Lo Faro Valeria, Nolte Ilja M, Ten Brink Jacoline B, Snieder Harold, Jansonius Nomdo M, Bergen Arthur A
Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Department of Clinical Genetics, Amsterdam University Medical Center (AMC), Amsterdam, Netherlands.
Front Genet. 2021 Dec 16;12:781189. doi: 10.3389/fgene.2021.781189. eCollection 2021.
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. 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. 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; = 0.006] within the gene, and for the T allele of rs35788393 (OR = 0.75; = 0.041) located in the gene. In the mitochondrial haplogroup analysis, the most significant -value was reached by haplogroup K ( = 1.2 × 10), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7-13.1). We identified an association between POAG and polymorphisms in the mitochondrial genes (rs2853496) and (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.
原发性开角型青光眼（POAG）是一种以视网膜神经节细胞死亡和视神经乳头萎缩为特征的视神经病变。视神经对损伤的易感性已被证明是由线粒体功能障碍介导的。在本研究中，我们旨在确定线粒体单核苷酸多态性（SNP）或单倍群与POAG之间可能存在的关联。使用Illumina Infinium全球筛选阵列-24（GSA）700K阵列集对线粒体DNA单核苷酸多态性（mtSNP）进行基因分型。在一项POAG病例对照研究中进行了遗传分析，该研究涉及格罗宁根纵向青光眼研究-生命线队列研究和阿姆斯特丹青光眼研究队列，总共包括721例患者和1951例对照。我们排除了核基因型未通过质量控制的样本以及线粒体变异检出率低的样本。线粒体变异体作为SNP和单倍群进行分析。这些是用生物信息学软件HaploGrep确定的，并且使用逻辑回归分析来研究关联以及SNP。对两个队列的结果进行荟萃分析发现，POAG与基因内的rs2853496的A等位基因[比值比（OR）= 0.64；P = 0.006]以及位于基因中的rs35788393的T等位基因（OR = 0.75；P = 0.041）之间存在显著关联。在线粒体单倍群分析中，单倍群K达到了最显著的P值（P = 1.2×10⁻⁴），其使POAG风险增加，OR为5.8（95%可信区间2.7 - 13.1）。我们确定了POAG与线粒体基因（rs2853496）和（rs35788393）中的多态性以及单倍群K之间存在关联。本研究提供了进一步的证据，表明线粒体基因组变异与POAG有关。需要进一步的遗传和功能研究来证实线粒体基因多态性与POAG之间的关联，并确定青光眼中线粒体功能障碍的病理生理机制。
