Shared genetic risk factors and their implications for treatment of IPF and systemic hypertension

More than 50% of individuals with idiopathic pulmonary fibrosis (IPF) have co-morbid hypertension. High blood pressure can lead to organ fibrosis or can be a consequence of artery stiffening due to fibrosis. Studies have implicated common processes, such as TGF-beta; signalling, in both traits regulation. Our goal was to identify shared genetic risk factors for IPF and hypertension. We analysed the genome-wide genetic correlation using LD Score Regression and the largest available genome-wide association studies of clinically defined IPF, and systolic and diastolic blood pressure (SBP and DBP, respectively). We then conducted a genome-wide colocalisation analysis to identify regions with a shared signal at P<10-5 between IPF and either SBP or DBP. There was no genome-wide correlation between IPF and SBP (correlation (95% CI) -0.077(-0.142, -0.011), P=0.022) or DBP (correlation (95% CI) -0.027(-0.093, 0.039), P=0.427). The genome-wide colocalisation identified 8 shared signals, 3 (near MAD1L1, GOLPH3L/HORMAD1, and at 17q21.31) had the same direction of effect on risk of IPF and hypertension and 5 (near TERC, OBFC1, DEPTOR, and at 7q22.1 and 6p21.2) had opposite effects. These findings support that there may be shared fibrotic mechanisms between IPF and hypertension. The opposite effects of variants at specific loci highlight the need for caution when considering therapeutic targeting of these shared pathways for either disease. ### Competing Interest Statement LVW reports funding from GSK, Pfizer, Orion Pharma and Genentech, outside of the submitted work. LVW reports consultancy for GSK, Galapagos and Boehringer-Ingelheim. RGJ has received grants from Astra Zeneca, Biogen, Galecto, GlaxoSmithKline, Nordic Biosciences, RedX and Pliant and consulting fees from AstraZeneca, Brainomix, Bristol Myers Squibb, Chiesi, Cohbar, Daewoong, GlaxoSmithKline, Veracyte, Resolution Therapeutics, Pliant and personal fees for advisory board participation or speaking fees Boehringer Ingelheim, Chiesi, Galapagos, Vicore, Roche, PatientMPower and AstraZeneca. ### Funding Statement GP is funded by a Wellcome Trust Genomic Epidemiology and Public Health Genomics Doctoral Training Programme studentship (218505/Z/19/Z). This work was supported by an MRC-NIHR Strategic Priority Fund Consortium Award (MR/W014491/1) DEMISTIFI Multi Morbidity: DEfining MechanIsms Shared across mulTI-organ FIbrotic disease to prevent the development of long-term multi-morbidity. BGG holds a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (221680/Z/20/Z). This is a summary of independent research funded by Wellcome Trust and MRC/NIHR and carried out at the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the Wellcome Trust, MRC, the NIHR or the Department of Health and Social Care. RGJ is funded by an NIHR Research Professorship (RP-2017-08-ST2-014). This research used the SPECTRE High Performance Computing Facility at the University of Leicester. For the purpose of open access, a CC BY or equivalent licence will be applied to any author accepted manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IPF GWAS data are available from: https://github.com/genomicsITER/PFgenetics. Blood pressure GWAS data are available from: https://www.ebi.ac.uk/gwas/publications/30224653 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors