An international research team, including the Trans-National Asthma Genetics Consortium (TAGC), has discovered five new regions of the genome that increase the risk of asthma. Their study (“Multiancestry Association Study Identifies New Asthma Risk Loci That Colocalize with Immune-Cell Enhancer Marks”) appears in Nature Genetics.

“We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies…of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms,” write the investigators.

The scientists’ major finding is that the genetic loci associated with asthma are enriched in epigenetic marks characterizing gene enhancers. Another key element is the shared associations of variants with asthma, autoimmune diseases, and diseases with an inflammatory component. The outcomes of this work open new avenues of research, with the goal of elucidating the biological mechanisms underlying asthma in relationship with environmental exposures and promoting the development of new therapies, note the researchers. 

The TAGC study brought together more than 45 research groups from Europe, North America, Mexico, Australia, and Japan. It allowed pooling data on millions of DNA polymorphisms throughout the genome in more than 142,000 asthmatic and nonasthmatic subjects of European, African, Latino, and Japanese ancestry. Meta-analyses of genome-wide association studies conducted in these ethnically diverse populations identified a total of 878 genetic variants belonging to 18 loci associated with asthma risk.

The TAGC study showed that genetic variants associated with asthma are preferentially located near epigenetic markers in immune cells, suggesting a role of these variants in the regulation of immunologically related mechanisms. Another key element concerns the involvement of several identified candidate genes in the immune response to viruses, thus highlighting the importance of viral infections in the risk of asthma.

The genetic variants associated with asthma also have effects on autoimmune diseases and other diseases with an inflammatory component, such as cardiovascular diseases, cancers, and neuropsychiatric diseases, thus strengthening the importance of pleiotropy in multifactorial diseases.

“These results highlight the importance of large-scale genetic studies to better characterize complex diseases,” according to the scientists who come from Inserm and Paris Diderot University, the University of Chicago, the National Heart and Lung Institute (U.K.), and the University of Colorado Anschutz Medical Campus. “This study opens new avenues of research aiming at integrating genomic and epigenomic data together with environmental exposures in order to elucidate the physiopathological mechanisms underlying asthma and to promote the development of new therapies.”

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