Association between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus and Multimorbidity

Abstract

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.

Multi-ancestry GWAS of Fuchs corneal dystrophy highlights roles of laminins, collagen, and endothelial cell regulation

“…6). This pleiotropy at TCF4 likely explains the robust association with increased serum bicarbonate we previously observed in a phenome-wide comorbidity scan of FECD case-control status 19 .…”

“…We identified FECD cases in MVP participants of EUR, AFR, and HIS ancestry (Supplementary Table 1) following a clinically validated phenotyping algorithm 19 . Cases were mostly male (88.6%), reflecting the predominantly male composition of the MVP dataset 32 .…”

“…Similarly, examining FECD by genetic ancestry in the Department of Veterans Affairs Million Veteran Program (MVP), we found signi cantly reduced prevalence in participants of admixed African (AFR) and Hispanic/Latino (HIS) continental ancestries relative to European ancestry (EUR) 19 .…”

“…Risk may also differ across populations; lower rates of FECD diagnosis have been observed in African Americans in both clinical settings 17 and Medicare claims 18 . Similarly, examining FECD by genetic ancestry in the Department of Veterans Affairs Million Veteran Program (MVP), we found significantly reduced prevalence in participants of admixed African (AFR) and Hispanic/Latino (HIS) continental ancestries relative to European ancestry (EUR) 19 .…”

“…Phenotyping. We previously developed a FECD case-control algorithm based on structured electronic health record data and con rmed its accuracy by chart review at three VA Medical Centers 19 . We applied the algorithm to conduct genome-wide association analyses (GWAS) and to analyze associated electronic health record (EHR) data.…”