PDF(Pubmed)
Abstract：
UNASSIGNED: Primary open-angle glaucoma (POAG) is a characteristic optic neuropathy, caused by degeneration of the optic nerve-forming neurons, the retinal ganglion cells (RGCs). High intraocular pressure (IOP) and aging have been identified as major risk factors; yet the POAG pathophysiology is not fully understood. Since RGCs have high energy requirements, mitochondrial dysfunction may put the survivability of RGCs at risk. We explored in buffy coat DNA whether mtDNA variants and their distribution throughout the mtDNA could be risk factors for POAG.
UNASSIGNED: The mtDNA was sequenced from age- and sex-matched study groups, being high tension glaucoma (HTG, n=71), normal tension glaucoma patients (NTG, n=33), ocular hypertensive subjects (OH, n=7), and cataract controls (without glaucoma; n=30), all without remarkable comorbidities.
UNASSIGNED: No association was found between the number of mtDNA variants in genes encoding proteins, tRNAs, rRNAs, and in non-coding regions in the different study groups. Next, variants that controls shared with the other groups were discarded. A significantly higher number of exclusive variants was observed in the D-loop region for the HTG group (~1.23 variants/subject), in contrast to controls (~0.35 variants/subject). In the D-loop, specifically in the 7S DNA sub-region within the Hypervariable region 1 (HV1), we found that 42% of the HTG and 27% of the NTG subjects presented variants, while this was only 14% for the controls and OH subjects. As we have previously reported a reduction in mtDNA copy number in HTG, we analysed if specific D-loop variants could explain this. While the majority of glaucoma patients with the exclusive D-loop variants m.72T>C, m.16163 A>G, m.16186C>T, m.16298T>C, and m.16390G>A presented a mtDNA copy number below controls median, no significant association between these variants and low copy number was found and their possible negative role in mtDNA replication remains uncertain. Approximately 38% of the HTG patients with reduced copy number did not carry any exclusive D-loop or other mtDNA variants, which indicates that variants in nuclear-encoded mitochondrial genes, environmental factors, or aging might be involved in those cases.
UNASSIGNED: In conclusion, we found that variants in the D-loop region may be a risk factor in a subgroup of POAG, possibly by affecting mtDNA replication.
UNASSIGNED: The mtDNA was sequenced from age- and sex-matched study groups, being high tension glaucoma (HTG, n=71), normal tension glaucoma patients (NTG, n=33), ocular hypertensive subjects (OH, n=7), and cataract controls (without glaucoma; n=30), all without remarkable comorbidities.
UNASSIGNED: No association was found between the number of mtDNA variants in genes encoding proteins, tRNAs, rRNAs, and in non-coding regions in the different study groups. Next, variants that controls shared with the other groups were discarded. A significantly higher number of exclusive variants was observed in the D-loop region for the HTG group (~1.23 variants/subject), in contrast to controls (~0.35 variants/subject). In the D-loop, specifically in the 7S DNA sub-region within the Hypervariable region 1 (HV1), we found that 42% of the HTG and 27% of the NTG subjects presented variants, while this was only 14% for the controls and OH subjects. As we have previously reported a reduction in mtDNA copy number in HTG, we analysed if specific D-loop variants could explain this. While the majority of glaucoma patients with the exclusive D-loop variants m.72T>C, m.16163 A>G, m.16186C>T, m.16298T>C, and m.16390G>A presented a mtDNA copy number below controls median, no significant association between these variants and low copy number was found and their possible negative role in mtDNA replication remains uncertain. Approximately 38% of the HTG patients with reduced copy number did not carry any exclusive D-loop or other mtDNA variants, which indicates that variants in nuclear-encoded mitochondrial genes, environmental factors, or aging might be involved in those cases.
UNASSIGNED: In conclusion, we found that variants in the D-loop region may be a risk factor in a subgroup of POAG, possibly by affecting mtDNA replication.
摘要：
■原发性开角型青光眼（POAG）是一种特征性的视神经病变，由视神经形成神经元的变性引起的，视网膜神经节细胞（RGC）。高眼压（IOP）和衰老已被确定为主要的危险因素；然而POAG的病理生理学尚未完全了解。由于RGC有很高的能量需求，线粒体功能障碍可能会使RGC的生存能力处于危险之中。我们在血沉棕黄层DNA中探索了mtDNA变体及其在整个mtDNA中的分布是否可能是POAG的危险因素。
■对年龄和性别匹配的研究组的mtDNA进行测序，是高眼压青光眼（HTG，n=71),正常眼压性青光眼患者（NTG，n=33),眼高血压受试者(OH，n=7),和白内障对照（无青光眼；n=30），都没有明显的合并症。
■编码蛋白质的基因中mtDNA变体的数量之间没有发现关联，tRNAs,rRNAs,以及不同研究组的非编码区域。接下来,与其他组共享的对照变体被丢弃.在HTG组的D-loop区域中观察到明显更多的专有变体（〜1.23变体/受试者），与对照(~0.35个变体/受试者)相反。在D循环中，特别是在高变区1（HV1）内的7SDNA亚区，我们发现42%的HTG和27%的NTG受试者呈现变异，而对照组和OH受试者的这一比例仅为14%。正如我们之前报道的HTG中mtDNA拷贝数的减少，我们分析了特定的D环变异是否可以解释这一点.虽然大多数青光眼患者具有独特的D-loop变异m.72T>C，m.16163A>G，m.16186C>T,m.16298T>C,m.16390G>A显示mtDNA拷贝数低于对照中位数，未发现这些变异与低拷贝数之间存在显著关联,它们在mtDNA复制中可能的负作用仍不确定.大约38％的HTG患者的拷贝数减少没有携带任何专有的D-loop或其他mtDNA变体，这表明核编码线粒体基因的变异，环境因素,或者在这些情况下可能涉及衰老。
■总而言之，我们发现D-loop区域的变异可能是POAG亚组的危险因素,可能通过影响mtDNA复制。
■对年龄和性别匹配的研究组的mtDNA进行测序，是高眼压青光眼（HTG，n=71),正常眼压性青光眼患者（NTG，n=33),眼高血压受试者(OH，n=7),和白内障对照（无青光眼；n=30），都没有明显的合并症。
■编码蛋白质的基因中mtDNA变体的数量之间没有发现关联，tRNAs,rRNAs,以及不同研究组的非编码区域。接下来,与其他组共享的对照变体被丢弃.在HTG组的D-loop区域中观察到明显更多的专有变体（〜1.23变体/受试者），与对照(~0.35个变体/受试者)相反。在D循环中，特别是在高变区1（HV1）内的7SDNA亚区，我们发现42%的HTG和27%的NTG受试者呈现变异，而对照组和OH受试者的这一比例仅为14%。正如我们之前报道的HTG中mtDNA拷贝数的减少，我们分析了特定的D环变异是否可以解释这一点.虽然大多数青光眼患者具有独特的D-loop变异m.72T>C，m.16163A>G，m.16186C>T,m.16298T>C,m.16390G>A显示mtDNA拷贝数低于对照中位数，未发现这些变异与低拷贝数之间存在显著关联,它们在mtDNA复制中可能的负作用仍不确定.大约38％的HTG患者的拷贝数减少没有携带任何专有的D-loop或其他mtDNA变体，这表明核编码线粒体基因的变异，环境因素,或者在这些情况下可能涉及衰老。
■总而言之，我们发现D-loop区域的变异可能是POAG亚组的危险因素,可能通过影响mtDNA复制。
