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Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy.

ABSTRACT: PURPOSE:We investigated whether mitochondrial DNA (mtDNA) variants affect the susceptibility of Fuchs endothelial corneal dystrophy (FECD). METHODS:Ten mtDNA variants defining European haplogroups were genotyped in a discovery dataset consisting of 530 cases and 498 controls of European descent from the Duke FECD cohort. Association tests for mtDNA markers and haplogroups were performed using logistic regression models with adjustment of age and sex. Subset analyses included controlling for additional effects of either the TCF4 SNP rs613872 or cigarette smoking. Our replication dataset was derived from the genome-wide association study (GWAS) of the FECD Genetics Consortium, where genotypes for three of 10 mtDNA markers were available. Replication analyses were performed to compare non-Duke cases to all GWAS controls (GWAS1, N = 3200), and to non-Duke controls (GWAS2, N = 3043). RESULTS:The variant A10398G was significantly associated with FECD (odds ratio [OR] = 0.72; 95% confidence interval [CI] = [0.53, 0.98]; P = 0.034), and remains significant after adjusting for smoking status (min P = 0.012). This variant was replicated in GWAS1 (P = 0.019) and GWAS2 (P = 0.036). Haplogroup I was significantly associated with FECD (OR = 0.46; 95% CI = [0.22, 0.97]; P = 0.041) and remains significant after adjusting for the effect of smoking (min P = 0.008) or rs613872 (P = 0.034). CONCLUSIONS:The 10398G allele and Haplogroup I appear to confer significant protective effects for FECD. The effect of A10398G and Haplogroup I to FECD is likely independent of the known TCF4 variant. More data are needed to decipher the interaction between smoking and mtDNA haplogroups.

SUBMITTER: Li YJ

PROVIDER: S-EPMC4109404 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy.

Li Yi-Ju YJ Minear Mollie A MA Qin Xuejun X Rimmler Jacqueline J Hauser Michael A MA Allingham R Rand RR Igo Robert P RP Lass Jonathan H JH Iyengar Sudha K SK Klintworth Gordon K GK Afshari Natalie A NA Gregory Simon G SG

Investigative ophthalmology & visual science 20140610 7

<h4>Purpose</h4>We investigated whether mitochondrial DNA (mtDNA) variants affect the susceptibility of Fuchs endothelial corneal dystrophy (FECD).<h4>Methods</h4>Ten mtDNA variants defining European haplogroups were genotyped in a discovery dataset consisting of 530 cases and 498 controls of European descent from the Duke FECD cohort. Association tests for mtDNA markers and haplogroups were performed using logistic regression models with adjustment of age and sex. Subset analyses included contr ...[more]

PMID: 24917144

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Project description:Purpose To develop a model to predict corneal improvement after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial corneal dystrophy (FECD) from Scheimpflug tomography. Design Cross-sectional study. Participants Forty-eight eyes (derivation group) and 45 eyes (validation group) with a range of severity of FECD undergoing DMEK. Methods Scheimpflug images were obtained before and after DMEK. Before DMEK, pachymetry map and posterior elevation map patterns were quantified by a special image analysis program measuring tomographic features of edema (loss of regular isopachs, displacement of the thinnest point of the cornea, posterior surface depression). Image-derived novel parameters were combined with instrument-derived parameters, and the relative influences of parameters associated with the change in central corneal thickness (CCT) after DMEK in the derivation group were determined by using a gradient boosting machine learning model. The parameters with highest relative influence were then fit in a linear regression model. The derived model was applied to the validation group. Correlations and agreement were assessed between predicted and observed changes in CCT. Main Outcome Measures Predictive power (R2) and mean difference between predicted and observed change in CCT. Results The gradient boosting machine model identified 4 novel parameters of isopach circularity and eccentricity and 1 instrument-derived parameter (posterior surface radius); preoperative CCT was a poor predictor. In the derivation group, the model strongly predicted the change in CCT after DMEK (R2 = 0.80; 95% confidence interval [CI], 0.71–0.89) and the mean difference between predicted and observed change was, by definition, 0 μm. When the same 5 parameters were fit to the validation group, the model performed very highly (R2 = 0.89; 95% CI, 0.84–0.94). When the coefficient estimates from the derivation model were used to predict the change in CCT in the validation group, the predictive power was also high (R2 = 0.78; 95% CI, 0.68–0.88), and the mean difference was 4 μm (predicted minus observed). Conclusions Scheimpflug tomography maps of corneas with FECD can predict the improvement in CCT after DMEK, independent of preoperative corneal thickness measurement. The model could be applied in clinical practice or for clinical research of FECD.

Dataset Information

Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy.

Publications

Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy.

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