Biobank Study Reveals New Gene Variants Implicated In Asthma

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Asthma is a chronic condition that can sporadically effect breathing. People with the condition have narrowed inflamed airways, which produce excess mucus, restricting breathing. The “Dutch” hypothesis suggests that asthma may develop into COPD. According to the US Centers for Disease Control and Prevention (CDC), about 25 million Americans have asthma, including more than six million children. Nearly two million emergency department visits are attributable to asthma each year.

Genetic associations with asthma have been reported previously, however a new study with senior author Kari Stefansson of Amgen deCODE genetics, Reykjavik, Iceland, report 10 newly associated variants (19 at the time of manuscript preparation) by combining UK biobank and Icelandic datasets. The study was published in the journal Nature Communications.

In particular the authors highlight a low frequency missense mutation in tumor necrosis receptor family member TNFRSF8 (CD30), which is expressed by activated immune T-cells, B-cells, and eosinophils. When the authors expressed the CD30 p.Cys273Tyr variant in HeLa cells they found lower cell surface expression, and lower soluble CD30, compared to wild type CD30. This CD30 variant was associated with decreased risk of asthma in Stefansson’s study, which is in line with previous reports that showed that CD30 knock-out protected mice from asthma.

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The authors also reported a gain of function variant in Transforming Growth Factor Beta Receptor 1 (TGFBR1). A 3 prime UTR variant that increased TGFBR1 expression associated with reduced asthma risk.

The mutation prevents microRNA miR-142-3p from recognizing and marking the transcript for degradation resulting in greater than normal levels of TGFBR1 mRNA and protein. TGFβ signalling has a complex role inflammation, with both pro and anti-inflammatory roles, however mice deficient in the pathway do develop autoimmunity.

Genes involved in fibrosis may also promote asthma. Increased collagen type I in the extracellular matrix (ECM) of the lung of asthma patients is known. This may be caused by eosinophils that secrete TGFβ. COL16A1 is a type of collagen that acts in concert with collagens type I and II to maintain the ECM. The present study found that a variant that increased COL16A1 secretion by fibroblasts was associated with asthma risk.

“In summary, our study considerably expands the number of asthma susceptibility loci and confirms many previous findings. The results highlight the role of Th cells in asthma in line with imbalanced T cell regulation reported to play a critical role in asthma pathogenesis. We show evidence that two low frequency variants in TNFRSF8 and TGFBR1 associate with decreased asthma risk through loss of function and gain of function, respectively. Other susceptibility loci point to genes involved in inflammation and airway remodeling,” the authors concluded.