Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups

Abstract

Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG.Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs.Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10−05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7–13.1).Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.

Mitochondrial dysfunction in glaucomatous degeneration

“…Mutations of related genes or defects in components of OXPHOS could contribute to mitochondrial dysfunction. For instance, mutations in the mitochondrially encoded cytochrome B (MT-CYB), which encodes cytochrome b in Complex III, can cause defects in Complex III and disrupts the production of ATP [51] . In TM cells, the complex I inhibitor Rotenone could increase the generation of ROS and induce the release of cytochrome c, finally leading to oxidative stress and cell apoptosis [52] .…”

Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by a Camouflaged Meta‐Defensome

“…The expression heatmap showed dozens of genes associated with mitochondrial dysfunction were downregulated in M1 macrophages (Figure 2B). Many of these genes are essential for the maintenance of mitochondrial biogenesis and energy production, including MT‐CO3, [ 37 ] MTATP6P1, [ 38 ] MT‐ATP6, [ 39 ] MT‐CYB, [ 40 ] MT‐ND4, [ 41 ] RNR2, [ 42 ] and MT‐DN1. [ 43 ] Moreover, MT‐ND3 [ 44 ] and MT‐CO3 [ 37,45 ] can be regulated by hypoxia, and their dysfunction is related to oxidative stress, oxygen supply, and lipid metabolism (Figure 2C, Figure S4, Supporting Information).…”

Role of Mitochondrial Mutations in Ocular Aggregopathy

“…Complex I is the first enzyme in the respiratory chain, making it vulnerable to oxidative stress. It is also involved in cellular functions such as apoptosis [ 32 ]. SNPs in MT-ND4 can have an impact on the first step of the electron transport chain.…”