Geneticists in the US have identified a new gene uniquely linked to asthma in African Americans; a variant of the gene called PYHIN1 that is absent in European Americans. The new national collaboration also confirmed four other “trans-ethnic” asthma genes revealed in a European study published last year. The new study, reported in the 31 July online issue of Nature Genetics, is said to represent a significant advance in a national effort to locate the genetic roots of asthma.
The researchers belong to the newly created EVE Consortium, which comprises nine groups of researchers who decided to team up after deciding that finding new genes is becoming very difficult unless you pool data and join forces.
Study senior author Dr Carole Ober, who co-chairs the EVE Consortium, and is Blum-Riese Professor of human genetics and obstetrics/gynecology at the University of Chicago, told the media she thought it was an “exciting time in asthma genetics”.
“We now have a really good handle on at least five genes that anyone would be comfortable saying are asthma risk loci,” said Ober, adding that:
“We were able to show that almost all of the genes other than PYHIN1 are trans-ethnic and important in all of the groups.”
The challenge the EVE Consortium faced was how to increse the power of genome-wide association studies, or GWAS. These are popular with geneticists searching for gene variants linked to higher risk of particular diseases. They take genetic data from a group of patients with the disease and compare it to a control group without the disease, and look for variants that occur more frequently in the disease group.
But the power of GWAS when you are looking for variants of complex diseases is only sufficient if you have data from thousands of participants, a logistical and financial challenge that is often beyond the resources of individual research teams. That is why more and more genetics studies using GWAS are the work of collaborating teams sharing resources.
Dr Dan Nicolae, associate professor of medicine, statistics, and human genetics at University of Chicago, is another senior author of the study and also co-chairs the EVE Consortium. He said more and more geneticists using GWAS to study diseases are realizing that “unless you pull together many researchers doing the same thing you’re just not going to have the power to find genes.”
“That was the motivation for nine groups of investigators coming together to form EVE,” he explained.
The research groups had been discussing the idea of the Consortium for some time but they lacked the other essential ingredient: finance. These projects are hugely expensive. So it wasn’t until they received a $5.6 million grant from the American Recovery and Reinvestment Act (ARRA) of 2009 that the teams could come together and start hiring the staff. They also had backing from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institutes of Health.
“The key was the ARRA funding that allowed us to move it faster,” said Nicolae; it would not have been possible without the grant.
Another important ingredient to increase the power of GWAS to the level necessary to find variants linked to asthma risk is to have a data set from an ethnically diverse population. The groups that came together for the EVE Consortium brought with them data that when pooled included European Americans, African Americans/African Caribbeans, and Latinos. This is something that studies from other countries have so far not been able to do.
“We believe that this heterogeneity is important,” said Ober, who went on to explain that:
“There are differences in asthma prevalence in these three groups, so it’s important to understand whether these are caused by environmental exposures or by differences in genetic risk factors.”
Asthma has been increasing in the US in recent years, particularly among African Americans.
For this study, the researchers pooled data from GWAS of asthma that altogether included 5,416 individuals with asthma who were of European American, African American or African Caribbean, and Latino ancestry, and replicated in another 12,649 individuals from the same ethnic groups.
They found five variants or “susceptibility loci” (one on the 17q21 gene, and three near the genes IL1RL1, TSLP and IL33), that had previously been identified in a separate data set by the GABRIEL Study researchers who studied 40,000 European asthma cases and wrote a paper on it published last year in the New England Journal of Medicine.
However, with the advantage of their diverese ethnic populations, the EVE researchers were able to add a new piece to the jigsaw about these four variants, as they write in their paper: “we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups”.
They also found a “new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent”. The polymorphism was not present in European-Americans.
The EVE researchers conclude:
“These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.”
Spurred by these discoveries, the EVE Consortium is now digging deeper into the data to find out more about the genetics of asthma. They want to explore gene-environment interactions, links with allergies and lung function, and the role of tissue-specific gene expression.
Nicolae said this paper is just the start of it, a foundation to make them all work together and start sharing data and ideas, and “that will generate a lot of research down the road”.
Written by Catharine Paddock, PhD