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Title: Genetic Analysis of Endometriosis.
Author: Lin, Jianghai
ISNI:       0000 0001 3610 3173
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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Endometriosis is a common, benign, oestrogen-dependent, gynaecological disorder that occurs in women in their reproductive years. Although it has been studied for many years, the aetiology and pathophysiology of endometriosis are still unclear. Accumulated evidence indicates that endometriosis has a heritable component. Recently, the International Endogene Study (IES) identified two significant linkage regions on chromosomes 7 and 10. The signal on chromosome 7 may be caused by a rare variant, with near-Mendelian inheritance, present in a subset of families. This thesis comprises follow-up studies aimed at: 1) narrowing down the linkage region on chromosome 7 through fine mapping and haplotype analyses; 2) screening candidate genes for mutations potentially responsible for the susceptibility to endometriosis through sequencing, and 3) conducting linkage analyses in two orthologous regions in a large, complex pedigree of rhesus monkeys with spontaneous disease. Firstly, linkage and haplotype analyses were conducted on 32 extended families, which contributed most to the linkage signal, from the Oxford dataset. Haplotype analyses narrowed down the linkage region to an area surrounding a single marker (D7S2251), containing 10 genes, although this result was dependent on a critical recombination in a single family. Secondly, fine mapping and haplotype analyses conducted to narrow an 11Mb region originally identified in the analysis of the combined IES dataset, identified a 1Mb region, comprising 5 genes, based on the haplotype segments shared between the affected members. The exons and part of the 5' untranslated regions ofINHBA, SFRP4 and HOXAlO were screened by TOCE and/or PCR-sequencing in affected members of the 32 Oxford families. Although some variants were identified, none of them were sufficiently frequent among cases to be responsible for the linkage signal in this group of women. Analyses were conducted in a 6-generational pedigree of 894 rhesus macaques residing at the Wisconsin National Primate Research Center, USA. Novel protocols were developed to extract DNA from paraffin-embedded tissues. Linkage analysis, conducted using Merlin and SimWalk2 on smaller sub-pedigrees, showed some evidence for linkage in both regions, particularly on chromosome 7, although results were not significant. The position of the linkage signals was close (2Mb and 500 kb) to the corresponding positions where the linkage signals had been found in humans. These results indicate that susceptibility genes to endometriosis might be located within the two regions. Possible studies following on from this thesis will include screening of more candidate genes in the linkage regions, re-sequencing of the linkage regions in humans, and performing a genome wide linkage analysis in the rhesus monkey model. Further investigations of biological pathways involved in endometriosis will lead to a better understanding of the aetiology of the disease, new treatments and improved patient quality of life.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available