Apart from associated genes, a candidate causative gene NTF4 was screened and two novel putative mutations (Gly157Ala and Ala182Val) detected, likely accounting for 0.29% of POAG. In the exploration of new POAG genes, two functional candidates CNTF and SPARC were screened and excluded. / Differential association profiles were found for SNPs in/near CAV1, CAV2, CYP46A1, LMX1B, PLXDC2, TLR4, TMTC2, ZP4 and 2p16.3. SNPs at CAV1, CAV2, TLR4 and 2p16.3 were associated with POAG, whilst SNPs around other genes were unlikely to be risk factors for the disease, at least in Chinese. TLR4 rs7037117 was associated with HTG in southern Chinese (P=0.0016, OR=2.72, recessive model). SNP rs1533428 at 2p16.3 showed an age-specific association of with late-onset POAG (age at diagnosis >60 years; P=1.14x10-5, OR=2.02, dominant model) but not with juvenile- and adult-onset POAG. Moreover, rs1533428 formed a joint effect with rs7037117 to confer stronger risk to HTG (P=2.8x10 -4, OR=4.53). Besides, rs4236601 near the CAV1 and CAV2 genes was confirmed as a risk factor for POAG and another two protective SNPs rs6975771 and rs959173 were identified; moreover, that the risk and protective alleles were located in different haplotypes suggested multiple roles of the genes. / Glaucoma is a group of degenerative optic neuropathies and the leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG) is a major type of glaucoma in most populations. It is classified into high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) according to the level of intraocular pressure. POAG has complex etiology. It could be monogenic or caused by multiple risk factors. At least 22 linkage loci have been mapped, with 3 genes (MYOC, OPTN, and WDR36 ) identified. Also, more than 30 susceptibility genes have been reported, many of which, however, remain unverified. / In the mapping of the causal gene at GLC1N, a truncation mutation c.1090delT in the MEGF11 gene was found to be cosegregated with glaucoma in the GLC1N-linked pedigree. Subsequent identification of c.1090delT in an unrelated JOAG patient supported that it is a disease-causing mutation. The identification of four splice-site mutations (IVS17+2insT, IVS17-4C>G, IVS17-2A>G and c.2472A>C) exclusively in patients provided further evidence supporting MEGF11 as a causative gene for POAG. Mutations in this gene likely account for approximately 1% of POAG or 2% of JOAG. / This thesis describes our work on the identification of new POAG genes by using a 3-tiered strategy: (1) to identify new genetic profiles of variants around the CAV1, CAV2, CYP46A1, LMX1B, NTF4, PLXDC2, TLR4, TMTC2, ZP4 genes and the 2p16.3 locus; (2) to evaluate CNTF and SPARC as disease genes for POAG; and (3) to map the causal gene at the GLC1N locus for juvenile-onset POAG (JOAG). / Totally 1645 unrelated participants were enrolled, including a Hong Kong cohort of 281 HTG, 311 NTG and 248 controls, a Shantou cohort of 102 HTG, 28 NTG and 298 controls and, a Beijing cohort of 177 HTG and 200 controls. Also involved were members of the GLC1M-linked Philippine pedigree and the GLC1N-linked Hong Kong pedigree with JOAG, which have been previously described. / Chen, Lijia. / Adviser: Chi Pui Pang. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 185-210). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344685 |
| Date | January 2010 |
| Contributors | Chen, Lijia., Chinese University of Hong Kong Graduate School. Division of Ophthalmology and Visual Sciences. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xxiv, 211 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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