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Title: Mechanisms of osteoporosis associated with common allelic variants of the COL1A1 gene
Author: Jin, Huilin
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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Three single nucleotide polymorphisms (SNP) have been identified in the 5’ flank of the COLIA1 gene (-1997G/T; -1663IndelT and +1245G/T) which have been associated with osteoporosis in various populations. The individual polymorphisms were all associated with BMD, but the haplotypes defined by all three SNP showed a stronger association with BMD, biomechanical strength of bone and hip fracture. Two haplotypes increased in frequency with age suggesting an effect on survival. However these haplotypes were particularly enriched in hip fracture patients. Biomechanical testing showed that all three SNPs were strongly associated with reduced bone strength, independently of BMD. Gel shift assays showed that the region surrounding the -1663insdeIT polymorphism recognised the nuclear binding proteins NMP4 and Osterix and the -1663deIT allele had greater binding affinity than -1663insT allele. the region surrounding the -1997 G/T polymorphism also recognised DNA binding proteins but the polymorphism did not have affect DNA protein binding significantly. Reporter assays showed significant differences between the ability of different haplotypes to drive gene expression and constructs containing haplotype (G-delT-T) had the highest transcriptional activity (p<0.001). Transgenic constructs containing different 5’ COL1A1 haplotypes were completed and transformed into mouse embryonic stem cells by electroporation in an attempt to generate a disease model of osteoporosis associated with common variants in the COLIA1 gene. The studies suggest that haplotypes, rather than individual polymorphisms in the 5’ flank of COL1A1 predispose to osteoporosis, by affecting DNA protein interactions and gene expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available