Causal association between body fat percentage and hidradenitis suppurativa: A two‐sample Mendelian randomization study

Mendelian randomization (MR) studies have identified elevated waist circumference (WC) and body mass index (BMI) as causal risk factors for hidradenitis suppurativa (HS). Obesity is highly heterogeneous, and simple anthropometric indices such as BMI and WC do not sufficiently reflect total body adiposity.1 Specifically, BMI does not differentiate between body composition (fat vs. fat-free mass), body fat distribution (truncal vs. gluteofemoral, subcutaneous vs. visceral) and adipocyte function. Visceral adipose tissue induces metabolic inflammation, insulin resistance and dysglycaemia via proinflammatory adipocytokines. We employed a two-sample MR methodology to interrogate the casual relationship between body fat percentage (BF%) as the exposure variable and HS as the outcome. The following summary statistics were obtained from publicly available genome-wide association study (GWAS) datasets. For BF%, we used UK Biobank data (data field 23,099, ID: ebi-a-GCST90013975) with a sample size of 401,772 individuals.2 For HS, we used FinnGen Biobank data including 409 individuals with HS and 211,139 without.3 Single nucleotide polymorphisms (SNP) associated with BF% (p < 5 × 10−8) were selected as IVs, and variants in linkage disequilibrium were eliminated (r2 < 0.001 and a clump window of 10,000 kb). R packages "MR-PRESSO" and "Two-SampleMR" were used to detect SNP outliers and carry out the MR analysis, respectively. In line with the current body of evidence, the inverse variance weighted (IVW) was selected as the primary assessment method to pool IV estimates. Additional methods (MR-Egger, weighted median) were applied to evaluate consistency and reliability. Leave-one-out analyses were performed to evaluate outlier SNPs. Three hundred IVs were selected for analysis. All IVs demonstrated weak instrument bias (F > 10). IVW analysis demonstrated a significant causal effect of genetically predicted BF% on HS (β; 1.98, SE 0.34, p 1.08 × 10−8) (Table 1; Figure 1a). This causal association was supported by weighed median and MR Egger methods. No heterogeneity of the causal estimate for each IV was demonstrated in the analysis (PIVW = 0.1618). MR-Egger regression and inspection of the funnel plots demonstrated no significant horizontal pleiotropy between the SNPs and outcomes (p = 0.153) (Figure 1b). Leave-one-out analysis confirmed that the observed causal relationship was not driven by a single SNP. This study leverages available GWAS data and utilizes two-sample MR to provide robust evidence of causality between genetically predicted adiposity and HS. The analysis withstands sensitivity analysis for bias and is free of significant heterogeneity. The complex association between HS and obesity phenotypes is supported by significant epidemiological evidence and carries direct clinical implications.4 Elevated BMI, BF%, WC and the waist-to-hip ratio have been identified as potential HS susceptibility or diagnostic biomarkers.5 Recent MR studies reinforce causal associations between waist circumference,6 BMI7 and HS risk (Figure 1c). Additionally, HS severity correlates with BMI and excess adiposity predicts poor adalimumab response and reduced quality of life.8 Compared to BF%, the availability of high quality GWAS data for HS and ergo, lack of appropriate genetic instruments, precluded bidirectional MR analysis. HS and excess adiposity share a chronic systemic proinflammatory state with elevated levels of pro-inflammatory cytokines (e.g. TNF-α, IL-1β, IL-6), activating NF-κB and JAK–STAT pathways. Visceral adiposity drives adipose tissue dysfunction, manifest by infiltration with M1 proinflammatory macrophages and upregulation of several proatherogenic and diabetogenic adipocytokines.9 HS patients generally exhibit metabolic dysfunction and MR studies have associated the metabolic syndrome with HS (Figure 1c).10 The association between excess adiposity and HS has therapeutic implications. GLP-1 receptor agonists have demonstrated significant efficacy in HS management, through weight loss and pleiotropic anti-inflammatory effects, potentially improving clinical outcomes beyond weight reduction alone. Furthermore, dermatologists should advocate for maintaining an ideal body weight and screening for metabolic complications of excess adiposity when managing HS patients. We would like to acknowledge the participants and investigators of the UK Biobank and FinnGen study. No funding. Dr. Mintoff and Prof. Pace have no conflicts of interest to declare. Not applicable. This research involved analysis of publicly available datasets, and no collection of identifiable personal/genetic data was performed. The data that support the findings of this study are available in UKBiobank (GCST90013975) and FinnGen Biobank. Additional instrument data is available from https://github.com/dillonmintoff/JEADV_MR.