Allergies affect 30% of the population and 10% of children suffer from asthma. Researchers in the United Kingdom, the United States, Sweden and Canada report in Nature that they have discovered more than 30 genes that have strong effects on Immunoglobulin E (IgE), allergies and asthma. IgE is the antibody that triggers allergic responses.
Amongst the genes are promising novel drug targets for treating allergies and asthma.
The researchers also found that the genes are concentrated in eosinophils, a white cell that ignites inflammation in asthmatic airways. The genes indicate when the eosinophils are activated and primed to cause the most damage.
Therapies that neutralise eosinophils already exist, but they are very expensive and only efficacious in some asthmatics. The newly found activation signals provide a possible means of directing treatments by predicting who will respond before starting therapy.
The research team used a novel technique to discover these genes, known as an “epigenome wide association study (EWAS)”. Epigenetic changes to DNA do not alter the underling sequence of the genetic code but can still be passed on as cells divide. They program the cells to form specialised types and tissues.
Epigenetic changes are most easily detected by alterations in methyl molecules that are attached at the side of the DNA chain. The researchers therefore concentrated on 27,000 methylation hotspots known as CpG islands that are positioned near many genes. They tested whether methylation levels in these islands in white cells from UK families with asthma was correlated with the level of the IgE in the blood.
To be sure of their positive results the researchers tested whether they held true in additional volunteers with high and low levels of IgE from Wales and further asthmatic families from Québèc.
They found strong associations between IgE and CGI methylation at 36 places in 34 genes. Some of the IgE-related genes were known to be present in eosinophil cells. The researchers therefore separated eosinophils from the blood of 24 subjects and showed all 34 genes to have their strongest effects in asthmatics with high IgE levels.
The paper shows the power of epigenome wide association analyses. Previous genetic association studies for IgE levels (looking at changes in DNA sequences) had only found genes that could explain 1% of individual differences in IgE, and did not discover any novel therapeutic targets or pathways underlying IgE regulation
By contrast the epigenetic associations accounted for more than 13% of IgE variation, 10 fold higher than that derived from traditional genetics. The associations identify novel potential drug targets for allergic diseases as well as biomarkers that may determine which patients will respond to particular therapies.
The increased power from epigenetic studies comes at the cost of controlling for many factors such as ageing and gender that are not important for simple genetic studies. The authors had to use advanced statistical techniques to be sure of their results, and as well as testing their validity in multiple additional sample sets.
The Freemasons’ Grand Charity, the Wellcome Trust and grants from the Québec Government provided the principal funding for the study.
An epigenome-wide association study of total serum immunoglobulin E concentration
Liming Liang, Saffron A. G. Willis-Owen, Catherine Laprise, Kenny C. C. Wong, Gwyneth A. Davies, Thomas J. Hudson, Aristea Binia, Julian M. Hopkin, Ivana V. Yang, Elin Grundberg, Stephan Busche, Marie Hudson, Lars Rönnblom, Tomi M. Pastinen, David A. Schwartz, G. Mark Lathrop, Miriam F. Moffatt, William O. C. M. Cookson. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature, 2015; DOI: 10.1038/nature14125