Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
STING-Associated Vasculopathy with Onset in Infancy (SAVI) is an IFN-mediated disease caused by gain-of-function mutations in TMEM173, the gene encoding the stimulator of interferon genes (STING). SAVI is a member of a subclass of interferon-mediated autoinflammatory disorders caused by chronic Type-I interferon (IFN) production. To evaluate genetic causes of the variable disease severity of the interstitial lung disease (ILD) in SAVI patients, we hypothesized that the severity of the interstitial lung disease may be modulated by a common SNP (R232H, rs1131769) that is functionally associated with decreased IFNB1 transcription.
Twelve SAVI patients, with N154S, V155M, V147L, or V147M TMEM173 mutations, were evaluated. Lung involvement was assessed by chest computed tomography (CT) and pulmonary function tests (PFTs) for all patients; lung biopsies were available for seven patients. Peripheral blood genomic DNA samples were obtained and TMEM173 (NM_198282.3) gene was sequenced by Sanger technique. STING function was evaluated in the different TMEM173 haplotypes by IFNB1 Luciferase Reporter assays performed with cells transfected with wildtype or mutant TMEM173 on the R232 and the H232 backgrounds.
Of twelve SAVI patients, nine had evidence of severe ILD characterized by moderate to severe abnormalities on chest CT, PFTs and/or lung biopsy. Four out of the nine patients with severe ILD succumbed to pulmonary complications. Two patients presented with mild ILD and one did not have any evidence of ILD. The only patient without ILD was homozygous for the H232 allele (H232/H232) and the two patients with mild ILD were heterozygous (R232/H232) for the SNP. On contrast, 8 out of the 9 patients with severe ILD were homozygous for R232 (R232/R232) and one was heterozygous for the SNP. Thus, the severity of interstitial lung disease seems to correlate with the STING haplotype. Transfection of HEK293T cells with the R232 TMEM173 haplotype with or without SAVI-causing mutations results in significantly increased IFNB1 expression in the presence of both low affinity and high affinity STING stimulator cGAMP in comparison with cells transfected with the H232 haplotype. These findings suggest that the H232 haplotype background may be protective from the development of ILD and that gain-of-function of STING in the R232 background seems to provoke a more severe lung phenotype.
The variable severities of ILD in SAVI patients are associated with the TMEM173 haplotype at amino acid position 232. Our functional data suggest that common polymorphisms can modify organ-specific disease expression and provide insights to understanding the variable disease phenotype in other IFN-mediated diseases.
To cite this abstract in AMA style:Malle L, Marrero B, Liu Y, Montealegre Sanchez GA, Chapelle DC, Kim H, O'Brien M, Ramsey S, Dueckers G, Ozen S, Wittkowski H, Föll D, Tenbrock K, Jones OY, Holland SM, Fontana J, Huang Y, Gonzalez B, Brogan P, Brunner J, Ramanan AV, Hilliard T, Santiago L, Brescia A, Paller A, Brooks S, Deng Z, Almeida de Jesus A, Goldbach-Mansky R. Interstitial Lung Disease in Sting-Associated Vasculopathy with Onset in Infancy (SAVI): Genotype-Phenotype Correlation [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/interstitial-lung-disease-in-sting-associated-vasculopathy-with-onset-in-infancy-savi-genotype-phenotype-correlation/. Accessed September 30, 2020.
« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/interstitial-lung-disease-in-sting-associated-vasculopathy-with-onset-in-infancy-savi-genotype-phenotype-correlation/