臺灣博碩士論文加值系統

本論文的第一個主題是討論與類風溼性關節炎(RA)相關的基因多型性。MUTYH醣基化酶與DNA修復路徑相關的許多種蛋白都有直接的作用，並且與自體免疫疾病的風險可能有關，因此，本研究便針對MUTYH基因多型性與RA進行討論。我收了台灣的192位RA病患檢體以及192位健康的人的檢體作為對照組，並利用限制酶切割片段多型性以研究MUTYH上的四個單核苷酸基因多型性，接著利用未區分染色體的基因型資料以及Bayesian法進行單倍群(haplotype)的研究，所有基因型頻率與對偶基因頻率都以chi-square法進行分析。結果發現，RA病患有兩個MUTYH的多型性，分別為rs3219463與rs3219476，其基因型頻率與對偶基因頻率與健康人相比均具有顯著差異；這四種基因多型性可以組合成各種單倍群，而我發現Ht6-GTGC 和Ht8-GGCG這兩種單倍群在RA的病人表現比率較低；被診斷出免疫球蛋白M類風濕因子的RA病患，其rs3219463多型性之中的G/-顯著較高，而rs3219463多型性則無差異。在此台灣族群的研究中，我發現rs3219463 和rs3219476多型性在RA的病人中會具有顯著差異，因此MUTYH基因可能會與RA的致病機制有關。
本論文的第二部分是探討近視與發炎的關係。近視的盛行率在近幾十年內快速的提升，且已經變成全球公共衛生問題，在第二、第三章我會分別討論兩種發炎相關的疾病: 川崎氏症(KD)與過敏性結膜炎，其與近視的關聯性，本研究均是利用台灣健保資料庫以進行族群世代分析。健保資料庫中罹患KD與過敏性結膜炎的患者資料會被蒐集，並且對應大致比例的性別、年齡以蒐集對照組，這些罹患發炎疾病的患者與健康對照組的資料，利用Cox比例風險回歸模式進行風險比以及信賴區間的比較，再利用Kaplan-Meier法測量兩組之間的累積發生率之差異。結果發現，罹患KD的病患其近視的風險顯著的比健康族群還要高(風險比: 1.31; 95% 信賴區間: 1.08-1.58; P <0.01)，而罹患過敏性結膜炎的患者也顯著地比健康族群有較高的近視比例。為了瞭解其中的機制，我進一步利用卵白蛋白的施打以及持續滴入大鼠眼中，以建立過敏性結膜炎之模式大鼠；結果發現，被誘發出過敏性結膜炎的大鼠具有近視以及較長的眼軸，且近視眼之中發現MMP2以及TGF-β的表現量上升、與眼睛發育過程中相關的主要組織重組蛋白:第一型膠原蛋白的表現量下降；此外，發炎相關的因子與細胞激素在過敏性結膜炎的眼中也有較高的表現。總而言之，利用大規模的病例、對照研究，我證明了KD與過敏性結膜炎這兩種與眼睛發炎相關的疾病，都與近視的發生有關聯，若我們能有效控制眼睛的發炎，也許可以抑制近視的進程。

The first topic of this thesis is about the gene polymorphism of rheumatoid arthritis (RA). MUTYH glycosylase directly interacts with various proteins involved in DNA repair pathways and may be associated with the risk of autoimmune diseases such as RA. Therefore, the association between polymorphisms in the MUTYH gene and RA was evaluated. We recruited 192 RA patients and 192 healthy subjects in Taiwan. The 4 MUTYH polymorphisms were detected by a polymerase chain reaction-restriction fragment length polymorphism technique. Haplotype analysis was performed using unphased genotype data using the Bayesian method. The genotype and allelic frequency distributions of the polymorphisms in both RA patients and healthy patients were compared by the chi-square test. Comparison of the genotype/allele frequencies between individuals with RA and the control groups revealed significant differences in 2 MUTYH gene polymorphisms, rs3219463 and rs3219476. The haplotype frequencies were estimated among the 4 identified polymorphisms. After we performed a haplotype-specific analysis, the haplotypes Ht6-GTGC and Ht8-GGCG had lower presenting rates in RA patients than in the control groups. The genotype frequency of rs3219463 G/- was significantly increased among patients with immunoglobulin M rheumatoid factors, whereas that of rs3219476 was not. We demonstrated that the rs3219463 and rs3219476 polymorphisms in RA patients from a Taiwan Chinese population were associated with disease susceptibility. These data indicate that the MUTYH gene may play a role in the progression of RA.
The second topic of this thesis is about the relationship between myopia and inflammation. The prevalence of myopia has rapidly increased in recent decades and has led to a considerable global public health concern. In the Chapter 2 and 3, I elucidate the relationship between Kawasaki disease (KD), allergic conjunctivitis and the incidence of myopia, respectively. I used Taiwan’s National Health Insurance Research Database to conduct a population-based cohort study. I identified patients diagnosed with KD or allergic diseases and individuals without these diseases who were selected by frequency matched based on sex, age, and the index year. The Cox proportional hazards regression model was used to estimate the hazard ratio and 95% confidence intervals for the comparison of the 2 cohorts. Kaplan-Meier analysis was used to measure the cumulative incidence of myopia in the 2 cohorts. The log-rank test was used to test the incidence of myopia in the 2 cohorts. The risk of myopia (hazard ratio, 1.31; 95% confidence interval, 1.08-1.58; P <0.01) was higher among patients with KD than among those in the non-KD cohort, and a significant higher myopia rate was observed in allergic conjunctivitis group. I had further established allergic conjunctivitis rat model by ovalbumin injection and continuously dropping into eyes. Lower refractive error and longer axial length were observed after induction of allergic conjunctivitis. The decrease in refractive error of allergic conjunctivitis eyes were accompanied by an up-regulation of MMP2 and TGF-β and down-regulation of collagen I, which were the major tissue remodeling proteins related to the myopia formation. The expression levels of inflammatory-related transcription factors and inflammatory cytokines were also up-regulated in allergic conjunctivitis eyes. To sum up, I prove that these two inflammatory ocular diseases are correlated with myopia in nationwide case-control study and in animal model. The prevalence of myopia might be eased if inflammation in eye is controlled effectively.

List of Contents

中文摘要····················································································i
Abstract····················································································iii

1. General Introduction
1.1 The mechanism of chronic inflammation···································· 1
1.2 The mechanism of base excision repair (BER) pathway ···················2
1.3 The relationship between reactive oxygen species (ROS) and MUTYH 3
1.4 The risk factors for myopia and the aetiology of myopia ··················4
1.5 The specific aims of this thesis ················································7

2. MUTYH gene polymorphisms as risk factors for rheumatoid arthritis
2.1 Abstract ·········································································10
2.2 Introduction ·····································································12
2.3 Materials and Methods ························································15
2.4 Results ···········································································18
2.5 Discussions ·····································································22
2.6 Tables and Figures ·····························································27
2.7 References ······································································33

3. Kawasaki disease increases the incidence of myopia
3.1 Abstract ·········································································36
3.2 Introduction ····································································38
3.3 Materials and Methods ·······················································40
3.4 Results ··········································································44
3.5 Discussions ·····································································46
3.6 Tables and Figures ·····························································50
3.7 References ······································································55

4. Allergic conjunctivitis is a risk factor of myopia: a national study in Taiwan
4.1 Abstract ·········································································58
4.2 Introduction ····································································60
4.3 Materials and Methods ························································63
4.4 Results ···········································································68
4.5 Discussions ·····································································72
4.6 Tables and Figures ·····························································77
4.7 References ······································································96

5. Conclusions and Prospects ·························································99
6. References ············································································102

Chapter 2
1.Feldmann M, Brennan FM, Maini RN: Rheumatoid arthritis. Cell 1996, 85(3):307-310.
2.Ziff M: Rheumatoid arthritis--its present and future. J Rheumatol 1990, 17(2):127-133.
3.Lynn AH, Kwoh CK, Venglish CM, Aston CE, Chakravarti A: Genetic epidemiology of rheumatoid arthritis. Am J Hum Genet 1995, 57(1):150-159.
4.Weyand CM, Klimiuk PA, Goronzy JJ: Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. Springer Semin Immunopathol 1998, 20(1-2):5-22.
5.Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 2004, 200(3):277-285.
6.Shao L, Fujii H, Colmegna I, Oishi H, Goronzy JJ, Weyand CM: Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J Exp Med 2009, 206(6):1435-1449.
7.Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS: Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A 2002, 99(15):10025-10030.
8.David SS, O'Shea VL, Kundu S: Base-excision repair of oxidative DNA damage. Nature 2007, 447(7147):941-950.
9.Meira LB, Bugni JM, Green SL, Lee CW, Pang B, Borenshtein D, Rickman BH, Rogers AB, Moroski-Erkul CA, McFaline JL et al: DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest 2008, 118(7):2516-2525.
10.Niessen RC, Sijmons RH, Ou J, Olthof SG, Osinga J, Ligtenberg MJ, Hogervorst FB, Weiss MM, Tops CM, Hes FJ et al: MUTYH and the mismatch repair system: partners in crime? Hum Genet 2006, 119(1-2):206-211.
11.Poulsen ML, Bisgaard ML: MUTYH Associated Polyposis (MAP). Curr Genomics 2008, 9(6):420-435.
12.Parker AR, Eshleman JR: Human MutY: gene structure, protein functions and interactions, and role in carcinogenesis. Cell Mol Life Sci 2003, 60(10):2064-2083.
13.Miyaishi A, Osawa K, Osawa Y, Inoue N, Yoshida K, Kasahara M, Tsutou A, Tabuchi Y, Sakamoto K, Tsubota N et al: MUTYH Gln324His gene polymorphism and genetic susceptibility for lung cancer in a Japanese population. J Exp Clin Cancer Res 2009, 28:10.
14.Zhang Y, Liu X, Fan Y, Ding J, Xu A, Zhou X, Hu X, Zhu M, Zhang X, Li S et al: Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. Int J Cancer 2006, 119(11):2592-2596.
15.Sliwinski T, Markiewicz L, Rusin P, Pietruszewska W, Olszewski J, Morawiec-Sztandera A, Mlynarski W, Majsterek I: Polymorphisms of the DNA base excision repair gene MUTYH in head and neck cancer. Exp Oncol 2009, 31(1):57-59.
16.Chen H, Xu L, Qi Q, Yao Y, Zhu M, Wang Y: A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese. BMC Cancer 2008, 8:269.
17.Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31(3):315-324.
18.Yen JH, Chen JR, Tsai WJ, Tsai JJ, Liu HW: HLA-DRB1 genotyping in patients with rheumatoid arthritis in Taiwan. J Rheumatol 1995, 22(8):1450-1454.
19.Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003, 73(5):1162-1169.
20.Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001, 68(4):978-989.
21.Koyama A, Kubota Y, Shimamura T, Horiuchi S: Possible association of the X-ray cross complementing gene 1 (XRCC1) Arg280His polymorphism as a risk for rheumatoid arthritis. Rheumatol Int 2006, 26(8):749-751.
22.Sakamoto K, Tominaga Y, Yamauchi K, Nakatsu Y, Sakumi K, Yoshiyama K, Egashira A, Kura S, Yao T, Tsuneyoshi M et al: MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis. Cancer Res 2007, 67(14):6599-6604.
23.Cheadle JP, Sampson JR: MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing. DNA Repair (Amst) 2007, 6(3):274-279.
24.Yen JH, Chang CM, Hsu YW, Lee CH, Wu MS, Hwang DY, Chen BK, Liao HT, Wu MT, Chang WC: A polymorphism of ORAI1 rs7135617, is associated with susceptibility to rheumatoid arthritis. Mediators Inflamm 2014, 2014:834831.
25.Chen JY, Wang CM, Ma CC, Hsu LA, Ho HH, Wu YJ, Kuo SN, Wu J: A transmembrane polymorphism in FcgammaRIIb (FCGR2B) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA. Genes Immun 2008, 9(8):680-688.
26.Chen JY, Wang CM, Wu JM, Ho HH, Luo SF: Association of rheumatoid factor production with FcgammaRIIIa polymorphism in Taiwanese rheumatoid arthritis. Clin Exp Immunol 2006, 144(1):10-16.
27.Chen S, Jiang F, Ren J, Liu J, Meng W: Association of IL-18 polymorphisms with rheumatoid arthritis and systemic lupus erythematosus in Asian populations: a meta-analysis. BMC Med Genet 2012, 13:107.
28.Li X, Chai W, Ni M, Xu M, Lian Z, Shi L, Bai Y, Wang Y: The effects of gene polymorphisms in interleukin-4 and interleukin-6 on the susceptibility of rheumatoid arthritis in a Chinese population. Biomed Res Int 2014, 2014:265435.
29.You SH, Wang X, Huang S, Wang M, Ji GZ, Xia JR, Fan ZN: MYH rs3219476 and rs3219472 polymorphisms and risk of cholangiocarcinoma. Mol Med Rep 2013, 7(1):347-351.
30.Pan WH, Fann CS, Wu JY, Hung YT, Ho MS, Tai TH, Chen YJ, Liao CJ, Yang ML, Cheng AT et al: Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations. Hum Hered 2006, 61(1):27-30.

Chapter 3
1.Charman N: Myopia: its prevalence, origins and control. Ophthalmic Physiol Opt 2011, 31(1):3-6.
2.Saw SM, Gazzard G, Shih-Yen EC, Chua WH: Myopia and associated pathological complications. Ophthalmic Physiol Opt 2005, 25(5):381-391.
3.Cheng CY, Hsu WM, Liu JH, Tsai SY, Chou P: Refractive errors in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Invest Ophthalmol Vis Sci 2003, 44(11):4630-4638.
4.Sawada A, Tomidokoro A, Araie M, Iwase A, Yamamoto T: Refractive errors in an elderly Japanese population: the Tajimi study. Ophthalmology 2008, 115(2):363-370 e363.
5.Xu L, Li J, Cui T, Hu A, Fan G, Zhang R, Yang H, Sun B, Jonas JB: Refractive error in urban and rural adult Chinese in Beijing. Ophthalmology 2005, 112(10):1676-1683.
6.Morgan IG, Ohno-Matsui K, Saw SM: Myopia. Lancet 2012, 379(9827):1739-1748.
7.Pan CW, Ramamurthy D, Saw SM: Worldwide prevalence and risk factors for myopia. Ophthalmic Physiol Opt 2012, 32(1):3-16.
8.Resnikoff S, Pascolini D, Mariotti SP, Pokharel GP: Global magnitude of visual impairment caused by uncorrected refractive errors in 2004. Bulletin of the World Health Organization 2008, 86(1):63-70.
9.Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y, Kotani K, Tsogzolbaatar EO, Yanagawa H: Epidemiologic features of Kawasaki disease in Japan: results of the 2009-2010 nationwide survey. J Epidemiol 2012, 22(3):216-221.
10.Wu MH, Chen HC, Yeh SJ, Lin MT, Huang SC, Huang SK: Prevalence and the long-term coronary risks of patients with Kawasaki disease in a general population <40 years: a national database study. Circ Cardiovasc Qual Outcomes 2012, 5(4):566-570.
11.Takahashi K, Oharaseki T, Yokouchi Y, Naoe S, Saji T: Kawasaki disease: basic and pathological findings. Clin Exp Nephrol 2013, 17(5):690-693.
12.Leung DY, Cotran RS, Kurt-Jones E, Burns JC, Newburger JW, Pober JS: Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease. Lancet 1989, 2(8675):1298-1302.
13.Matsubara T, Ichiyama T, Furukawa S: Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease. Clin Exp Immunol 2005, 141(3):381-387.
14.Rowley AH: Kawasaki disease: novel insights into etiology and genetic susceptibility. Annu Rev Med 2011, 62:69-77.
15.Yuan SM: Cardiac surgical procedures for the coronary sequelae of Kawasaki disease. Libyan J Med 2012, 7:19796.
16.Kim DS: Kawasaki disease. Yonsei Med J 2006, 47(6):759-772.
17.Grunebaum E, Blank M, Cohen S, Afek A, Kopolovic J, Meroni PL, Youinou P, Shoenfeld Y: The role of anti-endothelial cell antibodies in Kawasaki disease - in vitro and in vivo studies. Clin Exp Immunol 2002, 130(2):233-240.
18.Lin HJ, Wei CC, Chang CY, Chen TH, Hsu YA, Hsieh YC, Chen HJ, Wan L: Role of Chronic Inflammation in Myopia Progression: Clinical Evidence and Experimental Validation. EBioMedicine 2016, 10:269-281.
19.Hsing AW, Ioannidis JP: Nationwide Population Science: Lessons From the Taiwan National Health Insurance Research Database. JAMA Intern Med 2015, 175(9):1527-1529.
20.Liu CY, Hung, Y.T., Chung, Y.L., Chen, Y.J., Weng, W.S., Liu, J.S. and Liang, K.Y.: Incorporating Development Stratification of Taiwan Townships into Sampling Design of Large Scale Health Interview Survey J Health Manag 2006, 14:1-22.
21.Mohsenin A, Huang JJ: Ocular manifestations of systemic inflammatory diseases. Conn Med 2012, 76(9):533-544.
22.Gross SA, von Noorden GK, Jones DB: Necrotizing scleritis and transient myopia following strabismus surgery. Ophthalmic surgery 1993, 24(12):839-841.
23.Fledelius H, Zak M, Pedersen FK: Refraction in juvenile chronic arthritis: a long-term follow-up study, with emphasis on myopia. Acta ophthalmologica Scandinavica 2001, 79(3):237-239.
24.Herbort CP, Papadia M, Neri P: Myopia and inflammation. Journal of ophthalmic & vision research 2011, 6(4):270-283.
25.Fredrick DR: Myopia. Bmj 2002, 324(7347):1195-1199.
26.Lin LL, Shih YF, Tsai CB, Chen CJ, Lee LA, Hung PT, Hou PK: Epidemiologic study of ocular refraction among schoolchildren in Taiwan in 1995. Optometry and vision science : official publication of the American Academy of Optometry 1999, 76(5):275-281.
27.Vongphanit J, Mitchell P, Wang JJ: Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 2002, 109(4):704-711.
28.Celorio JM, Pruett RC: Prevalence of lattice degeneration and its relation to axial length in severe myopia. American journal of ophthalmology 1991, 111(1):20-23.
29.Grey RH, Burns-Cox CJ, Hughes A: Blind and partial sight registration in Avon. The British journal of ophthalmology 1989, 73(2):88-94.

Chaper 4
1.Morgan IG, Ohno-Matsui K, Saw SM: Myopia. Lancet 2012, 379(9827):1739-1748.
2.Leo SW, Young TL: An evidence-based update on myopia and interventions to retard its progression. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus 2011, 15(2):181-189.
3.BJ. C: The Myopias: Basic Science and Clinical Management. Philadelphia: Harper & Row 1985, xv:495.
4.McKanna JA CV: Atropine affects lid suture myopia development. Doc Ophthalmol Proc Ser 1981, 28:187-192.
5.Marzani D, Wallman J: Growth of the two layers of the chick sclera is modulated reciprocally by visual conditions. Investigative ophthalmology & visual science 1997, 38(9):1726-1739.
6.Rada JA, Johnson JM, Achen VR, Rada KG: Inhibition of scleral proteoglycan synthesis blocks deprivation-induced axial elongation in chicks. Experimental eye research 2002, 74(2):205-215.
7.McBrien NA, Lawlor P, Gentle A: Scleral remodeling during the development of and recovery from axial myopia in the tree shrew. Investigative ophthalmology & visual science 2000, 41(12):3713-3719.
8.Herbort CP, Papadia M, Neri P: Myopia and inflammation. Journal of ophthalmic & vision research 2011, 6(4):270-283.
9.Mimura T, Yamagami S, Usui T, Funatsu H, Noma H, Honda N, Amano S: Relationship between myopia and allergen-specific serum IgE levels in patients with allergic conjunctivitis. Clinical & experimental ophthalmology 2009, 37(7):670-677.
10.Mimura T, Usui T, Yamagami S, Miyai T, Amano S: Relationship between total tear IgE and specific serum IgE in autumnal allergic conjunctivitis. Cornea 2013, 32(1):14-19.
11.Tuft SJ, Kemeny DM, Dart JK, Buckley RJ: Clinical features of atopic keratoconjunctivitis. Ophthalmology 1991, 98(2):150-158.
12.Groneberg DA, Bielory L, Fischer A, Bonini S, Wahn U: Animal models of allergic and inflammatory conjunctivitis. Allergy 2003, 58(11):1101-1113.
13.Inamori Y, Ota M, Inoko H, Okada E, Nishizaki R, Shiota T, Mok J, Oka A, Ohno S, Mizuki N: The COL1A1 gene and high myopia susceptibility in Japanese. Hum Genet 2007, 122(2):151-157.
14.Guggenheim JA, McBrien NA: Form-deprivation myopia induces activation of scleral matrix metalloproteinase-2 in tree shrew. Investigative ophthalmology & visual science 1996, 37(7):1380-1395.
15.Hall NF, Gale CR, Ye S, Martyn CN: Myopia and polymorphisms in genes for matrix metalloproteinases. Investigative ophthalmology & visual science 2009, 50(6):2632-2636.
16.Norton TT, Rada JA: Reduced extracellular matrix in mammalian sclera with induced myopia. Vision Res 1995, 35(9):1271-1281.
17.Lin HJ, Wan L, Tsai Y, Liu SC, Chen WC, Tsai SW, Tsai FJ: Sclera-related gene polymorphisms in high myopia. Molecular vision 2009, 15:1655-1663.
18.Lin HJ, Wan L, Tsai Y, Tsai YY, Fan SS, Tsai CH, Tsai FJ: The TGFbeta1 gene codon 10 polymorphism contributes to the genetic predisposition to high myopia. Molecular vision 2006, 12:698-703.
19.Mimura T, Mimura Y, Arimoto A, Amano S, Yamagami S, Funatsu H, Usui T, Noma H, Honda N, Okamoto S: Relationship between refraction and allergic conjunctivitis. Eye (Lond) 2009, 23(1):63-66.
20.Rada JA, Shelton S, Norton TT: The sclera and myopia. Experimental eye research 2006, 82(2):185-200.
21.Zhu X, Zhang K, He W, Yang J, Sun X, Jiang C, Dai J, Lu Y: Proinflammatory status in the aqueous humor of high myopic cataract eyes. Experimental eye research 2015.
22.Matsumoto Y, Takahashi M, Ogata M: Relationship between glycoxidation and cytokines in the vitreous of eyes with diabetic retinopathy. Jpn J Ophthalmol 2002, 46(4):406-412.
23.de Vos AF, Klaren VN, Kijlstra A: Expression of multiple cytokines and IL-1RA in the uvea and retina during endotoxin-induced uveitis in the rat. Investigative ophthalmology & visual science 1994, 35(11):3873-3883.
24.Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS, D'Amore PA, Ksander BR: NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Investigative ophthalmology & visual science 2013, 54(1):110-120.
25.McGlinn AM, Baldwin DA, Tobias JW, Budak MT, Khurana TS, Stone RA: Form-deprivation myopia in chick induces limited changes in retinal gene expression. Investigative ophthalmology & visual science 2007, 48(8):3430-3436.
26.Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. The Journal of clinical investigation 1999, 103(9):1237-1241.
27.Cai J, Yin G, Lin B, Wang X, Liu X, Chen X, Yan D, Shan G, Qu J, Wu S: Roles of NFkappaB-miR-29s-MMP-2 circuitry in experimental choroidal neovascularization. J Neuroinflammation 2014, 11:88.

Chapter 6
1.Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE: Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation. Clin Exp Immunol 2007, 147(2):227-235.
2.Kim S, Shin S, Hyun B, Kong H, Han S, Lee A, Lee S, Kim K: Immunomodulatory Effects of Dioscoreae Rhizome Against Inflammation through Suppressed Production of Cytokines Via Inhibition of the NF-kappaB Pathway. Immune Netw 2012, 12(5):181-188.
3.Coussens LM, Werb Z: Inflammation and cancer. Nature 2002, 420(6917):860-867.
4.Wyatt MD, Pittman DL: Methylating agents and DNA repair responses: Methylated bases and sources of strand breaks. Chem Res Toxicol 2006, 19(12):1580-1594.
5.Thoms KM, Kuschal C, Emmert S: Lessons learned from DNA repair defective syndromes. Exp Dermatol 2007, 16(6):532-544.
6.Hakem R: DNA-damage repair; the good, the bad, and the ugly. EMBO J 2008, 27(4):589-605.
7.Nilsen H, Stamp G, Andersen S, Hrivnak G, Krokan HE, Lindahl T, Barnes DE: Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas. Oncogene 2003, 22(35):5381-5386.
8.Sakamoto K, Tominaga Y, Yamauchi K, Nakatsu Y, Sakumi K, Yoshiyama K, Egashira A, Kura S, Yao T, Tsuneyoshi M et al: MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis. Cancer Res 2007, 67(14):6599-6604.
9.Xie Y, Yang H, Cunanan C, Okamoto K, Shibata D, Pan J, Barnes DE, Lindahl T, McIlhatton M, Fishel R et al: Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors. Cancer Res 2004, 64(9):3096-3102.
10.Neeley WL, Essigmann JM: Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol 2006, 19(4):491-505.
11.Paz-Elizur T, Sevilya Z, Leitner-Dagan Y, Elinger D, Roisman LC, Livneh Z: DNA repair of oxidative DNA damage in human carcinogenesis: potential application for cancer risk assessment and prevention. Cancer Lett 2008, 266(1):60-72.
12.Parker AR, Eshleman JR: Human MutY: gene structure, protein functions and interactions, and role in carcinogenesis. Cell Mol Life Sci 2003, 60(10):2064-2083.
13.Tenesa A, Campbell H, Barnetson R, Porteous M, Dunlop M, Farrington SM: Association of MUTYH and colorectal cancer. Br J Cancer 2006, 95(2):239-242.
14.Dandona R, Dandona L: Refractive error blindness. Bull World Health Organ 2001, 79(3):237-243.
15.Morgan IG, Ohno-Matsui K, Saw SM: Myopia. Lancet 2012, 379(9827):1739-1748.
16.Rose KA, Morgan IG, Ip J, Kifley A, Huynh S, Smith W, Mitchell P: Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 2008, 115(8):1279-1285.
17.McKanna JA, Casagrande VA: Reduced lens development in lid-suture myopia. Exp Eye Res 1978, 26(6):715-723.
18.Lu B, Congdon N, Liu X, Choi K, Lam DS, Zhang M, Zheng M, Zhou Z, Li L, Sharma A et al: Associations between near work, outdoor activity, and myopia among adolescent students in rural China: the Xichang Pediatric Refractive Error Study report no. 2. Arch Ophthalmol 2009, 127(6):769-775.
19.Saw SM, Chan B, Seenyen L, Yap M, Tan D, Chew SJ: Myopia in Singapore kindergarten children. Optometry 2001, 72(5):286-291.
20.Ip JM, Huynh SC, Robaei D, Rose KA, Morgan IG, Smith W, Kifley A, Mitchell P: Ethnic differences in the impact of parental myopia: findings from a population-based study of 12-year-old Australian children. Invest Ophthalmol Vis Sci 2007, 48(6):2520-2528.
21.Hysi PG, Cheng CY, Springelkamp H, Macgregor S, Bailey JN, Wojciechowski R, Vitart V, Nag A, Hewitt AW, Hohn R et al: Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat Genet 2014, 46(10):1126-1130.
22.BJ. C: The Myopias: Basic Science and Clinical Management. Philadelphia: Harper & Row 1985, xv:495.
23.McKanna JA CV: Atropine affects lid suture myopia development. Doc Ophthalmol Proc Ser 1981, 28:187-192.
24.Marzani D, Wallman J: Growth of the two layers of the chick sclera is modulated reciprocally by visual conditions. Investigative ophthalmology & visual science 1997, 38(9):1726-1739.
25.Rada JA, Johnson JM, Achen VR, Rada KG: Inhibition of scleral proteoglycan synthesis blocks deprivation-induced axial elongation in chicks. Experimental eye research 2002, 74(2):205-215.
26.McBrien NA, Lawlor P, Gentle A: Scleral remodeling during the development of and recovery from axial myopia in the tree shrew. Investigative ophthalmology & visual science 2000, 41(12):3713-3719.
27.Rada JA, Nickla DL, Troilo D: Decreased proteoglycan synthesis associated with form deprivation myopia in mature primate eyes. Investigative ophthalmology & visual science 2000, 41(8):2050-2058.
28.Shih YF, Chen CH, Chou AC, Ho TC, Lin LL, Hung PT: Effects of different concentrations of atropine on controlling myopia in myopic children. J Ocul Pharmacol Ther 1999, 15(1):85-90.
29.Fan DS, Lam DS, Chan CK, Fan AH, Cheung EY, Rao SK: Topical atropine in retarding myopic progression and axial length growth in children with moderate to severe myopia: a pilot study. Jpn J Ophthalmol 2007, 51(1):27-33.
30.Lin HJ, Wan L, Chen WC, Lin JM, Lin CJ, Tsai FJ: Muscarinic acetylcholine receptor 3 is dominant in myopia progression. Investigative ophthalmology & visual science 2012, 53(10):6519-6525.