Highlights
- Mendelian randomization (MR) confirms causal impact of increased body mass index (BMI) and inflammatory bowel disease (IBD) on the risk of hidradenitis suppurativa (HS).
- Smoking shows initial genetic evidence of causality but lacks consistent support in sensitivity MR analyses.
- Genetic correlations link HS with multiple inflammatory disorders, including psoriasis and rheumatoid arthritis, while systemic sclerosis shows no causality with HS risk.
- These genetic insights offer clinicians evidence to advocate lifestyle modification and target systemic inflammation in HS management.
Background
Hidradenitis suppurativa (HS) is a chronic, painful inflammatory skin disease primarily affecting intertriginous areas, characterized by recurrent abscesses and scarring. With estimated prevalence rates up to 1%, HS imposes significant morbidity and healthcare burden. Clinically observed associations implicate environmental risk factors such as smoking and obesity in HS pathogenesis. However, the complexity of confounding and reverse causation has limited causal inference from observational studies. Moreover, HS often co-occurs with systemic inflammatory diseases like psoriasis, inflammatory bowel disease (IBD), and systemic sclerosis (SSc), warranting genetic analyses to elucidate shared etiologies and causal pathways. The recent advent of robust genome-wide association studies (GWAS) datasets and Mendelian randomization (MR) techniques enables assessment of causal relationships leveraging genetic instruments as proxies for exposures.
Key Content
Mendelian Randomization Study Design and Population
The pivotal Mendelian randomization study by Kjærsgaard Andersen et al. (2025) analyzed 5 exposure phenotypes — BMI, smoking, psoriasis, IBD, and SSc — for causal effects on HS risk using 2-sample MR. GWAS summary statistics were sourced from large cohorts composed primarily of White European ancestry individuals. The HS GWAS included 4,814 cases and >1.2 million controls spanning Denmark, Iceland, Finland, the UK, and the US. Exposure GWASs involved 700,000 participants for BMI (UK Biobank and GIANT consortium), 1.23 million for smoking (international consortium), 39,498 for psoriasis, 38,155 for IBD, and 9,095 for SSc. Genome-wide significant single nucleotide polymorphisms (SNPs) associated with exposure phenotypes served as instrumental variables.
Genetic Correlations Between HS and Exposures
Genetic correlation analyses identified statistically significant positive correlations (rg) of HS with BMI (rg=0.36, P<.001), smoking (rg=0.33, P<.001), IBD (rg=0.25, P<.001), and psoriasis (rg=0.34, P<.001), indicating shared polygenic architecture. SSc exhibited a moderate but not statistically significant correlation (rg=0.33, P=.22).
Causal Effects Estimated by Mendelian Randomization
- BMI and HS: MR analyses demonstrated a robust causal effect of increased BMI on HS risk with no evidence of pleiotropy (β=0.87; odds ratio [OR] per BMI unit=1.20; 95% confidence interval [CI], 1.17–1.23; P<.001). Sensitivity tests confirmed instrument validity and consistency.
- Smoking and HS: Initial MR indicated a significant causal estimate for smoking increasing HS risk (β=0.59; P<.001). However, subsequent sensitivity analyses yielded inconclusive results, suggesting potential pleiotropy or bias affecting inference.
- Inflammatory Diseases and HS: Among psoriasis, IBD, and SSc, only IBD showed a causal effect on HS risk (β=0.18; OR=1.20; 95% CI, 1.15–1.24; P<.001) without pleiotropic effects, underscoring a shared inflammatory-pathogenetic pathway. Psoriasis and SSc did not demonstrate causality in MR.
Supporting Evidence from Related Genetic and Molecular Studies
A GWAS meta-analysis of HS involving over 4,500 patients found 11 significant genetic loci related to HS susceptibility, with particular functional variants near KLF5 and SOX9 influencing transcriptional regulation in skin barrier and repair pathways (Br J Dermatol, 2025). Significant genetic overlap with IBD and other inflammatory conditions suggests mechanistic linkages involving immune dysregulation.
