中 文 摘 要

視力的品質百分之八十五決定於低階像差，是由近視、遠視或散光所組成，剩餘的部分則由高階像差決定。近視在台灣成年人的盛行率高達九成，高度近視的盛行率更高達四分之一，在眼科臨床門診當中是最普遍的疾病。
過去的雙胞胎及其他近視家族的研究證實基因與近視有關。這份博士論文的主題主要是研究基因及家族在近視所扮演的角色。我們的研究首先探討的基本問題有：近視有無家族傾向？父母本身近視的程度對子女的近視嚴重程度、發病早晚及眼球結構的影響如何？結果顯示父母高度近視是造成子女發展為近視的一個強烈危險因子。當父母之一有高度近視，子女發展為高度近視為一般人的八倍。還有父母高度近視時，子女近視發病年齡較一般人傾向早些。另外父母為高度近視的子女的則顯示眼軸明顯較長，但在前房深度與角膜弧度顯示並無差異。總括過去他人的研究及本實驗得知：近視具有家族傾向。依此推斷基因可能對近視扮演一個重要的角色。
由第一個研究提供了強有力的地基開始去尋找那些基因與近視有關。依據過去許多動物實驗及人類關於眼軸長度與近視的相關研究，皆顯示近視度數越深合併眼軸長度越長且近視與眼球的成長有關。既然基因與近視相關，我們便著手驗證可能的致病基因。首先挑選六個過去證實與眼睛成長或結構相關的基因: MMP2、MMP3、TIMP1、COL1A1、HGF及PAX6。我們執行了多次大型實驗-對照研究來檢測每個候選基因中的tSNP(tagging single nucleotide polymorphisms)與高度近視的相關性，並運用了數種統計分析方

法，包括single SNP分析、haplotype分析及subset分析等 。結果顯示六個候選基因皆與高度近視無關。全基因研究（whole genome study）將會是我們以後研究發展的主要方向。
過去在提論文研究計畫時，有委員建議將高階像差納入研究範圍，但發現與近視基因主軸並不完全相符，因此將這部份的研究及發表的文章放在後面的附錄。

ABSTRACT

85% Vision quality is determined by lower order aberrations. It includes myopia, hyperopia and astigmatism. About 15% Vision quality is determined by higher order aberrations. The prevalence of myopia in Taiwan adult is almost 90%. And high myopia is around one fourth. Myopia has serious complications and is the most commonly seen eye problem in the ophthalmologic clinics.

According to twin and family study, gene is related to myopia. The main theme of my dissertation is to investigate the role of genetic factors and family history in myopia. Our team first asked a fundamental problem – has myopia familial tendency and does parental myopic status influence offspring refraction, onset of myopia and ocular components? Our study found that family history was a strong risk factor for myopia. When there was one highly myopic parent, the odds ratio of developing high myopia was 6 and when both parents the odds ratio was almost 8. In addition, high myopia parents tended to have children whose onset of myopia was earlier than children with normal parents. Parental myopic state was also associated with ocular axial length, but not with anterior chamber depth or corneal curvature. To combine others and our result show that gene is an important role for myopia.

When we found that genetic component is likely to play an important role for myopia, we proceeded to identify susceptibility genes. We hypothesized six candidate genes: MMP2, MMP3, TIMP1, COL1A1, HGF and PAX6. These genes are either involved in the eye development or eye ball structure. These genes have been implied in myopia pathogenesis in either animal studies or linkage analysis. We conducted several large case-control to test for the associations between tagging single nucleotide polymorphisms (tSNP) of each candidate genes and high myopia (defined ≦ -6D). Several statistical methods were used including single SNP analysis, haplotype analysis, subset analyses (based on presence of family history or education level). However, none of the six candidate gene is associated with high myopia. Therefore, whole genome-wide study for myopia will be our major direction in the future.

There was one member of the proposal committee to ask us to include higher order aberrations for our study. But the result can’t be compatible with myopic gene study. Therefore we put this part related article to appendix.

目 錄

指導教授推薦書……………………………………………………….
口試委員會審定書…………………………………………………….
授權書………………………………………………………………….iii
誌謝………………………………………………….………………… v
中文摘要……………………………………………………………… vi
英文摘要……………………….……………………………….…......viii
目錄………………………………………………………………...…..x

ABBREVIATION …………………………………………………….. 1
CHAPTER I. INTRODUCTION ……………………………………. 2
1.1. Background and Significance
1.1.1 Epidemiology………………………….………………………………...4
1.1.2 Pathogenesis of Myopia and Higher Order Aberrations ……..5
1.1.3 Review of Risk Factors for Myopia …………………….........6

1.2. Introduction to Genetic studies …………………………….. 11
1.2.1 Genetic Components in Complex Diseases
1.2.1.1 Heritability …..…………………………………….... 11
1.2.1.2 Twin Study ……………………………………………12
1.2.1.3 Familial Correlation ………………………………… .14
1.2.2 Genetic Marker
1.2.2.1 Single nucleotide polymorphism and gene mapping….14
1.2.2.2 Tagging SNPs ………………………………………...15
1.2.2.3 Microsatellite markers ………………………….….. ..16
1.2.3 Gene Mapping Strategies ……………………………………17
1.2.3.1 Linkage study …………………………………………19
1.2.3.2 Population association study ………………………….22
1.2.3.3 LD mapping/Association mapping ……………………24
1.2.3.4 Admixture mapping …………………………………...25


CHAPTER 2. MOTIVATION AND OBJECTIVES ………….…….27
Specific Aims …………………………………………………… …28
Candidate genes …………………………………………………....28


CHAPTER 3. METHODS AND RESULTS ……………..………….34
3.1.1 Study I
The primary aim of this study is to quantify the parental effect on the development of myopia and three ocular components.
Method …………………………………………………………34
Results ………………………………………………………….38

3.1.2 Study II
This study is to test for association between the MMP3 and TIMP-1 genes and high myopia
Method ………………………………………………………….42
Results …………………………………………………………..47

3.1.3 Study III
This study is to test for association between the COL1A1 gene and high myopia
Method …………………………………………………………..50
Results …………………………………………………………..53

3.1.4 Study IV
This study is to test for association between the MMP2 gene and high myopia
Method ……………………………………………………………55
Results …………………………………………………………….57

3.1.5 Study V
This study is to test for association between the PAX6 gene and high myopia
Method ……………………………………………………………59
Results …………………………………………………………….59

3.1.6 Study VI
This study is to test for association between the HGF gene and high myopia
Method …………………………………………………………….61
Results ……………………………………………………………..61


CHAPTER 4. DISCUSSIONS …………………..………………………………… .63
4.1 Parental effect on the development of myopia and ocular component …………………………………………………………63
4.2 Association between genetic polymorphisms and high myopia
………………………………………………………………………67



CHAPTER 5. CONCLUSIONS AND PERSPECTIVE ……..………………………………………………74

TABLES AND FIGURES …………………………………………………………….78
REFERECES…………………………………………….…………110
APPENDIX …………………………………………………………116
PUBLISHED PAPERS …………………………………………….

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