Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

Aneas, Ivy; Decker, Donna C.; Howard, Carolyn M.; Sobreira, Débora R.; Sakabe, Noboru Jo; Blaine, Kelly M.; Stein, Michelle M.; Hrusch, Cara L.; Montefiori, Lindsey E.; Tena, Juan J.; Magnaye, Kevin M.; Clay, Selene M.; Gern, James E.; Jackson, Daniel J.; Altman, Matthew C.; Naureckas, Edward T.; Hogarth, D. Kyle; White, Steven R.; Gómez-Skármeta, José Luis; Schoetler, Nathan; Ober, Carole; Sperling, Anne I.; Nóbrega, Marcelo A.

doi:10.1038/s41467-021-26347-z

Cited by 34 publications

(28 citation statements)

References 47 publications

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“…12 ). This variant was also fine-mapped for eosinophil count in UKBB Europeans (PIP = 1.0; P = 1.3 × 10 −314 ) 16 and was previously reported to regulate IL33 gene expression in human airway epithelial cells via allele-specific transcription factor binding of OCT-1 (POU2F1) 77 . Likewise, we observed a missense variant rs16903574 (p.Phe319Leu) in OTULINL showed ΔPIP = 0.79 (PIP = 1.0 and 0.21 in GBMI and UKBB Europeans, respectively; Fig.…”

Section: Resultsmentioning

confidence: 80%

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Kanai

Elzur

Zhou

et al. 2022

Preprint

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Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWAS) into a more powerful whole. To resolve causal variants, meta-analysis studies typically apply summary statistics-based fine-mapping methods as they are applied to single-cohort studies. However, it is unclear whether heterogeneous characteristics of each cohort (e.g., ancestry, sample size, phenotyping, genotyping, or imputation) affect fine-mapping calibration and recall. Here, we first demonstrate that meta-analysis fine-mapping is substantially miscalibrated in simulations when different genotyping arrays or imputation panels are included. To mitigate these issues, we propose a summary statistics-based QC method, SLALOM, that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics based on ancestry-matched local LD structure. Having validated SLALOM performance in simulations and the GWAS Catalog, we applied it to 14 disease endpoints from the Global Biobank Meta-analysis Initiative and found that 68% of loci showed suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci were significantly depleted for having likely causal variants, such as nonsynonymous variants, as a lead variant (2.8x; Fisher's exact P = 6.2 × 10−4). Compared to fine-mapping results in individual biobanks, we found limited evidence of fine-mapping improvement in the GBMI meta-analyses. Although a full solution requires complete synchronization across cohorts, our approach identifies likely spurious results in meta-analysis fine-mapping. We urge extreme caution when interpreting fine-mapping results from meta-analysis.

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Section: Resultsmentioning

confidence: 80%

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Kanai

Elzur

Zhou

et al. 2022

Preprint

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“…And the Ovol1/IL-33 link regulates skin inflammation ( 14 ). An OCT-1 (POU2F1) binding site overlaps the asthma-associated single nucleotide polymorphism (SNP) rs1888909, which resides within 5kb of IL-33 gene and is associated with IL-33 expression ( 15 ). Focal adhesion kinase (FAK) can also translocate to the nucleus, where it binds to and promotes IL-33 expression in squamous cell carcinoma (SCC) cell lines ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Section: Many Stress and Inflammatory Signals Can Induce Il-33 Expres...mentioning

confidence: 99%

Tumor suppressor p53 deficiency increases tumor immunogenicity through promoting IL33-mediated anti-tumor immune responses

Gao

et al. 2022

Preprint

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Recent studies have shown that p53 contributes to poor survival during immune checkpoint blockade (ICB) therapy. Lung cancer patients with p53 mutations have significantly improved response rates to PD-1 ICB therapy. While previous studies have shown that tumor-derived IL-33 is required for the anti-tumor immune response and efficacy of ICB therapies, the relationship between p53 and IL-33 during ICB therapy is unknown. In this study, we characterized the role of the p53/IL-33 axis in regulating the tumor microenvironment (TME) in response to ICB therapy. CRISPR-Cas9- mediated deletion of Trp53 in tumor cells combined with PD-1 ICB therapy synergistically inhibited tumor growth in a murine MC38 colon adenocarcinoma model. We observed increased CD4+ and CD8+ T cell infiltration, as well as reduced Treg infiltration. IL-33 was upregulated and its expression increased with time and response to treatment. Simultaneous deletion of Il33 in the MC38 tumor cells reversed the efficacy of PD-1 ICB therapy. ST2-/- (IL-33 receptor) mice with Trp53-deficient MC38 tumors also showed no response to PD-1 ICB. Our findings depict a novel mechanism by which the loss of p53 in tumors treated with ICB therapy induces upregulation of tumoral IL-33 and host ST2 signaling. p53 mutations may be a double-edged sword for cancer, i.e. loss of the tumor suppressor initially facilitates tumorigenesis, but also leads to upregulation of danger signals in the tumor. These danger signals, such as IL-33, mediate the anti-tumor effect of ICB.

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“…Entre los genes más representativos en asma identificados por GWAS están el de la citocina IL-33 (IL33) y su receptor ST2 (IL1RL1). 30,35,36,41 Los GWAS han sido de vital importancia para la identificación de genes candidatos en asma, creando grandes bases de datos en diversas etnias. Se espera que, con esta información, se realicen futuros trabajos que mejoren nuestro entendimiento sobre esta enfermedad.…”

Section: Efecto Del Alelo De Riesgounclassified

Aspectos genéticos implicados en el asma

Corona‐Rivera

Peña-Padilla

Morales-Domínguez

et al. 2023

RAM

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El asma es una patología etiológicamente heterogénea resultante de una compleja interacción entre una susceptibilidad genética, factores del huésped y exposiciones ambientales. En el presente trabajo se revisan los aspectos genéticos implicados en el asma, los cuales fueron analizados desde la perspectiva del modelo tradicional de la herencia multifactorial. Fueron incluidos los estudios sobre su agregación familiar, concordancia en gemelos y heredabilidad, así como el conocimiento actual sobre genes candidatos, estudios de asociación amplia del genoma y las recientes contribuciones de la epigenómica y otros estudios ómicos, que en conjunto han aumentado nuestro conocimiento sobre su fisiopatología e interacciones ambientales.

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Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

Cited by 34 publications

References 47 publications

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Tumor suppressor p53 deficiency increases tumor immunogenicity through promoting IL33-mediated anti-tumor immune responses

Aspectos genéticos implicados en el asma

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