biome depletion”
to describe this current phenomenon. A few recommendations
can be found here to increase microbial diversity in the gut.
Just like the Biodome, our biomes are not closed systems and can let in and respond to passer-byers, for better or for worse. In the case of Pauly Shore, it’s always for the worse. |
Upon conception, epigenetic reprogramming occurs in the
zygote, like a reset button. However, some epigenetic marks remain and are
inherited by the offspring. So before and largely during pregnancy, the mother
encounters various environments and the body responds using epigenetics to regulate
genes at the appropriate time. These changes occur in the embryo or fetus as
well, as a way to prime the baby for its eventual environment.
There is evidence that the immune system is
under epigenetic regulation. At birth, atopy-prone infants tend to have
diminished Th1 cell responses, thought to be influenced by the maternal environment.
Additionally, maternal diet, microbial exposure, and smoking can influence
epigenetic regulation of key genes involved in immune regulation and allergy
development.
While there is no consensus on allergy prevention, there
are many options for treatment of allergies, which will be discussed in the
final allergy article in this series – coming soon!
Contributed by:
Julia van Rensburg, Ph.D.
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Grammatikos AP (2008). The genetic and environmental basis of atopic diseases. Annals of medicine, 40 (7), 482-95 PMID: 18608118
Strachan DP (2000). Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax, 55 Suppl 1 PMID: 10943631
Parker W (2014). The "hygiene hypothesis" for allergic disease is a misnomer. BMJ (Clinical research ed.), 348 PMID: 25161287
Martino D, & Prescott S (2011). Epigenetics and prenatal influences on asthma and allergic airways disease. Chest, 139 (3), 640-7 PMID: 21362650
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