Mitochondrial Haplogroups and Control Region Polymorphisms in Age-Related Macular Degeneration: A Case-Control Study

BackgroundOnset and development of the multifactorial disease age-related macular degeneration (AMD) are highly interrelated with mitochondrial functions such as energy production and free radical turnover. Mitochondrial dysfunction and overproduction of reactive oxygen species may contribute to destruction of the retinal pigment epithelium, retinal atrophy and choroidal neovascularization, leading to AMD. Consequently, polymorphisms of the mitochondrial genome (mtDNA) are postulated to be susceptibility factors for this disease. Previous studies from Australia and the United States detected associations of mitochondrial haplogroups with AMD. The aim of the present study was to test these associations in Middle European Caucasians. Methodology/Principal FindingsMitochondrial haplogroups (combinations of mtDNA polymorphisms) and mitochondrial CR polymorphisms were analyzed in 200 patients with wet AMD (choroidal neovascularization, CNV), in 66 patients with dry AMD, and in 385 controls from Austria by means of multiplex primer extension analysis and sequencing, respectively. In patients with CNV, haplogroup H was found to be significantly less frequent compared to controls, and haplogroup J showed a trend toward a higher frequency compared to controls. Five CR polymorphisms were found to differ significantly in the two study populations compared to controls, and all, except one (T152C), are linked to those haplogroups. Conclusions/SignificanceIt can be concluded that haplogroup J is a risk factor for AMD, whereas haplogroup H seems to be protective for AMD.

年龄相关性黄斑变性（age-related macular degeneration, AMD）是一种多因素疾病，其起病与进展与线粒体能量生成、自由基代谢等功能密切相关。线粒体功能障碍及活性氧过度生成，可能引发视网膜色素上皮破坏、视网膜萎缩与脉络膜新生血管形成，最终导致AMD。据此推测，线粒体基因组（mitochondrial genome, mtDNA）多态性是该疾病的易感因素。此前澳大利亚与美国的相关研究已发现线粒体单倍群与AMD存在关联。本研究的目标为在中欧高加索人群中验证这一关联。研究方法与主要结果：本研究采用多重引物延伸分析与测序技术，对奥地利地区200例湿性AMD（脉络膜新生血管（choroidal neovascularization, CNV））患者、66例干性AMD患者及385名健康对照者的线粒体单倍群（mtDNA多态性组合）与线粒体控制区（CR）多态性进行检测分析。结果显示，在CNV患者群体中，单倍群H的检出频率显著低于对照组，而单倍群J的检出频率则呈现高于对照组的趋势。与对照组相比，两组AMD患者群体中共存在5个CR多态性位点存在显著差异，其中除T152C外，其余位点均与上述线粒体单倍群存在关联。结论与意义：本研究可得出如下结论：单倍群J是AMD的危险因素，而单倍群H似乎对AMD具有保护作用。