Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity

Nealon, Cari L.; Halladay, Christopher; Gorman, Bryan R.; Simpson, Piana; Roncone, David P.; Canania, Rachael L.; Anthony, Scott A.; Rogers, Lea R Sawicki; Leber, Jenna N.; Dougherty, Jacquelyn M.; Bailey, Jessica N. Cooke; Crawford, Dana C.; Sullivan, Jack; Wu, Wen‐Chih; Greenberg, Paul B.; Lass, Jonathan H.; Wu, Wen‐Chih; Peachey, Neal S.

doi:10.1097/ico.0000000000003311

Cited by 4 publications

(9 citation statements)

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“…19 ), which was strongly associated withlaboratory measurements of increased serum bicarbonate ( P = 7.0 × 10 −62 ), decreased chloride ( P = 9.1 × 10 −24 ), and increased potassium ( P = 2.3 × 10 −9 ), followed by decreased platelet ( P = 1.3 × 10 −7 ), monocyte ( P = 1.9 × 10 −7 ), and neutrophil ( P = 2.1 × 10 −6 ) counts. The pleiotropic association with serum bicarbonate likely explains the significant association with this trait we previously observed in a phenome-wide comorbidity scan of FECD case-control status 9 .…”

Section: Resultsmentioning

confidence: 61%

“…Consistent with allele frequencies at our lead tagging SNP rs11659764, this result suggests that EUR haplotypes contain a higher frequency of pathogenic alleles compared to AFR and possibly also NAT haplotypes. The sample sizes for MVP Asian cohorts were too low to obtain reliable estimates 9 , but data from prior studies in Japanese cohorts 17 and allele frequencies from the 1000 Genomes Project suggest that East Asians have lower FECD prevalence 4 due to lower frequency of CTG18.1 expansions.…”

Section: Resultsmentioning

confidence: 96%

“…We identified FECD cases in MVP participants of EUR, AFR, and HIS ancestry (Supplementary Data 1 ) following a clinically validated phenotyping algorithm 9 . Cases were mostly male (88.6%), reflecting the predominantly male composition of the MVP dataset 16 .…”

Section: Resultsmentioning

confidence: 99%

“…Risk may also differ across populations; lower rates of FECD diagnosis have been observed in African Americans in both clinical settings and Medicare claims 10 . 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) 9 .…”

Section: Introductionmentioning

confidence: 89%

“…The etiology of FECD involves complex interactions of incompletely penetrant genetic factors with biological and environmental factors. Female sex and advanced age are established risk factors 4 , 9 . Risk may also differ across populations; lower rates of FECD diagnosis have been observed in African Americans in both clinical settings and Medicare claims 10 .…”

Section: Introductionmentioning

confidence: 99%

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A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

Gorman,

Francis,

Nealon

et al. 2024

Commun Biol

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Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

Gorman,

Francis,

Nealon

et al. 2024

Commun Biol

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Prevalence and Economic Burden of Fuchs Endothelial Corneal Dystrophy in the Medicare Population in the United States

Singh,

Parmar,

Kahale

et al. 2023

Cornea

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Purpose: The aim of this study was to assess the prevalence and economic burden of Fuchs endothelial corneal dystrophy (FECD) in patients older than 65 years in the United States. Methods: A retrospective analysis of the Medicare data reported to the Vision and Eye Health Surveillance System including patients diagnosed with FECD between 2014 and 2019 was performed. The crude prevalence rate of FECD was assessed and extrapolated to estimate the total case burden in the United States. The prevalence data were further compared between men and women and different racial groups. In addition, the economic burden was computed using inflation-adjusted direct costs of treatment to patients. Results: The Medicare database included 25,432,700 patients older than 65 years. The national prevalence of FECD in this population cohort was calculated to be 1.12% in 2019. In 2019, FECD case burden in Medicare patients older than 65 years was 284,846 and total estimated FECD case count in the country in this age group was 591,226. FECD prevalence was significantly higher in women as compared to men during the 6-year period evaluated in this study. The intergroup comparison revealed that FECD prevalence in the White population was significantly higher than all other racial groups (P < 0.0001). The total inflation-adjusted economic burden of FECD in the United States in 2019 was USD 291.648 million and has increased from USD 243.998 million over the 6-year study period. Conclusions: The estimated prevalence of FECD in the individuals older than 65 years is 1.12% in the United States. FECD prevalence is significantly higher in women and White population compared with other ethnicities.

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Comparison of Scheimpflug and Anterior Segment Optical Coherence Tomography Imaging Parameters for Japanese Patients With Fuchs Endothelial Corneal Dystrophy With and Without TCF4 Repeat Expansions

Maeno,

Oie,

Koto

et al. 2024

Cornea

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Purpose: The aim of this study was to investigate the association between cytosine–thymine–guanine trinucleotide repeat (TNR) expansion in TCF4 and the clinical phenotypes of corneal densitometry or anterior segment morphology in Fuchs endothelial corneal dystrophy. Methods: This retrospective cross-sectional study included 150 eyes from 75 Japanese consecutive patients with Fuchs endothelial corneal dystrophy. Cytosine–thymine–guanine repeat expansion of leukocyte-derived genomic DNA was analyzed through fragment analysis using polymerase chain reaction and triplet repeat primed polymerase chain reaction. Scheimpflug-based densitometry and anterior segment optical coherence tomography were applied. Corneal densitometry, and corneal and anterior segment morphology parameters were compared between patients with and without TNR expansion of 50 or more (expansion and nonexpansion groups, respectively) using a mixed model. Results: The average age of the patients was 66.8 ± 13.0 years, and the modified Krachmer grading scale was 1, 2, 3, 4, 5, and 6 for 7, 32, 28, 51, 6, and 18 eyes, respectively. Sixteen patients (21%) exhibited ≥50 TNR expansion. No significant differences in sex, age, history of keratoplasty, modified Krachmer grade, and corneal densitometry in either diameter or depth were observed between the 2 groups. No significant differences in anterior segment morphology, including the anterior chamber depth and anterior chamber angle width parameters, were observed using a univariate mixed model, except for central corneal thickness (P = 0.047). However, according to the multivariate mixed model, repeat expansion was not significantly associated with central corneal thickness (P = 0.27). Conclusions: No significant differences in clinical phenotypes were found between Japanese patients having Fuchs endothelial corneal dystrophy with and without TNR expansion.

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Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 4 publications

References 64 publications

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation

Prevalence and Economic Burden of Fuchs Endothelial Corneal Dystrophy in the Medicare Population in the United States

Comparison of Scheimpflug and Anterior Segment Optical Coherence Tomography Imaging Parameters for Japanese Patients With Fuchs Endothelial Corneal Dystrophy With and Without TCF4 Repeat Expansions

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