Moreover, MR studies on inflammatory cytokines and skin fibrosis identified stem cell growth factor beta (SCGF-β) as a putative mediator in fibrotic skin diseases, including HS, underscoring immune and fibrotic mechanisms (Eur J Dermatol, 2025).
Complementary MR analyses elucidating systemic inflammation, obesity, and nutrient mediators indicate that while BMI causally elevates pro-inflammatory biomarkers, vitamin D does not mediate obesity-related inflammation, emphasizing the complexity of inflammatory pathways in HS comorbidities (Am J Clin Nutr, 2020).
Expert Commentary
This Mendelian randomization study represents a landmark analysis clarifying causality in HS risk factors beyond observational associations. The strong causal effect of BMI on HS reinforces the central role of obesity as a modifiable clinical target. Adiposity may exacerbate follicular occlusion, inflammation, and dysregulated immune responses leading to HS lesion formation. The confirmed causal link with IBD aligns with clinical co-presentation patterns and supports shared immune pathogenic pathways, notably dysregulated innate and adaptive immunity and cytokine signaling.
The inconclusive role of smoking in MR sensitivity analyses highlights complexities in genetic instruments for smoking behaviors and potential confounding pleiotropy, reflecting challenges in capturing the multifaceted impacts of tobacco on inflammation and skin health. Nevertheless, smoking cessation remains clinically recommended due to consistent epidemiological evidence of harm.
The absence of a causal relationship between HS and psoriasis or systemic sclerosis in MR analyses suggests distinct pathogenic processes despite overlapping inflammatory milieus. Molecular genetic studies identifying HS-associated loci modulating skin barrier and inflammatory responses provide a translational framework for novel targeted therapeutics.
Collectively, these findings underscore the importance of integrating genetic epidemiology, immunology, and clinical practice to optimize patient risk stratification and intervention strategies.
Conclusion
The integration of large-scale GWAS and sophisticated Mendelian randomization analyses establishes increased BMI and IBD as causal drivers of hidradenitis suppurativa susceptibility. These data substantiate the imperative for clinicians to emphasize weight management and monitor for gastrointestinal inflammatory comorbidities in HS patients. Smoking’s causal status remains equivocal, warranting further research. Future investigations should expand to non-European ancestries and explore gene-environment interactions. Elucidation of molecular pathways converging on HS pathology will catalyze development of targeted, mechanism-based treatments. This evidence-based genetic perspective advances understanding and clinical management of HS within a precision medicine framework.
References
- Kjærsgaard Andersen R, Riis PT, Zachariae C, et al. Hidradenitis Suppurativa and Smoking, Obesity, Psoriasis, Inflammatory Bowel Disease, and Systemic Sclerosis: Results From A 2-Sample Mendelian Randomization Study. JAMA Dermatol. 2025 Dec 17. doi:10.1001/jamadermatol.2025.5010. PMID:41405899
- Kodama A, Gudjonsson JE. Genomic loci and molecular genetic mechanisms for hidradenitis suppurativa. Br J Dermatol. 2025 Oct;193(5):948-958. doi:10.1093/bjd/ljaf277. PMID:40650879
- Wang H, et al. Association between stem cell growth factor beta and fibrotic skin diseases. Eur J Dermatol. 2025 Oct;35(5):377-386. doi:10.1684/ejd.2025.4955. PMID:41277648
- Karimi F, et al. Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study. Am J Clin Nutr. 2020 May 1;111(5):1036-1047. doi:10.1093/ajcn/nqaa056. PMID:32232398
- Giustizieri ML, et al. Genetic polymorphisms in CYP2A6 are associated with a risk of cigarette smoking and predispose to smoking at younger ages. Gene. 2017 Sep 10;628:205-210. doi:10.1016/j.gene.2017.07.051. PMID:28734893