1. 연구방법 본 연구에서는 정상안압녹내장 환자를 대상으로 분자유전학적 분석을 통하여 미토콘드리아 유전자와의 관련성을 분석함. 미토콘드리아 유전자 전체 염기서열 분석을 시행하여 녹내장 발생에 관여하는 원인 유전자 변이를 발굴하고, 발견된 유전자 변이에 대한 환자-대조군 연구를 시행함. 2. 결과 정상안압녹내장 76명, 정상대조군 82명을 대상으로 유전자 분석을 시행함. 정상안압녹내장 20명을 대상으로 미토콘드리아 유전자 전체 염기서열 분석을 시행하여 총 156개의 유전자 변이를 발견함. 이 중정상안압녹내장 환자군에서
1. 연구방법 본 연구에서는 정상안압녹내장 환자를 대상으로 분자유전학적 분석을 통하여 미토콘드리아 유전자와의 관련성을 분석함. 미토콘드리아 유전자 전체 염기서열 분석을 시행하여 녹내장 발생에 관여하는 원인 유전자 변이를 발굴하고, 발견된 유전자 변이에 대한 환자-대조군 연구를 시행함. 2. 결과 정상안압녹내장 76명, 정상대조군 82명을 대상으로 유전자 분석을 시행함. 정상안압녹내장 20명을 대상으로 미토콘드리아 유전자 전체 염기서열 분석을 시행하여 총 156개의 유전자 변이를 발견함. 이 중정상안압녹내장 환자군에서 15% 이상의 빈도로 관찰되는 유전자 변이는 총 21개였으며 이를 후보유전자 변이로 선정함. 선정된 후보유전자변이에 대해 환자-대조군 비교 연구를 시행한 결과 12372G>A(ND5 gene), 14766C>T(CYTB gene) 변이에 대해 질환군과 대조군에서 유의한 빈도 차이가 관찰됨. 3. 결론 정상안압녹내장 환자를 대상으로 미토콘드리아 전체 염기서열 분석을 시행하여 질환군에서 비교적 높은 빈도로 관찰되는 후보유전자 변이를 발굴함. 이상의 결과는 정상안압녹내장의 발생에 미토콘드리아 유전자 이상이 관여함을 시사한다고 하겠음.
Abstract▼
Ⅰ. Background and Purpose Glaucoma is a leading cause of blindness worldwide and is the second most frequent cause of non-accidental blindness in industrialized countries. The global prevalence of glaucoma was estimated at 67 million people in 2001. Normal-tension glaucoma (NTG) is an entity of p
Ⅰ. Background and Purpose Glaucoma is a leading cause of blindness worldwide and is the second most frequent cause of non-accidental blindness in industrialized countries. The global prevalence of glaucoma was estimated at 67 million people in 2001. Normal-tension glaucoma (NTG) is an entity of progressive glaucomatous optic neuropathy and corresponding visual field defects with intraocular pressure (IOP) in the statistically normal range. Because of the normal IOP, other factors such as genetic predisposition are supposed to play an important role in the pathogenesis of NTG. Since up to 21% of NTG patients were reported to have a family history, it is suggested that these patients may be genetically predisposed to developing NTG. Over the last two decades, some candidate genes have been identified. However, the possible disease-causing genes have not been determined in normal-tension glaucoma subjects. Glaucoma is recognized as a neurodegenerative disorder, characterized by the accelerated loss of retinal ganglion cells and their axons. Previous studies points to the possibility that mitochondrial dysfunction in certain individuals may predispose to glaucoma. In this study, we performed a genetic analysis of the mitochondrial gene and revealed the genetic risk variants on Korean NTG patients. From this study, we could establish the genetic risk factor that contributed to the disease progression. Furthemore, we can understand the pathophysiology of NTG and use our results as fundamental data which is going to be used to build a new disease prediction model of NTG. Ⅱ. Materials and Methods DNA was extracted from the peripheral blood of the NTG patients and normal control subjects. We also established the subject research database including the demographic and clinical information. For the 20 NTG patients, the entire mitochondrial DNA (mtDNA) sequenced. From these results, we revealed new genetic risk variants for NTG patients. For the candidate genetic variants, we performed a disease-gene association study by using the Sanger's sequencing method. Ⅲ. Results 1. Seventy-six NTG patients and 82 normal control subjects were enrolled. For all subjects, DNA was extracted and clinical database was established. No significant differences were found between the two groups in terms of age, gender, and IOP. 2. For the 20 NTG patients, the entire mtDNA was sequenced by using the next generation sequencing. This study identified 156 different novel mtDNA sequence changes. Of these, 21 sequence variants were identified at the frequency of more than 15%, which were located in the ND2~ND6, RNR1, RNR2, COX1, COX3, ATP6, ATP8, and CYTB genes. 3. For the 21 candidate genetic variants, a disease-gene association study was performed by using the Sanger's sequencing method. The frequencies of 12372G>A (ND5 gene) and 14766C>T (CYTB gene) were significantly different between NTG patients and controls (18.9% vs 2.4%, P=0.002 by chi-square test; 8.0% vs 0.0%, P=0.028 by Fisher exact test). Ⅳ. Conclusions and future plans Glaucoma is a chronic progressive optic neuropathy, leading to progressive visual field loss and irreversible blindness. Despite of the effective treatment, such as the IOP control, many late glaucoma patients still lose their vision. Therefore, it is better to detect the patient early or to predict and prevent the glaucoma occurrence before the old people get the disease, than to treat devastating late glaucoma patients. We are going to reveal the genetic risk factors of NTG and to try to make a disease prediction model based on these risk factors in near future. This would be helpful to reduce economical and social burden which we have to pay the take care of glaucoma patients in Korea. Moreover, this study suggests a new concept to the pathogenesis of glaucoma, which will provide a new insight for glaucoma treatment including gene therapy.
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