Candidate Predisposition Variants in Kaposi Sarcoma as Detected by Whole-Genome Sequencing

Rinne, Sanni; Sipilä, Lauri J.; Sulo, Päivi; Jouanguy, Emmanuelle; Béziat, Vivien; Abel, Laurent; Casanova, Jean‐Laurent; Parvaneh, Nima; Balighi, Kamran; Guttman‐Yassky, Emma; Sarid, Ronit; Aaltonen, Lauri A.; Aavikko, Mervi

doi:10.1093/ofid/ofz337

Cited by 8 publications

(2 citation statements)

References 18 publications

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“…Previous studies have identified CDHR5- SNPs located close to IRF7 31 , 32 and associated with systemic sclerosis (SS) 32 . The candidate gene CDHR5 is a member of the cadherin family which interacts with the β-catenin pathway 33 . These observations are in agreement with a growing body of evidence that highlights that genetic effects are largely context and time-specific, and implicates that future research and data collection of pathological and molecular status within longitudinal larger autoimmune populations will be able to decipher many more genetic variants with important regulatory functions in autoimmunity 34 .…”

Section: Discussionmentioning

confidence: 99%

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants

Castellini-Pérez,

Povedano,

Barturen

et al. 2024

npj Genom. Med.

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The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered.

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Section: Discussionmentioning

confidence: 99%

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants

Castellini-Pérez,

Povedano,

Barturen

et al. 2024

npj Genom. Med.

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show abstract

“…Previous studies have identified CDHR5- SNPs located close to IRF7 (37,38) and associated with systemic sclerosis (SS) (38). The candidate gene CDHR5 is a member of the cadherin family which interacts with the β-catenin pathway (39). These observations are in agreement with agrowing body of evidence that highlights that genetic effects are largely context and time-specific, and implicates that future research and data collection of pathological and molecular status within longitudinal larger autoimmune populations will be able to decipher many more genetic variants with important regulatory functions in autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

The Lupus Epigenome Relates to Genetics, Transcription and Serological Profiles with Dependency on Molecular Subtypes and Informs Drug Discovery

Castellini-Pérez¹,

Barturen²,

Martínez-Bueno³

et al. 2023

Preprint

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Objective. The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. Methods. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. Results. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel potential drug targets for SLE. Conclusion. This study expands the number of genes associated with SLE and reveals novel pathways of disease. The findings reveal possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and the genetic architecture of DNAm in different molecular contexts. Finally, novel targets for drug development were discovered.

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Human Herpesviruses: Kaposi’s Sarcoma and Other Malignancies

Sarid

Dünn-Kittenplon

Calabrò

2022

Viral Infections of Humans

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Candidate Predisposition Variants in Kaposi Sarcoma as Detected by Whole-Genome Sequencing

Cited by 8 publications

References 18 publications

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants

The Lupus Epigenome Relates to Genetics, Transcription and Serological Profiles with Dependency on Molecular Subtypes and Informs Drug Discovery

Human Herpesviruses: Kaposi’s Sarcoma and Other Malignancies

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