Hidradenitis suppurativa presents a methylome dysregulation capable to explain the pro‐inflammatory microenvironment: Are these <scp>DNA</scp> methylations potential therapeutic targets?

Background: Hidradenitis suppurativa (HS) is a complex, chronic inflammatory skin disorder whose pathophysiology is poorly understood. Genetic studies have shown that HS is predisposed by mutations in the γ-secretase gene, but only a proportion of familial and partial sporadic cases have been shown to possess such mutations. HS has high genetic heterogeneity and is thought to be triggered by a combination of genetics and environmental factors. Aims: The study aimed to investigate the genetic causes of HS in a large cohort of patients and to update the mutation spectrum of γ-secretase complex genes. Methods: We conducted mutational screening of 95 sporadic HS cases and one large family with both HS and acne conglobata (AC) to identify mutations in the coding and splice junction region of γ-secretase complex genes (nicastrin ( NCSTN ), presenilin 1 ( PSEN1 ), presenilin enhancer 2 ( PSENEN ), and aph-1 homolog B, gamma-secretase subunit ( APH1B) ). Results: Our study identified a nucleotide substitution of 1876C>T in the NCSTN gene, which caused a stop codon (p.Arg626X) in the affected members of a large family with HS and AC. No pathogenic variants were detected in 95 sporadic cases of HS, indicating there is possible genetic heterogeneity. Conclusion: We report a new family with a nonsense mutation in the NCSTN gene that supports the role of the γ-secretase complex genes in HS with AC. The updated γ-secretase mutation spectrum for HS now includes 78 mutations.

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“…Recent studies identified microRNA, cytochrome, and cytokine gene methylation dysregulations associated with HS. [ 65 66 67 68 ]…”

Section: Discussionmentioning

confidence: 99%

An Updated Mutation Spectrum of the γ-Secretase Complex

Uppala

Jain

Jhala

et al. 2023

Indian Journal of Dermatology

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“…Epigenetic studies highlighted a dysmethylation background for HS patients, which disrupts cell aging and functionality, inflammatory response, and drug metabolism, consequently altering the cutaneous immune system–microbiome homeostasis [ 6 , 7 , 8 , 9 ]. Thus, a more detailed understanding of cutaneous dysbiosis occurrence is of paramount importance to prevent disease progression and innovate a curative intervention instead of merely treatment.…”

Section: Introductionmentioning

confidence: 99%

Rethinking Hidradenitis Suppurativa Management: Insights into Bacterial Interactions and Treatment Evolution

Huynh,

Damiani,

Bunick

2024

Antibiotics

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Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory dermatological condition characterized by painful and recurrent nodules and purulent abscesses. HS can have a devastating impact on the quality of life of patients. This condition is commonly localized to the axilla, groin, perineal, and inframammary regions, and can develop fistulas and sinus tracts over time. Its pathogenesis remains elusive and is best characterized at the moment as multi-factorial. Additionally, questions remain about the role of cutaneous dysbiosis as a primary HS trigger or as a secondary perturbation due to HS inflammation. This article features works in relation to HS and its interplay with bacterial microflora. We address current treatment approaches and their impact on HS-related bacteria, as well as areas of therapeutic innovation. In the future, disease-modifying or remittive therapy will likely combine an advanced/targeted anti-inflammatory approach with one that effectively modulates cutaneous and deep tissue dysbiosis.

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“…The immunopathology of HS includes genetic factors and environmental factors including obesity and smoking (both active and passive) and various epigenetic alterations have been reported. [6][7][8][9][10][11][12] Studies of various large-scale exomes and candidate γ-secretase gene mutations have been reported to have identified ~80 different gene variants involved in HS disease aetiology across the globe, 13,14 as well as genetic heterogeneity. 15 Most variants were detected in patients with a family history of HS, but a small number were also found in sporadic cases.…”

Section: Introductionmentioning

confidence: 99%

Hidradenitis suppurativa associated telomere‐methylome dysregulations in blood

Radhakrishna,

Ratnamala,

Jhala

et al. 2023

Acad Dermatol Venereol

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BackgroundHidradenitis suppurativa (HS) is a chronic debilitating disease with a significant burden of both organic and psychological comorbidities. It has been shown that certain telomere‐related genes (TRGs) affect a wide range of diseases, including HS and its associated comorbidities, but their exact role in HS pathogenesis is still unknown.ObjectivesTo determine whether TRG methylomes can be used as biomarkers in HS.MethodsUsing the Illumina HumanMethylation450 BeadChip array, we examined methylation variations associated with TRGs in HS cases and age‐, sex‐, and ethnicity‐matched healthy controls. The study utilized integrated bioinformatics statistical methods, such as a false discovery rate (FDR), the area under the receiver operating characteristic curve (AUC), and principal component analysis.ResultsThere were a total of 585 different differentially methylated CpG sites identified in 585 TRGs associated with HS (474 hypomethylated and 111 hypermethylated) (FDR p‐value <0.05). A number of these CpGs have been identified as being involved in increased pain sensitivity including EPAS1, AHR, CSNK1D, DNMT1, IKBKAP, NOS3, PLCB1, and PRDM16 genes; GABRB3 as a potential alcohol addiction marker; DDB1, NSMCE2, and HNRNPA2B1 associated with cancers. Pathway analysis identified 67 statistically significant pathways, including DNA repair, telomere maintenance, mismatch repair, and cell cycle control. (p<0.001).ConclusionThe disruption of TRGs leads to the shortening of telomeres, which is associated with HS progression, aging, cellular senescence, and an increased risk of various diseases, including cancer and associated comorbidities, such as metabolic syndrome, cardiovascular disease, and inflammatory disorders. Further research is necessary to better understand the underlying mechanisms and establish causal links between TRGs and HS. The present study is the first effort to comprehend potential pathomechanisms of sporadic HS cases concentrating on PBMC methylome since ours.

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Hidradenitis suppurativa presents a methylome dysregulation capable to explain the pro‐inflammatory microenvironment: Are these DNA methylations potential therapeutic targets?

Cited by 8 publications

References 76 publications

An Updated Mutation Spectrum of the γ-Secretase Complex

An Updated Mutation Spectrum of the γ-Secretase Complex

Rethinking Hidradenitis Suppurativa Management: Insights into Bacterial Interactions and Treatment Evolution

Hidradenitis suppurativa associated telomere‐methylome dysregulations in blood

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