NEW YORK (GenomeWeb) – Many genetic contributors to allergic rhinitis, or hay fever, appear to be peppered across parts of the genome that mediate immune pathways, according to a new meta-analysis and fine-mapping study.
Members of an international consortium headed by investigators in Denmark and Germany brought together data for hundreds of thousands of individuals with or without allergic rhinitis, narrowing in on variants at 21 loci previously linked to hay fever or related allergies and 20 loci not implicated in the inflammatory condition in the past. Through a series of fine-mapping and functional annotation efforts, they found that this set included variants in and around genes from multiple immune-related pathways.
"[W]e expanded the number of established susceptibility loci for allergic rhinitis and highlighted the involvement of allergic rhinitis-susceptibility loci in diverse immune cell types and both innate and adaptive IgE-related mechanisms," corresponding author Klaus Bønnelykke, a researcher at the University of Copenhagen, and his colleagues wrote in a paper published online yesterday in Nature Genetics.
For the initial meta-analysis, the researchers included genotyping data for 59,762 individuals with hay fever and 152,358 without, searching more than 16.5 million genotyped or imputed markers across the genome for variants that were overrepresented in cases. They tracked down more than two dozen suspicious sites in the genome, along with 21 known risk loci, prompting a replication analysis focused on 25 loci in another 60,720 cases and 618,527 controls.
After that analysis, the team was left with significant associations at 20 new disease-linked loci, which were folded in with known loci and examined in more detail using available expression quantitative trait locus, methylation quantitative trait locus, and enhancer-promoter data. At least 33 of the sites appeared to contain regulatory variants, including those influencing B cells, T cells, and other immune cell functions, though the variant set also highlighted more than 255 genes with possible roles in allergic rhinitis.
When the researchers fine-mapped the major histocompatibility complex region — an immune region on chromosome 6 that appeared to have strong ties to allergic rhinitis risk — they uncovered a regulatory variant influencing the expression of human leukocyte antigen genes in lung or immune tissue types. These and other findings pointed to ties between hay fever-associated variants and the immune system, though some variants without obvious disease-related roles turned up as well.
"The risk loci we have identified can help understanding the mechanisms causing allergic rhinitis and hopefully also to find targets for treatment and prevention," Bønnelykke said in a statement, noting that "the genes we identified only partly explain why so many people develop allergic rhinitis."
"One important next step is to understand how risk genes interact with our environment," he added.
At least some variants unearthed in the meta-analysis were also implicated in a GWAS reported by members of the same team last year, which focused on asthma, eczema, and allergic rhinitis. This prompted the authors of the new analysis to suggest that the three immune conditions "are related but distinct disease entities."
In the new study, meanwhile, the researchers' GWAS, based on data for more than 8,000 cases and 16,441 controls, led to 10 loci associated with allergic sensitization, with all but one of the allergic rhinitis-linked variants displaying comparable relationships to allergic sensitization. From thousands more non-allergic rhinitis cases and controls, they did not pick up significant individual risk loci, though there were further hints of overlap with allergic rhinitis.
Overall, the authors wrote, they saw "a strong correlation between allergic rhinitis and allergic sensitization, a moderate correlation with asthma, and a weaker correlation with eczema."