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A Granulin Variant Causing Childhood Interstitial Lung Disease Responsive to anti-TNF-a Biologic Therapy

ABSTRACT: We combined whole exome sequencing with digital spatial mRNA profiling of clinical lung biopsies in the diagnostic evaluation ofapre-teen with progressive idiopathic fibrotic lung and liver disease refractory to standard therapies. The combined findings of homozygosity for the p.Cys139Arg loss-of-function progranulin (GRN) variant and an alveolar macrophage transcriptomic signature consistent with TNF-alpha pathway activation motivated treatment with anti-TNF monoclonal antibodies, resulting in dramatic improvement of her lung and liver disease. These findings demonstrate the clinical utility of convergent multiomics in the evaluation and treatment of rare disease

ORGANISM(S): Homo sapiens

PROVIDER: GSE273182 | GEO | 2025/02/27

REPOSITORIES: GEO

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Project description:Objective: use comprehensive molecular profiling to understand the molecular mechanisms that affect clinical response to anti-TNF therapy in rheumatoid arthritis (RA) and to identify predictive markers to differentiate good responders and non-responders. Methods: two independent cohorts of 40 and 36 biologic-naïve RA patients were selected from the Corrona (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) CERTAIN registry and categorized by EULAR response criteria. Whole-blood RNA and plasma samples from baseline and after 3 months of anti-TNF treatment were profiled using RNA-seq, shotgun proteomics and glycopeptide analysis. A cell type-specific transcriptional data analysis was applied to RNA-seq data to evaluate the impact of the most common immune cell sub-populations. Results: a treatment-related molecular signature was identified that showed a high level of correlation (ρ=0.62; permutation p<0.01) between cohorts. Treatment led to a reduction of neutrophils, independent of the status of response. Gene expression differences between good responders and non-responders at baseline did not manifest statistically significant concordance genome-wide between the two cohorts. However, a cell type-specific analysis indicated increased representation of innate cell type signatures in good responders and, conversely, increased expression of adaptive cell type signatures in non-responders at baseline in both cohorts. This result was confirmed by applying the cell-type specific analysis to other publicly available RA datasets. Evaluation of the neutrophil to lymphocyte ratio (NLR) at baseline in the remaining patients (n=1962) from the CERTAIN database using a logistic regression model further confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03 – 1.41; p = 0.02]). Conclusion: differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

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A Granulin Variant Causing Childhood Interstitial Lung Disease Responsive to anti-TNF-a Biologic Therapy

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