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Additional file 1: Supplementary methods; supplementary results; references; supplementary tables 1 & 2; supplementary figures 1, 2 & 3

Additional file 1. Supplementary methods, figures, and tables.The supplementary methods include a description of the GEN-SEP and MESSI study populations, genotyping and quality control, more details of the genome-wide association study of 28-day sepsis survival and the index event bias assessment, tools for the annotation of the functional effects of the sentinel variants and the gene expression of related genes, the association of polygenic risks of sepsis with the 28-day sepsis survival, the replication of genes from previous sepsis mortality GWAS, and related references. The supplementary figures include a principal component analysis, the quantile-quantile plot of the GWAS, regional plots for the genome-wide significant variants, Kaplan-Meier 28-day survival plots, a manhattan plot of sepsis 28-day survival association study results in the HLA region, a plot of expression of related genes across cell types, a boxplot of SAMD9 gene expression values in GSE54514 and GSE65682, a boxplot of SAMD9 gene expression values in GSE32707, and polygenic risk score (PRS) model fitting. The supplementary tables show the relevant demographic and clinical features of cases and controls used for the GWAS of sepsis risk and for the GEN-SEP patients, the list of previous candidate genes associated with sepsis risk, the prioritized independent SNPs, the index bias event results, the association results with 28-day mortality and the percentage of variation explained by the sentinel SNPs by separate or as part of a PRS, the association results of the sentinel variants from other sepsis mortality GWAS studies, the nominally significant results for the classical HLA alleles and amino acids, and the functional assessment of variants associated with 28-day sepsis survival.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF., Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females., Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results., Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females., Competing Interests: AA declares funding from NIH (K23HL146942); consulting fees from Genentech, Inogen, Medscape, Abbvie, PatientMpower and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim. ADS is a full-time employee of Genentech/Roche with stock and stock options in Roche. AFG was a full-time employee of PPD, Part of Thermo Fisher Scientific until June 2023. BGG declares fellowship funding from Wellcome Trust (221680/Z/20/Z). BLY is a full-time employee of Genentech/Roche with stock and stock options in Roche. CF declares funding Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III and Instituto Tecnológico y de Energías Renovables; honoraria in educational events from Fundación Instituto Roche. DAS declares being the founder and chief scientific officer of Eleven P15, Inc., a company dedicated to the early diagnosis and treatment of pulmonary fibrosis. HP declares grant payment to institution from Boehringer Ingelheim Ltd; consulting fees from Boehringer Ingelheim Ltd, Roche Limited, Trevi Therapeutics, Pilant Therapeutics; speaker fees from Boehringer Ingelheim Ltd; member of TIPAL trial management group, trustee for Action for Pulmonary Fibrosis, member of scientific advisory board for European Pulmonary Fibrosis Federation. IN declares funding from National Institutes of Health (UG3HL145266) to institution; grant funding to institution from Veracyte; consulting fees from Boerhinger Ingelheim and Sanofi. IPH declares funding from Wellcome Trust and NIHR; vice chair Trustees for Asthma + Lung UK. JMO declares funding from National Institutes of Health (R01HL169166 & K23HL138190); consulting fees from Boehringer Ingelheim, Lupin pharmaceuticals, AmMax Bio, Roche and Veracyte; patent for TOLLIP TT genotype for NAC use in IPF; participation on a Data Safety Monitoring Board or Advisory Board for Endeavor Biomedicines, Novartis and Genentech; Associate editor for CHEST, on Program Committee for American Thoracic Society and Editorial board for AJRCCM. LVW declares funding from UK Research and Innovation (MR/V00235X/1) and GSK/Asthma + Lung UK (Professorship (C17-1)) to complete this work; funding from Orion Pharma, GSK, Genentech, AstraZeneca, Nordic Bioscience, Sysmex (OGT); Consulting fees Galapagos, Boehringer Ingelheim, GSK; support for attending meetings and/or travel Genentech; participation on Advisory Board for Galapagos; leadership or fiduciary roles as Associate Editor for European Respiratory Journal and Medical Research Council Board member and Deputy Chair. MKBW declares funding from National Institutes of Health (K23HL146942); consulting fees from Genentech, Inogen, Medscape, Abbvie, PatientMpower and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim. MN is a full-time employee of Genentech/Roche with stock and stock options in Roche. NK declares grant funding from National Institutes of Health; grant funding to institution from BMS, Boehringer Ingelheim and Three Lakes Foundation; consultancy fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, Three Lake Partners, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Thyron, Gilead, Galapagos, Chiesi, Arrowhead, Sofinnova, GSK and Merk; patent for new therapies for IPF (Biotech), new therapies for ARDS (Biotech) and new Biomarkers in IPF (Biotech); equity in Pilant and Thyron; reports serving as the scientific founder of Thyron. PLM declares grant funding to institution from AstraZeneca; consultancy fees from Hoffman-La Roche, Boehringer Ingelheim, AstraZeneca, Trevi and Qureight; speaker fees from Boehringer Ingelheim and Hoffman-La Roche. RGJ declares funding from UK Research and Innovation (MR/V00235X/1); that their institute received funding from Astra Zeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX and Pliant; consulting fees from AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Veracyte, Resolution Therapeutics and Pliant; payment for lectures and presentations received from Boehringer Ingelheim, Chiesi, Roche, PatientMPower, AstraZeneca; payment for expert testimony from Pinsent Masons LLP; participation on a Data Safety Monitoring Board or Advisory Board for Boehringer Ingelheim, Galapagos, Vicore; leadership or fiduciary role for NuMedii and president for Action for Pulmonary Fibrosis. SPH declares grant funding to institution from Boehringer Ingelheim; consulting fees from Trevi therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi and Trevi therapeutics; support for attending meetings and/or travel from Chiesi; Participation on a Data Safety Monitoring Board or Advisory Board for Trevi therapeutics; Chair for BTS Standards of Care Committee (till November 2022) and Trustee for Action for Pulmonary Fibrosis. TMM declares consulting fees from Boehringer Ingelheim, Roche/Genentech, Astra Zeneca, Bayer, Blade Therapeutics, Bristol-Myers Squibb, CSL Behring, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pfizer, Pliant, Respivant, Sanofi, Theravance, Trevi, Veracyte and Vicore; participation on a Data Safety Monitoring Board or Advisory Board for Fibrogen, Blade Therapeutics and Nerre. XRS is a full-time employee of Genentech/Roche with stock and stock options in Roche.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk., Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p <4.5×10 -4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report., Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies., Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF., Competing Interests: COMPETING INTERESTS LJD, AS, MN, XRS and BLY are full-time employees of Genentech; AS, MN, XRS, and BLY and hold stock options in Roche. JMO reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio and Lupin Pharmaceuticals outside of the submitted work. DAS is the founder and chief scientific officer of Eleven P15, a company focused on the early detection and treatment of pulmonary fibrosis. RGJ reports honoraria from Chiesi, Roche, PatientMPower, AstraZeneca, GSK, Boehringer Ingelheim, and consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant, Chiesi. LVW reports research funding from GlaxoSmithKline, Roche and Orion Pharma, and consultancy for GlaxoSmithKline and Galapagos, outside of the submitted work. The other authors declare no competing interests.