Methodological concerns in hidradenitis suppurativa genomic and proteomic profiling

We thank He and Li for their thoughtful comments on our study1 and for their interest in our integrative genomic and proteomic analysis of hidradenitis suppurativa (HS).2 We agree that several points would benefit from clarification and are happy to address them. First, the term ‘60 genome-wide significant loci’ in the Abstract Results should more precisely read ‘60 genome-wide significant annotated SNPs’ as stated in the Results section and we appreciate this correction. Second, IHS4 (international HS4 score) categories shown in Table 1 of our original publication2 do not include all 314 patients because these severity scores were not available for all participants; this should have been stated explicitly. Third, the coordinate reported for the top chromosome 3 SNP (rs11715932) contains a typographical error and should rather be chr3:48366855 based on the hg38 build coordinates. Regarding the interpretation of the HLA-DRA associations, we would like to clarify that the manuscript does not attribute these associations to the Greek cohort alone. On the contrary, the text explicitly states that these variants reached genome-wide significance only after meta-analysis with FinnGen and were not significant in the Greek cohort. Thus, these findings are appropriately presented as meta-analysis-driven rather than internally replicated signals. Regarding the pQTL enrichment results, we need to clarify that they rely on a selective comparison framework. The enrichment was initially observed when analysing all 51 differentially expressed proteins (DEPs) versus all 15 non-DEPs. The comparison restricted to 15 DEPs and 15 non-DEPs was included only in response to reviewer feedback requesting groups of comparable size. We report the inflation λ values for the 51 DEPs in the FinnGen cohort as 1.523 and in the Greek cohort as 1.211. Furthermore, Fisher's exact test demonstrated that pQTLs with nominal significance in FinnGen's GWAS were more likely to be associated with DEPs than with non-DEPs (p = 0.0131, compared to the p = 0.0274 in the publication), indicating that these findings are robust and not dependent on the selected subset. As noted in the manuscript, pathway analyses can be influenced by gene density within the MHC region, and we have explicitly acknowledged this limitation. Similarly, our statements regarding IL-6, IL-17A and FGF21 are intended to generate hypotheses for future validation studies. We trust that addressing the comments raised by He and Li strengthens our findings regarding the autoimmune counterpart of HS pathogenesis and its unique proteomic profile. This study was supported by the Hellenic Institute for the Study of Sepsis; Netherlands Organization for Scientific Research, Grant/Award Number: OCENW. XL.23.055. Mihai G. Netea is a scientific founder of Biotrip, Lemba, TtxD and Salvina. Evangelos J. Giamarellos-Bourboulis reports honoraria from Abbott Products Operations, AbbVie, bioMérieux, GSK, InflaRx GmbH, ThermoFisher Brahms GmbH and Sobi (paid to the National and Kapodistrian University of Athens); independent educational grants from Abbott Products Operations, aBionic, bioMérieux Inc., MSD, Swedish Orphan Biovitrum AB; Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPIC-CROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis) and from AbbVie, Inflammatix, InflaRx, Novartis, UCB and Sanofi (paid to the National and Kapodistrian University of Athens). Emmanouil Stylianakis and Vinod Kumar do not have any competing interests to declare. The study was approved by the Ethics Committee of the ATTIKON University General Hospital (approvals ΕBD11/10-01-2019; A12/26-02-2019). Not applicable. Raw data are available for download from the server of the Hellenic Institute for the Study of Sepsis (https://wshiss.com/). Username and Password are provided upon request to the corresponding author at [email protected].