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Ancestry empowers discoveries of novel genetic associations in asthma

Published online: September 7, 2018

Asthma continues to be one of the most common chronic diseases in the world, yet much of the genetic basis of this condition remains unknown, particularly in individuals of non-European descent. Over 80% of participants in genome-wide association studies have been of European descent, making it unclear if discoveries from these studies are relevant to individuals of other continental descents. Traditionally, large-scale genome-wide association studies have been used to identify novel genetic variation involved in disease susceptibility. However, leveraging the mixture of continental genetic ancestries of Hispanic/Latino individuals allows further opportunity to re-investigate genome-wide association data, and identify additional risk loci.

To address the limited understanding of genetic discoveries across multiple populations, the trans-ethnic EVE consortium, was devised to determine the underpinnings of asthma. The EVE Consortium included over 3,900 Hispanic/Latino individuals. In a recently published manuscript in The Journal of Allergy and Clinical Immunology (JACI), Gignoux, Torgerson and colleagues used the patterns of mixed ancestry found in populations from Latin America to identify an ancestry-based genetic association on chromosome 18 that replicated in an additional ~3,800 individuals in the GALA II study. This genomic signal was centered on the SMAD2 gene, a key messenger molecule in the TGF-beta signaling pathway known to modulate the immune response involved in asthma.

While SMAD2 is a well-studied candidate gene for its role in asthma biology, variation in the gene had never been previously associated with asthma. Further, with deep characterization of disease severity in the GALA II patients with asthma, Gignoux, Torgerson and colleagues discovered differences in SMAD2 expression in the blood of asthma cases vs. controls. In particular, low SMAD2 gene expression was associated with a ~4-fold increase in asthma susceptibility. Within asthma cases, lower expression was associated with an increased frequency of asthma exacerbations, particularly in Puerto Ricans, a group with the highest prevalence of asthma and elevated levels of asthma severity.

The author’s findings highlight the importance of 1) including diverse populations and 2) considering genetic ancestry in genome-wide investigations to better characterize the genetic architecture of common chronic diseases such as asthma. In fact, the researchers found that standard genome-wide association techniques would have failed to implicate SMAD2. By deconvoluting patterns of genetic ancestry, Gignoux, Torgerson and colleagues identified a novel genetic association that replicated across multiple studies, which enabled the identification of a possible new biomarker to identify individuals needing medical intervention. As the field moves towards personalized medicine, it is critical to include individuals with diverse genetic ancestry in studies of complex disease to address the needs of all individuals and to better understand the biology of the disease.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

JACI 15-01422, An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos