Association between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus and Multimorbidity

Purpose To assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). Methods We developed a FECD case-control algorithm based on structured EHR data and accuracy confirmed by individual review of charts at three VA Medical Centers. This algorithm was applied to the Department of Veterans Affairs Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes and laboratory values were extracted. Single and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. Results Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and non-ocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for four being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. Conclusions Female gender, European ancestry and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes as well as altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. DM may modify FECD onset and encourage progression among susceptible individuals, suggesting that optimizing glucose control may be an effective preventative for FECD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by VA Office of Research & Development (I01 BX003364), the Cleveland Institute for Computational Biology, NIH Core Grants (P30 EY025585, P30 EY011373), the Clinical and Translational Science Collaborative of Cleveland (UL1TR002548) from the National Center for Advancing Translational Sciences (NCATS) component of the NIH and NIH Roadmap for Medical Research, and unrestricted grants from Research to Prevent Blindness to Case Western Reserve University, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and the University of Buffalo. ### 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: Central IRB of Department of Veterans Affairs Office of Research & Development gave ethical approval for this work. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript