Inflammatory Proteins and Hidradenitis Suppurativa: Insights from Genetic Correlation and Mendelian Randomization Studies

Research Background

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent nodules, abscesses, and sinus tracts, commonly found in areas of skin friction such as the armpits, groin, perianal region, and inframammary folds. The prevalence of HS is estimated to be between 1% and 4%, with onset typically occurring between the ages of 10 and 30, and it is more common in female patients. However, due to inconsistencies in data collection, diagnostic challenges, and the stigma associated with the disease, the actual prevalence of HS may be underestimated.

The pathogenesis of HS is complex, involving multiple factors such as genetic susceptibility, follicular occlusion and rupture, mechanical stress, immune system dysregulation, and hormonal disturbances. Current treatments primarily include medications such as antibiotics, corticosteroids, retinoids, and hormone therapy, as well as physical/surgical methods like carbon dioxide laser therapy, incision and drainage, deroofing, and wide excision. However, clinical evidence supporting these treatments is relatively limited, and the recurrence rate after surgery is high. Therefore, there is an urgent need to develop new treatments to improve patient outcomes.

Recent studies have shown that inflammatory proteins play a significant role in the pathological process of HS. Currently, two main hypotheses have been proposed to explain the inflammatory mechanisms of HS: the “excessive inflammation” hypothesis, which suggests that the pathological changes in HS result from the overactivation of local and systemic inflammatory responses; and the “immune dysregulation” hypothesis, which posits that HS is associated with abnormal immune system regulation. Although existing studies have revealed the roles of various inflammatory proteins in HS, these studies are often limited by sample selection and research design, leaving the potential causal relationships unclear.

Research Source

This study was conducted by a research team from the Department of Traditional Chinese Medicine at Xiangyun County People’s Hospital in Dali, China, and was published in the Journal of Dermatology in 2024. The research team employed Mendelian Randomization (MR) analysis and Linkage Disequilibrium Score Regression (LDSC) to explore the genetic correlations and potential causal relationships between 91 circulating inflammatory proteins (CIPs) and HS.

Research Process and Results

1. Study Design and Data Sources

The study utilized LDSC and bidirectional two-sample MR analysis, leveraging publicly available Genome-Wide Association Studies (GWAS) data to investigate the genetic correlations and causal relationships between 91 CIPs and HS. The study was divided into two parts: the forward MR analysis treated HS as the outcome and selected instrumental variables (IVs) related to each CIP to infer their causal relationship with HS; the reverse MR analysis treated HS as the exposure and assessed its causal effects on CIPs.

Data sources included:
- GWAS data for CIPs were derived from a large-scale genomic association study based on the Olink targeted inflammation protein panel, analyzing 91 plasma proteins from 14,824 participants.
- GWAS data for HS were obtained from the latest version of the FinnGen study, which included 1,209 cases and 432,686 controls, all of European ancestry.

2. Genetic Correlation Analysis

Through LDSC regression analysis, the research team calculated the genetic correlations between 79 CIPs and HS. The results showed significant genetic correlations between Fibroblast Growth Factor 21 (FGF-21) and Stem Cell Factor (SCF) with HS. Specifically, the genetic correlation estimate between FGF-21 levels and HS was 0.494 (p=0.017), while the genetic correlation estimate between SCF levels and HS was -0.298 (p=0.043).

3. Mendelian Randomization Analysis

In the forward MR analysis, the research team selected 7 to 30 IVs related to each CIP and used methods such as Inverse Variance Weighted (IVW), MR-Egger, and weighted median to assess their causal relationship with HS. The results indicated that elevated levels of T-cell surface glycoprotein CD5 (CD5) and C-X-C motif chemokine 11 (CXCL11) were associated with an increased risk of HS, while elevated levels of C-C motif chemokine 4 (CCL4), protein S100-A12 (EN-RAGE), interleukin-10 receptor subunit beta (IL-10RB), and programmed cell death 1 ligand 1 (PD-L1) were associated with a reduced risk of HS.

In the reverse MR analysis, the research team found that HS could lead to increased levels of four CIPs, including interleukin-20 (IL-20), leukemia inhibitory factor (LIF), LIF receptor (LIF-R), and thymic stromal lymphopoietin (TSLP).

4. Sensitivity Analysis

To verify the robustness of the results, the research team conducted sensitivity analyses, including Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and radial MR analysis. The results showed no significant heterogeneity or horizontal pleiotropy in either the forward or reverse MR analyses, further confirming the reliability of the findings.

Research Conclusions and Significance

1. Main Findings

The study revealed that elevated levels of CD5 and CXCL11 in serum were associated with an increased risk of HS, while elevated levels of CCL4, CX3CL1, EN-RAGE, IL-10RB, and PD-L1 were associated with a reduced risk of HS. Additionally, HS could lead to increased circulating levels of IL-20, LIF, LIF-R, and TSLP. These findings provide new insights into the inflammatory mechanisms of HS and offer references for future therapeutic interventions and potential treatment targets.

2. Scientific Value

By employing LDSC and MR analysis, this study effectively minimized the interference of confounding factors and reverse causality, enhancing the reliability of causal inference. The research uncovered potential upstream factors and downstream effects in the pathogenesis of HS, laying the foundation for treatment strategies.

3. Application Value

The findings of this study offer new perspectives for the diagnosis and treatment of HS. For example, CD5 and CXCL11 could serve as new therapeutic targets for HS, while the elevation of IL-20, LIF, LIF-R, and TSLP may be closely related to the pathological process of HS. These results not only contribute to a deeper understanding of HS pathogenesis but also provide a theoretical basis for developing innovative therapies for HS.

Research Highlights

1. Innovation: This study is the first to systematically analyze the genetic correlations and causal relationships between 91 CIPs and HS using GWAS data and MR methods, filling a gap in this research field.
   
2. Comprehensiveness: The study not only explored the potential causal effects of CIPs on HS but also revealed the impact of HS on CIPs through reverse MR analysis, providing a more comprehensive understanding of HS pathology.
   
3. Robustness: Through multiple sensitivity analyses, the research team validated the reliability of the results, enhancing the credibility of the conclusions.
   
4. Clinical Significance: The findings identified multiple inflammatory proteins associated with HS, offering potential targets for future clinical interventions and drug development.

Prospects and Limitations

Although this study has made significant progress, there are still some limitations. For instance, the data were primarily from European populations, which may limit the generalizability of the conclusions. Additionally, the measurement of CIPs was based on plasma samples, which may not fully reflect the inflammatory state of skin tissue. Future research should include data from more ethnic groups and further further