An Investigation of Mitochondrial Haplogroups in Fuchs Endothelial Corneal Dystrophy

Abstract

Purpose: To investigate whether European mitochondrial DNA (mtDNA) haplogroups contribute to the susceptibility of Fuchs endothelial corneal dystrophy (FECD). Oxidative stress has been implicated in the pathogenesis of FECD, which suggests the potential role of mitochondria in FECD. Although mtDNA haplogroups have been well-established for each ethnicity, no studies have examined the mtDNA variation in FECD.

Methods: 529 patients with FECD and 463 controls, all Caucasians, were studied. All FECD patients had guttata grading ≥ 2 by modified Krachmer. Controls had a normal corneal exam and age at the enrollment ≥ 50. Nine common European mtDNA haplogroups were predefined by 10 single nucleotide polymorphisms (SNPs) in the coding and control regions of the mtDNA genome. We genotyped these 10 SNPs using custom-designed TaqMan® allelic discrimination assays. A logistic regression model with age and gender as covariates was used to test each mtDNA SNP and haplogroup using the full dataset, and also in a subset of higher graded FECD cases [Grade3+] (grade ≥ 3, N=457). For the haplogroup analysis, we compared each haplogroup to the most common European haplogroup H. Secondary analyses were conducted to investigate the interaction between haplogroups and the SNP rs613872 in TCF4, a known risk variant for FECD, and between haplogroup and current smoking status. Since only limited smoking status data were available in cases (N=234), a case-only model was applied.

Results: Three SNPs (rs3021089, rs2853826, and rs34301918) showed nominal significance in both full dataset (min p=0.05) and Grade3+ subset (min p=0.03). On average, 39.7% of subjects have haplogroup H. Subjects with haplogroup I (3.53%) showed significant decrease in risk of FECD comparing to those with haplogroup H in both full (p=0.024, odds ratio [OR]=0.42, 95% confidence interval [CI] 0.20-0.89) and Grade3+ (p=0.017, OR=0.37, 95%CI=0.16-0.84) datasets. None of the mtDNA SNPs and haplogroups interact with rs613872 in TCF4 (min p=0.26), or with current smoking status (min p=0.08).

Conclusions: Our data show that mtDNA haplogroup I confers a significant protective effect on FECD risk. . We found that the role of TCF4 in FECD is independent to the mtDNA haplogroup. While no significant results were obtained for smoking status, more data are needed to confirm the current finding. Our study presents an important step in understanding the effect of mtDNA in FECD.

Keywords: 480 cornea: basic science • 539 genetics • 600 mitochondria