The R213G polymorphism in SOD3 protects against allergic airway inflammation
Rohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, Russell P. Bowler
Rohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, Russell P. Bowler
View: Text | PDF
Research Article Inflammation Pulmonology

The R213G polymorphism in SOD3 protects against allergic airway inflammation

Abstract

Oxidative stress is important in the pathogenesis of allergic asthma. Extracellular superoxide dismutase (EC-SOD; SOD3) is the major antioxidant in lungs, but its role in allergic asthma is unknown. Here we report that asthmatics have increased SOD3 transcript levels in sputum and that a single nucleotide polymorphism (SNP) in SOD3 (R213G; rs1799895) changes lung distribution of EC-SOD, and decreases likelihood of asthma-related symptoms. Knockin mice analogous to the human R213G SNP had lower airway hyperresponsiveness, inflammation, and mucus hypersecretion with decreased interleukin-33 (IL-33) in bronchoalveolar lavage fluid and reduced type II innate lymphoid cells (ILC2s) in lungs. SOD mimetic (Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin) attenuated Alternaria-induced expression of IL-33 and IL-8 release in BEAS-2B cells. These results suggest that R213G SNP potentially benefits its carriers by resulting in high EC-SOD in airway-lining fluid, which ameliorates allergic airway inflammation by dampening the innate immune response, including IL-33/ST2–mediated changes in ILC2s.

Authors

Rohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, Russell P. Bowler

×

Figure 2

The association between SOD3 R213G genotype and asthma phenotypes in logistic regression and in single- and multiple-failures-per-subject Cox regression in the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS) separately and combined.

Options: View larger image (or click on image) Download as PowerPoint
The association between SOD3 R213G genotype and asthma phenotypes in log...
In all analyses, SOD3 R213G is used as a continuous variable for maximal power. Cox regression was with entry at 1977, when the Danish Patient Registry began, thus including both incident and prevalent cases. Any asthma: either self-reported asthma, a hospital diagnosis of asthma, or medication for asthma among never-smokers. Allergic asthma: individuals with any asthma who also reported allergy triggers such as food, grass, flowers, animals, or others. *Combined in a fixed effect meta-analysis using the metan command in STATA. OR, odds ratio from logistic regression; CI, confidence interval. In the CGPS, a total of 99,958 R213G non-carriers (97.5%), 2,533 R213G heterozygotes (2.5%), and 15 R213G homozygotes (0.01%) were identified. In the CCHS, 8,634 were R213G non-carriers (97.6%), 207 were R213G heterozygotes (2.3%), and 2 (0.02%) were R213G homozygotes.